374 results on '"Schlicker, Eberhard"'
Search Results
152. Virodhamine and abnormal cannabidiol relax the human pulmonary artery via the putative endothelial cannabinoid receptor
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Baranowska, Marta, Hanna Kozłowska, Kozowski, Mirostaw, Schlicker, Eberhard, and Malinowska, Barbara
153. Atypical beta-adrenoceptors
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Malinowska, Barbara, Hanna Kozłowska, Zakrzeska, Agnieszka, and Schlicker, Eberhard
154. Autoreceptor-mediated inhibition of 3H-5-hydroxytryptamine release from rat brain cortex slices by analogues of 5-hydroxytryptamine
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Göthert, Manfred, primary and Schlicker, Eberhard, additional
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- 1983
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155. EFFECTS OF VASODILATOR DRUGS, ALKALINE PHOSPHTASE, AND CYCLIC AMP-DEPENDENT PROTEIN KINASE ON THE 45CALCIUM UPTAKE OF SARCOLEMMAL MICROSOMES FROM HUMAN UMBILICAL ARTERIES
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KREYE, VOLKER A.W., primary and SCHLICKER, EBERHARD, additional
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- 1980
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156. Modulation of noradrenaline release in human saphenous vein via presynaptic α2-adrenoceptors
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Göthert, Manfred, primary, Schlicker, Eberhard, additional, Hentrich, Frank, additional, Rohm, Norbert, additional, and Zerkowski, Hans-Reinhard, additional
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- 1984
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157. Antagonistic properties of quipazine at presynaptic serotonin receptors and ?-adrenoceptors in rat brain cortex slices
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Schlicker, Eberhard, primary and G�thert, Manfred, additional
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- 1981
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158. Inhibition of noradrenaline release in the pig coronary artery via a novel serotonin receptor
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Molderings, Gerhard J., primary, Göthert, Manfred, additional, Fink, Klaus, additional, Roth, Ekkehard, additional, and Schlicker, Eberhard, additional
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- 1989
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159. Histamine H3receptor‐mediated inhibition of noradrenaline release in the human brain
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Schlicker, Eberhard, Werthwein, Sven, and Zentner, Josef
- Abstract
Abstract—Stimulation‐evoked 3H‐noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3receptor‐mediated inhibition of noradrenaline release in human brain.
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- 1999
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160. β1-Blockers enhance inotropy of endogenous catecholamines in chronic heart failure
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Feuerstein, Thomas, primary and Schlicker, Eberhard, additional
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161. Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex
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Schlicker, Eberhard, Betz, Roland, and Göthert, Manfred
- Abstract
Rat brain cortex slices preincubated with
3 H-serotonin were superfused with physiological salt solution (containing citalopram, an inhibitor of serotonin uptake) and the effect of histamine on the electrically (3 Hz) evoked3 H overflow was studied. Histamine decreased the evoked overflow in a concentration-dependent manner. The inhibitory effect of histamine was antagonized by impromidine and burimamide, but was not affected by pheniramine, ranitidine, metitepine and phentolamine. Given alone, impromidine facilitated the evoked overflow, whereas burimamide, pheniramine and ranitidine had no effect. The results suggest that histamine inhibits serotonin release in the rat brain cortex via histamine H3 receptors, which may be located presynaptically.- Published
- 1988
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162. Liebevoll gestaltetes Nachschlagewerk nicht nur für die Examensvorbereitung.
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Schlicker, Eberhard
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- 2015
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163. Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis.
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Toczek, Marek, Ryszkiewicz, Piotr, Remiszewski, Patryk, Schlicker, Eberhard, Krzyżewska, Anna, Kozłowska, Hanna, and Malinowska, Barbara
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BLOOD pressure , *HYPERTENSION , *WEIGHT gain , *RATS , *LABORATORY rats , *HEART beat , *LIPASES , *CANNABINOIDS - Abstract
The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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164. [Pro 34]peptide YY is a Y 1-selective agonist at peptide YY/neuropeptide Y receptors
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Grandt, Daniel, Feth, Friedhelm, Rascher, Wolfgang, Reeve, Joseph R., Jr., Schlicker, Eberhard, Schimiczek, Michael, Layer, Peter, Goebell, Harald, Eysselein, Viktor E., and Michel, Martin C.
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- 1994
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165. Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance.
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Mińczuk, Krzysztof, Baranowska-Kuczko, Marta, Krzyżewska, Anna, Schlicker, Eberhard, and Malinowska, Barbara
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CANNABINOID receptors , *RENIN-angiotensin system , *ANGIOTENSIN II , *ANGIOTENSIN receptors , *DRUG interactions , *COVID-19 treatment - Abstract
This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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166. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?
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Malinowska, Barbara, Baranowska-Kuczko, Marta, and Schlicker, Eberhard
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BLOOD pressure , *CANNABINOIDS , *CANNABIS (Genus) , *TETRAHYDROCANNABINOL , *PSYCHIATRIC drugs , *PHARMACODYNAMICS , *ANANDAMIDE - Abstract
The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB1 and CB2 receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB1 receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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167. Chronic cannabidiol treatment reduces the carbachol-induced coronary constriction and left ventricular cardiomyocyte width of the isolated hypertensive rat heart.
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Pędzińska-Betiuk, Anna, Weresa, Jolanta, Schlicker, Eberhard, Harasim-Symbor, Ewa, Toczek, Marek, Kasacka, Irena, Gajo, Bernadetta, and Malinowska, Barbara
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RATS , *CANNABIDIOL , *LEFT ventricular hypertrophy , *MUSCARINIC receptors , *HYPERTENSION , *HEART , *HEART atrium - Abstract
Cannabidiol (CBD) is suggested to possess cardioprotective properties. We examined the influence of chronic (10 mg/kg once daily for 2 weeks) CBD administration on heart structure (e.g. cardiomyocyte width) and function (e.g. stimulatory and inhibitory responses induced by β-adrenoceptor (isoprenaline) and muscarinic receptor (carbachol) activation, respectively). Experiments were performed on hearts and/or left atria isolated from spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats; Wistar-Kyoto (WKY) and sham-operated rats (SHAM) served as the respective normotensive controls. CBD diminished the width of cardiomyocytes in left ventricle and reduced the carbachol-induced vasoconstriction of coronary arteries both in DOCA-salt and SHR. However, it failed to affect left ventricular hypertrophy and even aggravated the impaired positive and negative lusitropic effects elicited by isoprenaline and carbachol, respectively. In normotensive hearts CBD led to untoward structural and functional effects, which occurred only in WKY or SHAM or, like the decrease in β 1 -adrenoceptor density, in either control strain. In conclusion, due to its modest beneficial effect in hypertension and its adverse effects in normotensive hearts, caution should be taken when using CBD as a drug in therapy. Unlabelled Image • CBD diminished cardiomyocytes width in left ventricle of hypertensive rats. • CBD reduced carbachol-induced vasoconstriction of coronary arteries in hypertension. • CBD failed to diminish cardiac hypertrophy and diastolic stiffness in hypertension. • CBD exerts untoward structural and functional effects in normotensive hearts. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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168. Antagonistic properties of four suramin-related compounds at vascular purine P 2X receptors in the pithed rat
- Author
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Urbanek, Ernst, Nickel, Peter, and Schlicker, Eberhard
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- 1990
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169. GPR18-Mediated Relaxation of Human Isolated Pulmonary Arteries.
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Kozłowska, Hanna, Malinowska, Barbara, Baranowska-Kuczko, Marta, Kusaczuk, Magdalena, Nesterowicz, Miłosz, Kozłowski, Mirosław, Müller, Christa E., Kieć-Kononowicz, Katarzyna, and Schlicker, Eberhard
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PULMONARY arterial hypertension , *PULMONARY artery , *PROTEIN receptors , *CARDIOVASCULAR system - Abstract
GPR18 receptor protein was detected in the heart and vasculature and appears to play a functional role in the cardiovascular system. We investigated the effects of the new GPR18 agonists PSB-MZ-1415 and PSB-MZ-1440 and the new GPR18 antagonist PSB-CB-27 on isolated human pulmonary arteries (hPAs) and compared their effects with the previously proposed, but unconfirmed, GPR18 ligands NAGly, Abn-CBD (agonists) and O-1918 (antagonist). GPR18 expression in hPAs was shown at the mRNA level. PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD fully relaxed endothelium-intact hPAs precontracted with the thromboxane A2 analog U46619. PSB-CB-27 shifted the concentration-response curves (CRCs) of PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD to the right; O-1918 caused rightward shifts of the CRCs of PSB-MZ-1415 and NAGly. Endothelium removal diminished the potency and the maximum effect of PSB-MZ-1415. The potency of PSB-MZ-1415 or NAGly was reduced in male patients, smokers and patients with hypercholesterolemia. In conclusion, the novel GPR18 agonists, PSB-MZ-1415 and PSB-MZ-1440, relax hPAs and the effect is inhibited by the new GPR18 antagonist PSB-CB-27. GPR18, which appears to exhibit lower activity in hPAs from male, smoking or hypercholesterolemic patients, may become a new target for the treatment of pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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170. Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System.
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Karsak, Meliha, Gaffal, Evelyn, Date, Rahul, Wang-Eckhardt, Lihua, Rehnelt, Jennifer, Petrosino, Stefania, Starowicz, Katarzyna, Steuder, Regina, Schlicker, Eberhard, Cravatt, Benjamin, Mechoulam, Raphael, Buettner, Reinhard, Werner, Sabine, Di Marzo, Vincenzo, Tüting, Thomas, and Zimmer, Andreas
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CONTACT dermatitis , *CANNABINOIDS , *ALLERGIES , *LABORATORY mice , *OCCUPATIONAL diseases , *SKIN inflammation , *DRUG receptors - Abstract
Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity, we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase-deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated allergic inflammation, whereas receptor agonists attenuated inflammation. These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin and suggest a target for therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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171. Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19 †.
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Malinowska, Barbara, Baranowska-Kuczko, Marta, Kicman, Aleksandra, Schlicker, Eberhard, and Putnam, William C.
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COVID-19 , *COVID-19 treatment , *CANNABIDIOL , *SARS-CoV-2 , *POST-traumatic stress , *MARIJUANA growing , *MEDICAL marijuana - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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172. Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism.
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Remiszewski, Patryk, Jarocka-Karpowicz, Iwona, Biernacki, Michał, Jastrząb, Anna, Schlicker, Eberhard, Toczek, Marek, Harasim-Symbor, Ewa, Pędzińska-Betiuk, Anna, and Malinowska, Barbara
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BLOOD pressure , *ESSENTIAL hypertension , *LIPID metabolism , *CANNABIDIOL , *OXIDATIVE stress , *FREE fatty acids - Abstract
We investigated the influence of cannabidiol (CBD) on blood pressure (BP) and heart rate (HR) in spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats. Hypertension was connected with increases in cardiac and plasma markers of lipid peroxidation in both models, whereas cardiac endocannabinoid levels decreased in SHR and increased in DOCA-salt. CBD (10 mg/kg once a day for 2 weeks) did not modify BP and HR in hypertension but counteracted pro-oxidant effects. Moreover, it decreased cardiac or plasma levels of anandamide, 2-arachidonoylglycerol and oleoyl ethanolamide in DOCA-salt and inhibited the activity of fatty acid amide hydrolase (FAAH) in both models. In the respective normotensive control rats, CBD increased lipid peroxidation, free fatty acid levels and FAAH activity. In conclusion, chronic CBD administration does not possess antihypertensive activity in a model of primary and secondary (DOCA-salt) hypertension, despite its antioxidant effect. The latter may be direct rather than based on the endocannabinoid system. The unexpected CBD-related increase in lipid peroxidation in normotensive controls may lead to untoward effects; thus, caution should be kept if CBD is used therapeutically. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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173. Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria.
- Author
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Pędzińska-Betiuk A, Schlicker E, Weresa J, and Malinowska B
- Abstract
Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB
2 receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to re-evaluate the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and co-medications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB2 receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo)cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pędzińska-Betiuk, Schlicker, Weresa and Malinowska.)- Published
- 2024
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174. Function of Presynaptic Inhibitory Cannabinoid CB 1 Receptors in Spontaneously Hypertensive Rats and Its Modification by Enhanced Endocannabinoid Tone.
- Author
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Toczek M, Schlicker E, Remiszewski P, and Malinowska B
- Subjects
- Rats, Animals, Rats, Inbred WKY, Endocannabinoids pharmacology, Rats, Inbred SHR, Phenylephrine, Cannabinoids, Hypertension, Carbamates, Cyclohexanols, Piperazines, Succinimides
- Abstract
We studied whether the function of presynaptic inhibitory cannabinoid CB
1 receptors on the sympathetic nerve fibres innervating resistance vessels is increased in spontaneously hypertensive rats (SHR) like in deoxycorticosterone (DOCA)-salt hypertension. An increase in diastolic blood pressure (DBP) was induced by electrical stimulation of the preganglionic sympathetic neurons or by phenylephrine injection in pithed SHR and normotensive Wistar-Kyoto rats (WKY). The electrically (but not the phenylephrine) induced increase in DBP was inhibited by the cannabinoid receptor agonist CP55940, similarly in both groups, and by the endocannabinoid reuptake inhibitor AM404 in SHR only. The effect of CP55940 was abolished/reduced by the CB1 receptor antagonist AM251 (in both groups) and in WKY by endocannabinoid degradation blockade, i.e., the monoacylglycerol lipase (MAGL) inhibitor MJN110 and the dual fatty acid amide hydrolase (FAAH)/MAGL inhibitor JZL195 but not the FAAH inhibitor URB597. MJN110 and JZL195 tended to enhance the effect of CP55940 in SHR. In conclusion, the function of presynaptic inhibitory CB1 receptors depends on the hypertension model. Although no differences occurred between SHR and WKY under basal experimental conditions, the CB1 receptor function was better preserved in SHR when the endocannabinoid tone was increased by the inhibition of MAGL or the endocannabinoid transporter.- Published
- 2024
- Full Text
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175. Polypharmacology: promises and new drugs in 2022.
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Ryszkiewicz P, Malinowska B, and Schlicker E
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- Humans, Polypharmacology
- Abstract
Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this 'classic' approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The 'novel' polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease., (© 2023. The Author(s).)
- Published
- 2023
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176. Effects of the peripheral CB 1 receptor antagonist JD5037 in mono- and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension.
- Author
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Remiszewski P, Pędzińska-Betiuk A, Mińczuk K, Schlicker E, Klimek J, Dzięcioł J, and Malinowska B
- Abstract
Pulmonary hypertension (PH) is a disease leading to increased pressure in the pulmonary artery and right heart failure. The adenosine monophosphate-activated protein kinase (AMPK) activator, metformin, has a protective effect against PH. CB
1 receptor blockade reduces the number of pathological alterations in experimental lung fibrosis. The current study evaluates the effect of the peripheral cannabinoid CB1 receptor antagonist JD5037 in mono- and polytherapy with metformin in rat monocrotaline-induced mild PH. Animals received metformin (100 mg/kg), JD5037 (3 mg/kg), or a combination of both once daily for 21 days. Monocrotaline (60 mg/kg) increased right ventricular (RV) systolic pressure (RVSP), led to RV and lung hypertrophy and remodeling, and decreased oxygen saturation. Metformin partially restored the monocrotaline-induced effects, i.e., decreased RVSP, increased oxygen saturation, and counteracted cardiac fibrotic, hypertrophic, and inflammatory changes. JD5037 modified parameters related to inflammation and/or fibrosis. Only polytherapy with metformin and JD5037 improved Fulton's index and coronary artery hypertrophy and tended to be more effective than monotherapy against alterations in RVSP, oxygen saturation and coronary artery tunica media vacuolization. In conclusion, monotherapy with JD5037 does not markedly influence the PH-related changes. However, polytherapy with metformin tends to be more efficient than any of these compounds alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Remiszewski, Pędzińska-Betiuk, Mińczuk, Schlicker, Klimek, Dzięcioł and Malinowska.)- Published
- 2022
- Full Text
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177. Eighth pharmacologic-historical forum.
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Philippu A, Greim H, Schlicker E, and von Kügelgen I
- Abstract
Scope, Historical Overview and Perspectives: Athineos Philippu, Department of Pharmacology and Toxicology, University of Innsbruck, Austria The eighth pharmacologic-historical Forum was held online in 2022 in Bonn during the Meeting of the DGPT. In this forum the personalities of Hans Dengler, Paul Martini, Manfred Göthert, and Rudolf Buchheim were honoured by describing their lives and scientific achievements., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2022
- Full Text
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178. Cross-Talk between CB 1 , AT 1 , AT 2 and Mas Receptors Responsible for Blood Pressure Control in the Paraventricular Nucleus of Hypothalamus in Conscious Spontaneously Hypertensive Rats and Their Normotensive Controls.
- Author
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Mińczuk K, Schlicker E, and Malinowska B
- Subjects
- Angiotensin Receptor Antagonists pharmacology, Animals, Blood Pressure, Losartan pharmacology, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Hypertension metabolism, Paraventricular Hypothalamic Nucleus metabolism
- Abstract
We have previously shown that in urethane-anaesthetized rats, intravenous injection of the angiotensin II (Ang II) AT
1 receptor antagonist losartan reversed the pressor effect of the cannabinoid CB1 receptor agonist CP55940 given in the paraventricular nucleus of hypothalamus (PVN). The aim of our study was to determine the potential interactions in the PVN between CB1 receptors and AT1 and AT2 receptors for Ang II and Mas receptors for Ang 1-7 in blood pressure regulation in conscious spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. The pressor effects of Ang II, Ang 1-7 and CP55940 microinjected into the PVN were stronger in SHRs than in WKYs. Increases in blood pressure in response to Ang II were strongly inhibited by antagonists of AT1 (losartan), AT2 (PD123319) and CB1 (AM251) receptors, to Ang 1-7 by a Mas antagonist (A-779) and AM251 and to CP55940 by losartan, PD123319 and A-779. Higher (AT1 and CB1 ) and lower (AT2 and Mas) receptor expression in the PVN of SHR compared to WKY may partially explain the above differences. In conclusion, blood pressure control in the PVN depends on the mutual interaction of CB1 , AT1 , AT2 and Mas receptors in conscious spontaneously hypertensive rats and their normotensive controls.- Published
- 2022
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179. Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?
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Weresa J, Pędzińska-Betiuk A, Mińczuk K, Malinowska B, and Schlicker E
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- Adolescent, Analgesics, Cannabinoid Receptor Agonists, Heart, Humans, Cannabinoids adverse effects, Cannabis adverse effects, Myocardial Infarction chemically induced, Myocardial Infarction drug therapy
- Abstract
The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB
1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9 -tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.- Published
- 2022
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180. Beneficial and harmful effects of CB 1 and CB 2 receptor antagonists on chronotropic and inotropic effects related to atrial β-adrenoceptor activation in humans and in rats with primary hypertension.
- Author
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Weresa J, Pędzińska-Betiuk A, Schlicker E, Hirnle G, Mitrosz M, and Malinowska B
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- Animals, Humans, Rats, Male, Piperidines pharmacology, Myocardial Contraction drug effects, Heart Rate drug effects, Pyrazoles pharmacology, Rats, Inbred WKY, Receptors, Adrenergic, beta metabolism, Indoles pharmacology, Cannabinoid Receptor Antagonists pharmacology, Female, Propanolamines, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 metabolism, Rats, Inbred SHR, Heart Atria drug effects, Heart Atria metabolism, Heart Atria physiopathology, Receptor, Cannabinoid, CB2 antagonists & inhibitors, Receptor, Cannabinoid, CB2 metabolism, Isoproterenol pharmacology, Hypertension physiopathology, Hypertension drug therapy, Hypertension metabolism, Hypertension chemically induced
- Abstract
We have previously shown that cannabinoid CB
1 and CB2 receptor antagonists, AM251 and AM630, respectively, modulate cardiostimulatory effects of isoprenaline in atria of Wistar rats. The aim of the present study was to examine whether such modulatory effects can also be observed (a) in the human atrium and (b) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Inotropic effects of isoprenaline and/or CGP12177 (that activate the high- and low-affinity site of β1 -adrenoceptors, respectively) were examined in paced human atrial trabeculae and rat left atria; chronotropic effects were studied in spontaneously beating right rat atria. AM251 modified cardiostimulatory effects more strongly than AM630. Therefore, AM251 (1 μM) enhanced the chronotropic effect of isoprenaline in WKY and SHR as well as inotropic action of isoprenaline in WKY and in human atria. It also increased the inotropic influence of CGP12177 in SHR. AM630 (1 μM) decreased the inotropic effect of isoprenaline and CGP12177 in WKY, but enhanced the isoprenaline-induced inotropic effect in SHR and human atria. Furthermore, AM251 (0.1 and 3 μM) and AM630 (0.1 μM) reduced the inotropic action of isoprenaline in human atria. In conclusion, cannabinoid receptor antagonists have potentially harmful and beneficial effects through their amplificatory effects on β-adrenoceptor-mediated positive chronotropic and inotropic actions, respectively., (© 2021 John Wiley & Sons Australia, Ltd.)- Published
- 2021
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181. β 1 -Blockers Enhance Inotropy of Endogenous Catecholamines in Chronic Heart Failure.
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Feuerstein TJ and Schlicker E
- Abstract
Although β
1 -blockers impressively reduce mortality in chronic heart failure (CHF), there are concerns about negative inotropic effects and worsening of hemodynamics in acute decompensated heart failure. May receptor theory dispel these concerns and confirm clinical practice to use β1 -blockers? In CHF, concentrations of catecholamines at the β1 -adrenoceptors usually exceed their dissociation constants ( KD s). The homodimeric β1 -adrenoceptors have a receptor reserve and display negative cooperativity. We considered the binomial distribution of occupied receptor dimers with respect to the interaction of an exogenous β1 -blocker and elevated endogenous agonist concentrations > [ KD s], corresponding to an elevated sympathetic tone. Modeling based on binomial distribution suggests that despite the presence of a low concentration of the antagonist, the activation of the dimer receptors is higher than that in its absence. Obviously, the antagonist improves the ratio of the dimer receptors with only single agonist activation compared with the dimer receptors with double activation. This leads to increased positive inotropic effects of endogenous catecholamines due to a β1 -blocker. To understand the positive inotropic sequels of β1 -blockers in CHF is clinically relevant. This article may help to eliminate the skepticism of clinicians about the use of β1 -blockers because of their supposed negative inotropic effect, since, on the contrary, a positive inotropic effect can be expected for receptor-theoretical reasons., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feuerstein and Schlicker.)- Published
- 2021
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182. Reduction of the serotonin 5-HT 1B and 5-HT 2A receptor-mediated contraction of human pulmonary artery by the combined 5-HT 1B receptor antagonist and serotonin transporter inhibitor LY393558.
- Author
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Baranowska-Kuczko M, Kozłowska H, Schlicker E, Göthert M, MacLean MR, Kozłowski M, Kloza M, Sadowska O, and Malinowska B
- Subjects
- Aged, Benzamides pharmacology, Citalopram pharmacology, Female, Humans, Male, Middle Aged, Piperidones pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT2A, Spiro Compounds pharmacology, Cyclic S-Oxides pharmacology, Pulmonary Artery drug effects, Serotonin 5-HT1 Receptor Antagonists pharmacology, Serotonin 5-HT2 Receptor Antagonists, Selective Serotonin Reuptake Inhibitors pharmacology, Thiadiazines pharmacology, Vasoconstriction drug effects
- Abstract
Background: LY393558 is a combined antagonist of serotonin (5-HT) 5-HT
1B receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and remodelling of rat and/or mouse pulmonary arteries. The aim of our study was to examine the effect of LY393558 on the 5-HT-stimulated vasoconstriction of human pulmonary arteries (hPAs) and to determine the underlying mechanism(s)., Methods: Vascular effects of 5-HT receptor agonists, antagonists and a SERT inhibitor were examined in organ bath studies on intralobar hPAs obtained from patients during resection of lung carcinoma., Results: Serotonin and agonists of the 5-HT1B receptor (5-carboxamidotryptamine, 5-CT) and 5-HT2A receptor (α-methyl-5-HT) contracted endothelium-intact hPAs in a concentration-dependent fashion. The 5-HT1B antagonists SB224289 and GR55562 reduced responses induced by 5-HT and 5-CT and the 5-HT2A antagonist ketanserin inhibited the effects of 5-HT and α-methyl-5-HT. Administration of the SERT inhibitor citalopram (at a concentration that failed to modify the 5-HT-induced vasoconstriction) in combination with SB224289 or GR55562 was more effective in inhibiting the response to 5-HT than the 5-HT1B antagonists alone. LY393558 showed the greatest antagonistic effect against the vasoconstriction elicited by 5-HT, 5-CT and α-methyl-5-HT., Conclusions: LY393558 reduces the 5-HT-induced contraction antagonizing 5-HT1B and 5-HT2A receptors probably due to synergic interaction between SERT inhibition and 5-HT1B receptor antagonism. Thus, it might represent a valuable future option in the pulmonary arterial hypertension therapy.- Published
- 2020
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183. Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part II. Some contributions of Manfred Göthert.
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Göthert M, Bönisch H, Malinowska B, and Schlicker E
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- Animals, Antidepressive Agents history, Antidepressive Agents pharmacology, Drug Discovery history, History, 20th Century, History, 21st Century, Humans, Receptors, Serotonin history, Serotonin history, Selective Serotonin Reuptake Inhibitors history, Selective Serotonin Reuptake Inhibitors pharmacology, Receptors, Serotonin physiology, Serotonin physiology
- Abstract
About 40% of the papers within the scientific oeuvre of Manfred Göthert (1939-2019) were dedicated to serotonin (5-hydroxytryptamine, 5-HT). He was not only the witness of the gradual definition of the fourteen 5-HT receptor subtypes but also was involved directly by identifying 5-HT
1B , 5-HT1D and 5-HT3 receptors. Moreover, he identified presynaptic 5-HT receptors on central and/or peripheral serotoninergic, noradrenergic and/or cholinergic neurones. Two inhibitory (5-HT1B , 5-HT1D ) and two facilitatory (5-HT3 , 5-HT4 ) receptors were found, the 5-HT1B receptor representing a possible target for antidepressant drugs. Ten years earlier than electrophysiologists, he identified ligand-gated receptors like the 5-HT3 and the nicotinic acetylcholine (nACh) receptor as targets of halothane. Simultaneously with, but independent of, other authors he found that ethanol allosterically inhibits N-methyl-D-aspartate (NMDA) receptors, which are affected at an even lower concentration than 5-HT3 and nACh receptors. The latter two receptors were shown to be subject to allosteric inhibition also by cannabinoids via a mechanism unrelated to cannabinoid CB1 or CB2 receptors; cannabinoid inhibition of 5-HT3 receptors may represent a new target for the treatment of neuropathic pain.- Published
- 2020
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184. Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT 3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats.
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Kossakowski R, Schlicker E, Toczek M, Weresa J, and Malinowska B
- Abstract
Cannabidiol (CBD) is a nonpsychotropic constituent of Cannabis sativa L. It is suggested to be useful in hypertension. Under in vitro conditions, it activates vanilloid TRPV1 and inhibits serotonin 5-HT
3 receptors, i.e., receptors involved in the Bezold-Jarisch reflex stimulation. The aim of our study was to compare the cardiovascular effects of CBD in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Experiments were performed on conscious, urethane-anesthetized, and pithed rats. In pithed SHR and WKY, CBD increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP) in a manner insensitive to adrenalectomy. Propranolol strongly impaired the CBD-induced increases in HR and SBP without affecting the decreases in DBP. Desipramine also reduced the CBD-induced effects on HR and SBP and further increased its effects on DBP. In anesthetized rats, bolus i.v. injection of single doses of CBD induced short-lasting decreases in HR, SBP, and DBP, stronger in SHR than in WKY and prevented by bilateral vagotomy. The CBD-induced fall in HR but not in BP was diminished by the TRPV1 receptor antagonist capsazepine and almost completely abolished if CBD was re-injected after previous administration. CBD reduced the Bezold-Jarisch reflex elicited by the 5-HT3 receptor agonist phenylbiguanide but not that evoked by the TRPV1 agonist capsaicin. In conscious rats, CBD did not affect cardiovascular parameters. In isolated left atria, CBD decreased contractile force. Conclusions: Cannabidiol (1) induces the Bezold-Jarisch reflex likely via TRPV1 receptors (which undergo tachyphylaxis) more markedly in SHR than in WKY; (2) inhibits the Bezold-Jarisch reflex induced by activation of 5-HT3 but not TRPV1 receptors; (3) has peripheral sympathomimetic, (4) vasodilatory, and (5) negative inotropic effects. The above properties of CBD should be taken under consideration when CBD is used for therapeutic purposes.- Published
- 2019
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185. N-Ethylmaleimide differentiates between the M 2 - and M 4 -autoreceptor-mediated inhibition of acetylcholine release in the mouse brain.
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Etscheid J, Mohr K, and Schlicker E
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- Animals, Corpus Striatum metabolism, Hippocampus metabolism, Isoxazoles pharmacology, Male, Mice, Muscarinic Agonists pharmacology, Quaternary Ammonium Compounds pharmacology, Receptor, Muscarinic M2 agonists, Tritium, Acetylcholine metabolism, Autoreceptors metabolism, Corpus Striatum drug effects, Ethylmaleimide pharmacology, Hippocampus drug effects, Receptor, Muscarinic M2 metabolism, Receptor, Muscarinic M4 metabolism
- Abstract
Muscarinic M
2 and M4 receptors resemble each other in brain distribution, function, and Gi/o protein signaling. However, there is evidence from human recombinant receptors that the M4 receptor also couples to Gs protein whereas such an alternative signaling is of minor importance for its M2 counterpart. The question arises whether this property is shared by native receptors, e.g., the murine hippocampal M2 - and the striatal M4 -autoreceptor. To this end, the electrically evoked tritium overflow was studied in mouse hippocampal and striatal slices pre-incubated with3 H-choline.3 H-Acetylcholine release in either region was inhibited by the potent muscarinic receptor agonist iperoxo (pIC50 8.6-8.8) in an atropine-sensitive manner (apparent pA2 8.6-8.8); iperoxo was much more potent than oxotremorine (pIC50 6.5-6.6). In hippocampal slices, N-ethylmaleimide (NEM) 32 μM, which inactivates Gi/o proteins, tended to shift the concentration-response curve of iperoxo (pIC50 8.8) to the right (pIC50 8.5) and depressed its maximum from 85 to 69%. In striatal slices, the inhibitory effect of iperoxo declined at concentrations higher than 0.1 μM, yielding a biphasic curve with a pIC50 of 8.6 for the falling part and a pEC50 of 6.4 for the rising part of the curve. The inhibitory effect of iperoxo 10 μM (47%) after NEM pre-treatment was lower by about 35% compared to the maximum (74%) obtained without NEM. In conclusion, our data, which need to be confirmed by pertussis toxin, might suggest that in the striatum, unlike the hippocampus, stimulatory Gs protein comes into play at high concentrations of a muscarinic receptor agonist.- Published
- 2018
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186. Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor.
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Seemann WK, Wenzel D, Schrage R, Etscheid J, Bödefeld T, Bartol A, Warnken M, Sasse P, Klöckner J, Holzgrabe U, DeAmici M, Schlicker E, Racké K, Kostenis E, Meyer R, Fleischmann BK, and Mohr K
- Subjects
- Allosteric Regulation drug effects, Animals, CHO Cells, Cricetinae, Cricetulus, Cyclic AMP metabolism, Female, Heart drug effects, Intracellular Space drug effects, Intracellular Space metabolism, Male, Mice, Muscarinic Agonists adverse effects, Signal Transduction drug effects, Drug Discovery, Muscarinic Agonists pharmacology, Receptor, Muscarinic M2 agonists, Receptor, Muscarinic M2 metabolism
- Abstract
Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M
2 -receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2017
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187. Role of the Histamine H 3 Receptor in the Central Nervous System.
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Schlicker E and Kathmann M
- Subjects
- Animals, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Central Nervous System drug effects, Histamine metabolism, Histamine Agonists pharmacology, Histamine Agonists therapeutic use, Histamine Antagonists pharmacology, Histamine Antagonists therapeutic use, Humans, Central Nervous System metabolism, Receptors, Histamine H3 metabolism
- Abstract
The G
i/o protein-coupled histamine H3 receptor is distributed throughout the central nervous system including areas like cerebral cortex, hippocampus and striatum with the density being highest in the posterior hypothalamus, i.e. the area in which the histaminergic cell bodies are located. In contrast to the other histamine receptor subtypes (H1 , H2 and H4 ), the H3 receptor is located presynaptically and shows a constitutive activity. In detail, H3 receptors are involved in the inhibition of histamine release (presynaptic autoreceptor), impulse flow along the histaminergic neurones (somadendritic autoreceptor) and histamine synthesis. Moreover, they occur as inhibitory presynaptic heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic, GABAergic and perhaps cholinergic neurones. This review shows for four functions of the brain that the H3 receptor represents a brake against the wake-promoting, anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors) and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1 agonists and H3 inverse agonists elicit essentially the same effects, at least in rodents; these effects are opposite in direction to those elicited by brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3 inverse agonists for the symptomatic treatment of dementias is inconclusive, several members of this group have shown a marked potential for the treatment of disorders associated with excessive daytime sleepiness. In March 2016, the European Commission granted a marketing authorisation for pitolisant (WakixR ) (as the first representative of the H3 inverse agonists) for the treatment of narcolepsy.- Published
- 2017
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188. CB 1 receptor activation in the rat paraventricular nucleus induces bi-directional cardiovascular effects via modification of glutamatergic and GABAergic neurotransmission.
- Author
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Grzęda E, Schlicker E, Toczek M, Zalewska I, Baranowska-Kuczko M, and Malinowska B
- Subjects
- Adrenalectomy, Animals, Cannabinoid Receptor Agonists administration & dosage, Cyclohexanols administration & dosage, Heart Rate drug effects, Hypertension metabolism, Hypertension physiopathology, Hypotension metabolism, Hypotension physiopathology, Male, Microinjections, Neural Inhibition drug effects, Neural Pathways drug effects, Neural Pathways metabolism, Neural Pathways physiopathology, Nitric Oxide metabolism, Paraventricular Hypothalamic Nucleus metabolism, Paraventricular Hypothalamic Nucleus physiopathology, Rats, Wistar, Receptor, Angiotensin, Type 1 metabolism, Receptor, Cannabinoid, CB1 metabolism, Receptors, Adrenergic, beta-2 metabolism, Receptors, Thromboxane A2, Prostaglandin H2 metabolism, Sympathetic Nervous System metabolism, Sympathetic Nervous System physiopathology, Blood Pressure drug effects, Cannabinoid Receptor Agonists toxicity, Cyclohexanols toxicity, Glutamic Acid metabolism, Hypertension chemically induced, Hypotension chemically induced, Paraventricular Hypothalamic Nucleus drug effects, Receptor, Cannabinoid, CB1 agonists, Sympathetic Nervous System drug effects, Synaptic Transmission drug effects, gamma-Aminobutyric Acid metabolism
- Abstract
We have shown previously that the cannabinoid receptor agonist CP55940 microinjected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anaesthetized rats induces depressor and pressor cardiovascular effects in the absence and presence of the CB
1 antagonist AM251, respectively. The aim of our study was to examine whether the hypotension and/or hypertension induced by CP55940 given into the PVN results from its influence on glutamatergic and GABAergic neurotransmission. CP55940 was microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2 , 20 min apart). Antagonists of the following receptors, NMDA (MK801), β2 -adrenergic (ICI118551), thromboxane A2 -TP (SQ29548), angiotensin II-AT1 (losartan) or GABAA (bicuculline), or the NO synthase inhibitor L-NAME were administered intravenously 5 min before S2 alone or together with AM251. The CP55940-induced hypotension was reversed into a pressor response by AM251, bicuculline and L-NAME, but not by the other antagonists. The CP55940-induced pressor effect examined in the presence of AM251 was completely reversed by losartan, reduced by about 50-60 % by MK801, ICI118551 and SQ29548, prevented by bilateral adrenalectomy but not modified by bicuculline and L-NAME. Parallel, but smaller, changes in heart rate accompanied the changes in blood pressure. The bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids microinjected into the PVN of anaesthetized rats depend on stimulatory glutamatergic and inhibitory GABAergic inputs to the sympathetic tone; the glutamatergic input is related to AT1 , TP and β2 -adrenergic receptors and catecholamine release from the adrenal medulla whereas the GABAergic input is reinforced by NO., Competing Interests: The authors declare that they have no conflicts of interest.- Published
- 2017
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189. A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.
- Author
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Petri D and Schlicker E
- Subjects
- Animals, Aorta drug effects, Aorta metabolism, Choline metabolism, Guinea Pigs, Heart Atria drug effects, Heart Atria metabolism, Hippocampus drug effects, Hippocampus metabolism, Histamine metabolism, Kidney drug effects, Kidney metabolism, Male, Neural Inhibition drug effects, Norepinephrine metabolism, Presynaptic Terminals drug effects, Presynaptic Terminals metabolism, Tissue Culture Techniques, Vas Deferens drug effects, Vas Deferens metabolism, Neural Inhibition physiology, Receptors, Histamine metabolism, Receptors, Presynaptic metabolism
- Abstract
The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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190. Lack of hippocampal CB1 receptor desensitization by Δ(9)-tetrahydrocannabinol in aged mice and by low doses of JZL 184.
- Author
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Feliszek M, Bindila L, Lutz B, Zimmer A, Bilkei-Gorzo A, and Schlicker E
- Subjects
- Age Factors, Animals, Arachidonic Acids metabolism, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Endocannabinoids metabolism, Genotype, Glycerides metabolism, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Hippocampus metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Monoacylglycerol Lipases antagonists & inhibitors, Monoacylglycerol Lipases metabolism, Motor Activity drug effects, Phenotype, Receptor, Cannabinoid, CB1 deficiency, Receptor, Cannabinoid, CB1 genetics, Receptor, Cannabinoid, CB1 metabolism, Benzodioxoles pharmacology, Cannabinoid Receptor Agonists pharmacology, Dronabinol pharmacology, Drug Tolerance, Enzyme Inhibitors pharmacology, Hippocampus drug effects, Piperidines pharmacology, Receptor, Cannabinoid, CB1 drug effects
- Abstract
Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Δ(9)-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated (35)S-GTPγS binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on (35)S-GTPγS binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. (35)S-GTPγS binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated (35)S-GTPγS binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184.
- Published
- 2016
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191. The adrenal medulla, not CB1 receptors, mediates the inhibitory effect of acute transverse aortic constriction on the neurogenic vasopressor response.
- Author
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Karabowicz P, Schlicker E, Pędzińska-Betiuk A, Kloza M, and Malinowska B
- Subjects
- Animals, Autonomic Fibers, Preganglionic drug effects, Electric Stimulation, Heart Rate drug effects, Male, Myocardial Contraction drug effects, Phenylephrine pharmacology, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Vasopressins pharmacology, Adrenal Medulla pathology, Blood Pressure drug effects, Constriction, Pathologic pathology, Receptor, Cannabinoid, CB1 drug effects
- Published
- 2015
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192. Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA-salt hypertensive rats.
- Author
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Toczek M, Schlicker E, Grzęda E, and Malinowska B
- Subjects
- Animals, Benzamides pharmacology, Blood Pressure drug effects, Cannabinoid Receptor Agonists pharmacology, Cannabinoid Receptor Antagonists pharmacology, Carbamates pharmacology, Desoxycorticosterone Acetate, Hypertension chemically induced, Male, Nephrectomy, Phenylephrine pharmacology, Rats, Rats, Wistar, Sodium, Dietary adverse effects, Hypertension physiopathology, Receptor, Cannabinoid, CB1 drug effects, Receptors, Presynaptic drug effects, Sympathetic Nervous System drug effects
- Abstract
Aims: This study was performed to examine whether hypertension affects the sympathetic transmission to resistance vessels of pithed rats via inhibitory presynaptic cannabinoid CB1 receptors and whether endocannabinoids are involved in this response., Materials and Methods: We compared uninephrectomised rats rendered hypertensive by high salt diet and deoxycorticosterone acetate (DOCA) injections with normotensive animals (uninephrectomy only). Experiments were performed on vagotomised and pithed animals. Increases in diastolic blood pressure (DBP) were induced four times (S1-S4) by electrical stimulation or phenylephrine injection., Key Findings: Electrical stimulation (0.75Hz, 1ms, 50V, 5 impulses) of the preganglionic sympathetic nerve fibres innervating the blood vessels more strongly increased DBP in normotensive than in DOCA-salt rats. Phenylephrine (0.01μmol/kg) induced similar increases in DBP in both groups. The cannabinoid receptor agonist CP55940 (0.01-1μmol/kg) did not modify the rises in DBP induced by phenylephrine. However, it inhibited the electrically stimulated increases in DBP, more strongly in DOCA-salt than in normotensive animals (maximally by 50 and 30%, respectively). The effect of CP55940 was attenuated by the CB1 antagonist AM251 (3μmol/kg). AM251 enhanced the neurogenic vasopressor response during S4 by itself in hypertensive rats only. URB597 (3μmol/kg), which inhibits degradation of the endocannabinoid anandamide, did not modify the electrically stimulated increases in DBP., Significance: The function of inhibitory presynaptic CB1 receptors on sympathetic nerves is enhanced in DOCA-salt hypertensive rats. Thus, the CB1 receptor-mediated inhibition of noradrenaline release from the sympathetic nerve fibres innervating the resistance vessels might play a protective role in hypertension., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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193. A search for functional histamine H4 receptors in the human, guinea pig and mouse brain.
- Author
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Feliszek M, Speckmann V, Schacht D, von Lehe M, Stark H, and Schlicker E
- Subjects
- Adolescent, Adult, Animals, Child, Female, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guinea Pigs, Histamine pharmacology, Histamine Agonists pharmacology, Humans, Male, Methylhistamines pharmacology, Mice, Inbred C57BL, Middle Aged, Norepinephrine metabolism, Receptors, G-Protein-Coupled agonists, Receptors, Histamine H3 metabolism, Receptors, Histamine H4, Young Adult, Cerebral Cortex metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, Histamine metabolism
- Abstract
Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPγS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPγS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S-GTPγS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPγS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPγS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex.
- Published
- 2015
- Full Text
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194. MH-3: evidence for non-competitive antagonism towards the low-affinity site of β1-adrenoceptors.
- Author
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Schlicker E, Pędzińska-Betiuk A, Kozłowska H, Szkaradek N, Żelaszczyk D, Baranowska-Kuczko M, Kieć-Kononowicz K, Marona H, and Malinowska B
- Subjects
- Animals, Binding Sites, Heart drug effects, Heart physiology, In Vitro Techniques, Male, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Rats, Wistar, Adrenergic beta-1 Receptor Antagonists pharmacology, Piperazines pharmacology, Receptors, Adrenergic, beta-1 metabolism, Xanthones pharmacology
- Abstract
β-Adrenoceptor antagonists are important drugs for the treatment of cardiovascular diseases and some of those drugs also block the so-called low-affinity site of β1-adrenoceptors although at much higher concentrations. This low-affinity site, also identified in vivo and in human tissue, may come into play under certain pathophysiological situations including arrhythmias. The aim of our study was to determine the potency of 14 compounds chemically related to bupranolol or bevantolol and two xanthone derivatives at the low-affinity site of the β1-adrenoceptor. The potency of the compounds at the low- and high-affinity site of β1-adrenoceptors (β1L and β1H; both increasing heart rate) was compared in the pithed rat. One compound was also studied in the isolated rat heart and its α1-adrenolytic effect determined in the isolated rat mesenteric artery. In the pithed rat, four compounds blocked the β1L-adrenoceptor at a ≥10-fold lower potency than the β1H-adrenoceptor whereas the xanthone derivative (-)-MH-3 was equipotent. In the spontaneously beating right atrium (-)-MH-3 was a non-competitive antagonist of comparable potency at either receptor; its apparent pD'2 value for the β1L-adrenoceptor ranged from 5.6 to 6.4 under various conditions, including the Langendorff preparation. Its apparent pA2 at the α1-adrenoceptor in the mesenteric artery was 8.4. (-)-MH-3 is the first compound with virtually the same potency at the low- and high-affinity site of β1-adrenoceptors in vivo; it appears to be a non-competitive antagonist at either site in vitro.
- Published
- 2014
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195. O-2050 facilitates noradrenaline release and increases the CB1 receptor inverse agonistic effect of rimonabant in the guinea pig hippocampus.
- Author
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Jergas B, Schulte K, Bindila L, Lutz B, and Schlicker E
- Subjects
- Animals, Arachidonic Acids metabolism, Benzoxazines pharmacology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Dronabinol pharmacology, Drug Interactions, Endocannabinoids metabolism, Glycerides metabolism, Guinea Pigs, Hippocampus metabolism, In Vitro Techniques, Male, Morpholines pharmacology, Naphthalenes pharmacology, Polyunsaturated Alkamides metabolism, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Rimonabant, Cannabinoid Receptor Antagonists pharmacology, Dronabinol analogs & derivatives, Hippocampus drug effects, Norepinephrine metabolism, Piperidines pharmacology, Pyrans pharmacology, Pyrazoles pharmacology, Receptor, Cannabinoid, CB1 metabolism
- Abstract
The cannabinoid CB1 receptors on the noradrenergic neurons in guinea pig hippocampal slices show an endogenous endocannabinoid tone. This conclusion is based on rimonabant, the facilitatory effect of which on noradrenaline release might be due to its inverse CB1 receptor agonism and/or the interruption of a tonic inhibition elicited by endocannabinoids. To examine the latter mechanism, a neutral antagonist would be suitable. Therefore, we studied whether O-2050 is a neutral CB1 receptor antagonist in the guinea pig hippocampus and whether it mimics the facilitatory effect of rimonabant. CB1 receptor affinity of O-2050 was quantified in cerebrocortical membranes, using (3)H-rimonabant binding. Its CB1 receptor potency and effect on (3)H-noradrenaline release were determined in superfused hippocampal slices. Its intrinsic activity at CB1 receptors was studied in hippocampal membranes, using (35)S-GTPγS binding. Endocannabinoid levels in hippocampus were determined by liquid chromatography-multiple reaction monitoring. O-2050 was about ten times less potent than rimonabant in its CB1 receptor affinity, potency and facilitatory effect on noradrenaline release. Although not affecting (35)S-GTPγS binding by itself, O-2050 shifted the concentration-response curve of a CB1 receptor agonist to the right but that of rimonabant to the left. Levels of anandamide and 2-arachidonoyl glycerol in guinea pig hippocampus closely resembled those in mouse hippocampus. In conclusion, our results with O-2050 confirm that the CB1 receptors on noradrenergic neurons of the guinea pig hippocampus show an endogenous tone. To differentiate between the two mechanisms leading to an endogenous tone, O-2050 is not superior to rimonabant since O-2050 may increase the inverse agonistic effect of endocannabinoids.
- Published
- 2014
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196. Increased CB2 mRNA and anandamide in human blood after cessation of cannabis abuse.
- Author
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Muhl D, Kathmann M, Hoyer C, Kranaster L, Hellmich M, Gerth CW, Faulhaber J, Schlicker E, and Leweke FM
- Subjects
- Adult, Female, Humans, Leukocytes, Mononuclear metabolism, Male, Marijuana Abuse genetics, Receptor, Cannabinoid, CB1 genetics, Young Adult, Arachidonic Acids blood, Endocannabinoids blood, Marijuana Abuse blood, Polyunsaturated Alkamides blood, RNA, Messenger blood, Receptor, Cannabinoid, CB2 genetics
- Abstract
In previous studies, long-term cannabis use led to alterations of the endocannabinoid system including an increase in CB1 and/or CB2 receptor messenger RNA (mRNA) in blood cells and an increase in the serum level of the endocannabinoid 2-arachidonoyl glycerol. However, in those studies, cannabis use was stopped only few days before testing or not interrupted at all. Therefore, one cannot decide whether the alterations are due to long-term cannabis abuse or are confounded by acute effects of cannabis. Blood was sampled from donors that had smoked marijuana ≥20 times in their lives but had abstained from cannabis for ≥6 months (high-frequency users, HFU) and from controls (cannabis use ≤5 times lifetime). CB1 and CB2 mRNA was determined in peripheral mononuclear blood cells using the reverse transcriptase polymerase chain reaction. Serum anandamide level was assayed using electrospray tandem mass spectrometry. CB2 mRNA was increased by 45 % in HFU when compared to controls, whereas CB1 mRNA did not differ. The anandamide level in HFU exceeded that in controls by 90 %. Tobacco smoking could be excluded as a confounding factor. In conclusion, marijuana users that had smoked marijuana ≥20 times in their lives and stopped cannabis use at least 6 months before the study show an increase in CB2 receptor mRNA in the blood and in serum anandamide level. These alterations resemble those obtained for marijuana smokers that had stopped cannabis use only few days before testing and may be implicated in the pathogenesis of disorders associated with long-term cannabis use.
- Published
- 2014
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197. Mechanisms of endothelium-dependent relaxation evoked by anandamide in isolated human pulmonary arteries.
- Author
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Baranowska-Kuczko M, Kozłowska H, Kozłowski M, Schlicker E, Kloza M, Surażyński A, Grzęda E, and Malinowska B
- Subjects
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid pharmacology, Aged, Amidohydrolases metabolism, Female, Humans, Male, Middle Aged, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide physiology, Peptides pharmacology, Pulmonary Artery physiology, Serotonin pharmacology, Arachidonic Acids pharmacology, Endocannabinoids pharmacology, Endothelium, Vascular physiology, Polyunsaturated Alkamides pharmacology, Pulmonary Artery drug effects, Vasodilation drug effects
- Abstract
Endocannabinoids contract, relax or do not affect vessels with different calibre and tone in the pulmonary circulation in four species. The aim of the present study was to determine the mechanisms involved in the anandamide-induced relaxation of human pulmonary arteries (hPAs). Studies were performed in the isolated hPAs pre-constricted with the prostanoid TP receptor agonist, U-46619. To detect fatty acid amide hydrolase (FAAH) expression, Western blots were used. Anandamide concentration dependently relaxed the endothelium-intact hPAs pre-constricted with U-46619. The anandamide-induced relaxation was virtually abolished by removal of the endothelium and strongly attenuated by inhibitors of cyclooxygenases (indomethacin, COX-1/COX-2, and nimesulide, COX-2), nitric oxide synthase (N (G) -nitro-L-arginine methyl ester) given separately or in combination, FAAH (URB597), and the prostanoid IP receptor antagonist, RO1138452. The anandamide-evoked relaxation in the endothelium-intact vessels was attenuated in KCl pre-constricted preparations or by the inhibitor of large-conductance Ca(2+)-activated K(+) channels, iberiotoxin. In experiments performed in the presence of URB597 to exclude effects of anandamide metabolites, the antagonist of the endothelial cannabinoid receptor, O-1918, diminished the anandamide-evoked relaxation whereas the antagonists of cannabinoid CB1, CB2 and vanilloid TRPV1 receptors, AM251, SR144528 and capsazepine, respectively, had no effect. Western blot studies revealed the occurrence of FAAH protein in the hPAs. The present study shows that anandamide breakdown products, cyclooxygenase pathways, nitric oxide, potassium channels and the O-1918-sensitive cannabinoid receptor play a role in the anandamide-induced relaxation of the hPAs with intact endothelium.
- Published
- 2014
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198. Do cannabinoids exhibit a tyramine-like effect?
- Author
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Ilayan E, Feliszek M, Malinowska B, and Schlicker E
- Subjects
- Adrenergic Uptake Inhibitors pharmacology, Animals, Arachidonic Acids pharmacology, Benzoxazines pharmacology, Cannabidiol pharmacology, Cyclohexanols pharmacology, Dose-Response Relationship, Drug, Dronabinol pharmacology, Endocannabinoids pharmacology, Glycerides pharmacology, Kidney Cortex metabolism, Male, Mice, Mice, Inbred C57BL, Morpholines pharmacology, Naphthalenes pharmacology, Norepinephrine Plasma Membrane Transport Proteins antagonists & inhibitors, Norepinephrine Plasma Membrane Transport Proteins metabolism, Polyunsaturated Alkamides pharmacology, Rats, Rats, Sprague-Dawley, Time Factors, Cannabinoids pharmacology, Kidney Cortex drug effects, Norepinephrine metabolism, Tyramine pharmacology
- Abstract
The major constituent of the cannabis plant, Δ(9)-tetrahydrocannabinol, has stimulatory and depressant effects on cardiovascular functions. There is evidence from an in vivo study on the urethane-anaesthetized rat that part of the stimulatory effects is related to a tyramine-like activity. In the present study, we examined whether Δ(9)-tetrahydrocannabinol induces carrier-mediated noradrenaline release in vitro. The study was extended to another phytocannabinoid, cannabidiol, to the synthetic cannabinoids CP 55,940 and WIN 55,212-2 and to the endocannabinoids anandamide and 2-arachidonoyl glycerol. Tissue pieces of the renal cortex from the mouse and the rat were preincubated with (3)H-noradrenaline and superfused. The effect of the cannabinoids on basal (3)H-noradrenaline release was studied. Tyramine served as a positive control. In the mouse kidney, basal (3)H-noradrenaline release was increased by tyramine 0.1, 1 and 10 μM by 39, 91 and 212 %, respectively, and, in the rat kidney, (3)H-noradrenaline release was increased by tyramine 10 μM by 158 %. All effects were abolished by desipramine 1 μM, an inhibitor of the neuronal noradrenaline transporter. The cannabinoids at 0.1, 1 and 10 μM (CP 55,940 at 0.1, 1 and 3.2 μM) did not affect (3)H-noradrenaline release in the mouse kidney. The highest concentration of the cannabinoids (10 μM and in the case of CP 55,940 3.2 μM) also failed to affect (3)H-noradrenaline release in the rat kidney. In conclusion, the cannabinoids Δ(9)-tetrahydrocannabinol, cannabidiol, CP 55,940, WIN 55,212-2, anandamide and 2-arachidonoyl glycerol do not possess a tyramine-like effect on noradrenaline release.
- Published
- 2013
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199. Relaxation of human pulmonary arteries by PPARγ agonists.
- Author
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Kozłowska H, Baranowska-Kuczko M, Schlicker E, Kozłowski M, Kloza M, and Malinowska B
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Organ Culture Techniques, Pulmonary Artery drug effects, Vasodilation drug effects, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid pharmacology, PPAR gamma agonists, PPAR gamma physiology, Pulmonary Artery physiology, Vasodilation physiology
- Abstract
It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01-100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the KATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration-response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and KATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.
- Published
- 2013
- Full Text
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200. Cannabinoid CB1 receptor activation, pharmacological blockade, or genetic ablation affects the function of the muscarinic auto- and heteroreceptor.
- Author
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Schulte K, Steingrüber N, Jergas B, Redmer A, Kurz CM, Buchalla R, Lutz B, Zimmer A, and Schlicker E
- Subjects
- Analgesics, Opioid pharmacology, Animals, Arachidonic Acid metabolism, Arachidonic Acids metabolism, Cerebral Cortex drug effects, Cerebral Cortex physiology, Cholinergic Neurons drug effects, Cholinergic Neurons physiology, Endocannabinoids, Enkephalin, D-Penicillamine (2,5)- pharmacology, Glycerides metabolism, Hippocampus drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscarinic Agonists pharmacology, Oxotremorine pharmacology, Piperidines pharmacology, Polyunsaturated Alkamides metabolism, Pyrazoles pharmacology, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptors, Opioid, delta agonists, Rimonabant, Synaptosomes drug effects, Synaptosomes physiology, Vas Deferens drug effects, GTP-Binding Protein alpha Subunits metabolism, Hippocampus physiology, Receptor, Cannabinoid, CB1 physiology, Receptors, Muscarinic physiology, Receptors, Opioid, delta physiology, Vas Deferens physiology
- Abstract
Different types of presynaptic inhibitory Gα(i/o) protein-coupled receptors usually do not act independently of each other but rather pre-activation of receptor X impairs the effect mediated via receptor Y. It is, however, unknown whether this interaction extends to the cannabinoid CB(1) receptor on cholinergic neurones and hence we studied whether its activation, pharmacological blockade, or genetic inactivation affects the function of other presynaptic inhibitory receptors. The electrically evoked acetylcholine or noradrenaline release was determined in superfused rodent tissues preincubated with (3)H-choline or (3)H-noradrenaline. The muscarinic M(2) receptor, Gα(i), and Gα(o) proteins were determined in hippocampal synaptosomes by Western blotting. Hippocampal anandamide and 2-arachidonoyl glycerol levels were determined by LC-MS/MS. The inhibitory effect of the muscarinic receptor agonist oxotremorine on acetylcholine release in hippocampal slices was increased by genetic CB(1) receptor ablation (mouse) and the CB(1) antagonist rimonabant (rat but not mouse) and decreased by a cannabinoid receptor agonist (mouse). In mouse tissues, CB(1) receptor ablation also increased the effect of a δ opioid receptor agonist on acetylcholine release in the hippocampus and the effect of oxotremorine on noradrenaline release in the vas deferens. CB(1) receptor ablation, to a very slight extent, increased Gα(o) protein levels without affecting either Gα(i) and M(2) receptor protein or the levels of anandamide and 2-arachidonoyl glycerol in the hippocampus. In conclusion, the CB(1) receptor shows an inhibitory interaction with the muscarinic and δ opioid receptor on cholinergic neurones in the rodent hippocampus and with the muscarinic receptor on noradrenergic neurones in the mouse vas deferens.
- Published
- 2012
- Full Text
- View/download PDF
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