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We have previously shown that cannabinoid CB1 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. [ABSTRACT FROM AUTHOR]

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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]

Background and Purpose: Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor.Experimental Approach: Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined.Key Results: In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each).Conclusions and Implications: Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension. [ABSTRACT FROM AUTHOR]

Activation by CGP 12177 and cyanopindolol of the human and rat low-affinity state of β1-adrenoceptors increases frequency and contractile force and hastens relaxation in isolated cardiac tissues, and probably relaxes isolated vessels. In order to identify the positive inotropic, positive lusitropic and vasodilator effects of both agonists also in vivo, we have determined their effects on the left ventricular systolic pressure (LVSP), the rate of intraventricular pressure rise (+dP dt−1max) and decline (−dP dt−1max), the diastolic blood pressure (DBP) and the mesenteric blood flow (MBF) in pithed and vagotomized rats.CGP 12177 (0.1–100 nmol kg−1) and cyanopindolol (1–1000 nmol kg−1) dose-dependently enhanced all cardiac parameters. The nonselective β-adrenoceptor antagonist bupranolol 10 μmol kg−1 diminished the CGP 12177 (100 nmol kg−1)-stimulated increases in LVSP from 26.3±8.2 to 13.1±1.8 mmHg (P<0.05), +dP dt−1max from 5287±290 to 2439±296 mmHg s−1 (P<0.001) and −dP dt−1max from −3836±301 to −2187±443 mmHg s−1 (P<0.05), respectively. The β1-adrenoceptor antagonist CGP 20712A 10 μmol kg−1 (known to block the low-affinity state of β1-adrenoceptors at high doses) inhibited increases in ±dP dt−1max elicited by the highest dose of CGP 12177.The highest doses of CGP 12177 and cyanopindolol increased DBP by about 10 mmHg and MBF by 1.4±0.3 and 0.6±0.3 ml min−1, respectively. The vascular effects of CGP 12177 were not affected by bupranolol and CGP 20712A.In conclusion, activation of the low-affinity state of β1-adrenoceptors by CGP 12177 and cyanopindolol in pithed rats causes a positive inotropic and lusitropic effect. By contrast, the vascular effects of CGP 12177 and cyanopindolol are not mediated by these receptors and have only marginal influence under in vivo conditions.British Journal of Pharmacology (2005) 146, 760–768. doi:10.1038/sj.bjp.0706382; published online 5 September 2005 [ABSTRACT FROM AUTHOR]

We wanted to search for the mechanism(s) responsible for the brief pressor response induced by anandamide in urethane-anaesthetized rats.The anandamide-induced pressor effect was not modified by the antagonists of cannabinoid CB1 and vanilloid TRPV1 receptors, SR 141716A (3 μmol kg−1) and capsazepine (1 μmol kg−1), respectively, by bilateral vagotomy and by pithing. Replacement of urethane by pentobarbitone virtually abolished the pressor effect of anandamide, both in pithed and vagotomized and in ‘intact’ rats (i.e. not treated in this manner).The pressor effect of anandamide was reduced by the nonselective TRPV family inhibitor ruthenium red (3 μmol kg−1) and by the blocker of L-type calcium channels nifedipine (1 μmol kg−1), both in pithed urethane-anaesthetized rats and in ‘intact’ urethane-anaesthetized rats. The nonselective β-adrenoceptor antagonist propranolol (0.1 or 0.3 μmol kg−1) and the nonselective NMDA receptor antagonist MK-801 (1 μmol kg−1) diminished the anandamide-induced vasopressor response in ‘intact’ but not in pithed rats. The inhibitory effect of propranolol in ‘intact’ rats was mimicked by the β2-adrenoceptor antagonist ICI 118551 (1 μmol kg−1), but not by the β1-adrenoceptor antagonist CGP 20712 (1 μmol kg−1).The present study revealed that two mechanisms may be responsible for the anandamide-induced pressor response in urethane-anaesthetized rats. The first involves the central nervous system (probably the medulla oblongata) and is sensitive to propranolol and MK-801. The second, which is located peripherally (most probably in blood vessels), is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca2+-dependent mode of action.British Journal of Pharmacology (2005) 145, 567–575. doi:10.1038/sj.bjp.0706195 Published online 18 April 2005 [ABSTRACT FROM AUTHOR]

Presynaptically localized adrenoceptors occur on a variety of neurones. In particular,α2-adrenoceptors, occurring on neurones of the peripheral and central nervous system, inhibit the release of the respective transmitters whereasβ2-adrenoceptors on some types of postganglionic sympathetic neurones facilitate noradrenaline release. Since only little information is available whether there are also presynapticβ3-adrenoceptors, we examined the effect ofβ3-adrenoceptor agonists on noradrenaline release from the resistance vessels and the hippocampus of the rat and on serotonin and acetylcholine release from the rat hippocampus. In rat hippocampal slices preincubated with3H-noradrenaline,3H-serotonin and3H-choline and superfused in the presence of an inhibitor of the neuronal transporter of the respective neurone, theβ3-adrenoceptor agonist CL 316243 did not affect the electrically evoked tritium overflow. The latter was, however, inhibited by at least 50% by agonists of the respective autoreceptors. CL 316243 and another threeβ3-adrenoceptor agonists (BRL 37344, ZD 2079 and CGP 12177) failed to affect the electrically evoked tritium overflow also in slices preincubated with3H-noradrenaline and superfused in the presence of theα2-adrenoceptor antagonist rauwolscine whereas prostaglandin E2 caused a marked inhibition. In pithed and vagotomized rats, the increase in diastolic blood pressure induced by electrical stimulation of the sympathetic outflow was also not affected by CL 316243 but markedly inhibited by the cannabinoid receptor agonist WIN 55212–2. CL 316243 and WIN 55212–2 were devoid of an effect on the rise in diastolic blood pressure induced by exogenous noradrenaline. In conclusion, our data suggest that the noradrenergic neurones innervating the resistance vessels of the rat and the noradrenergic, serotoninergic and cholinergic neurones of the rat hippocampus are not endowed with presynapticβ3-adrenoceptors. [ABSTRACT FROM AUTHOR]

1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response. [ABSTRACT FROM AUTHOR]

1: Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2: In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1?Hz, 1?ms, 50?V for 10?s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3?nmol?kg-1) increased the diastolic blood pressure (DBP) by about 30?mmHg. Administration of LPS (0.4 and 4?mg?kg-1) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3: The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB1 receptor antagonist SR 141716A (0.1?µmol?kg-1), but not by the CB2 receptor antagonist SR 144528 (3?µmol?kg-1), the vanilloid VR1 receptor antagonist capsazepine (1?µmol?kg-1) or the histamine H3 receptor antagonist clobenpropit (0.1?µmol?kg-1). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4: We conclude that in the initial phase of septic shock, the activation of presynaptic CB1 receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response.British Journal of Pharmacology (2004) 142, 701-708. doi:10.1038/sj.bjp.0705839 [ABSTRACT FROM AUTHOR]

1. We studied whether cannabinoid CB1 receptor gene disruption (to yield CB1-/- mice) affects the electrically evoked tritium overflow from vas deferens and atrial pieces preincubated with [3H]-noradrenaline (NA) ('noradrenaline release') and from cerebral cortex slices preincubated with [3H]-choline ('acetylcholine release'). 2. NA release was higher by 37% in vas deferens from CB1-/- mice than in vas deferens from CB1+/+ mice. The cannabinoid receptor agonist WIN 55,212-2 inhibited, and the CB1 receptor inverse agonist/antagonist SR 141716, increased NA release in vas deferens from CB1+/+ mice without affecting it in vas deferens from CB1-/- mice. 3. Atrial NA release did not differ between CB1+/+ and CB1-/- mice nor did WIN 55,212-2 affect NA release in either strain. 4. Cortical acetylcholine (Ach) release did not differ between CB1+/+ and CB1-/- mice. WIN 55,212-2 inhibited, but SR 141716 did not affect, Ach release in the cortex from CB1+/+ mice. Both drugs did not alter Ach release in the cortex from CB1-/- mice. 5. Tritium content did not differ between CB1+/+ and CB1-/- mice in any preparation. 6. In conclusion, the increase in NA release associated with CB1 receptor deficiency in the vas deferens, which cannot be ascribed to an alteration of tritium content of the preparations, suggests an endogenous tone at the CB1 receptors of CB1+/+ mice in this tissue. Furthermore, the effect of WIN 55,212-2 on NA release in the vas deferens and on cortical Ach release involves CB1 receptors, whereas the involvement of non-CB1-non-CB2 receptors can be excluded. [ABSTRACT FROM AUTHOR]

Examines whether beta3- or atypical beta-adrenoreceptors relax the rat isolated mesenteric artery. Concentration-response curves for cyanopindolol; Effect of removing the endothelium on the vasorelaxant effects of cyanopindolol; Impact of bupranolol on the relaxant effect of cyanopindolol.

1 The cannabinoid CB[SUB1] receptor inverse agonist/antagonist SR 141716 increases acetylcholine release in rodent hippocampus and improves memory in some experimental paradigms. Since drugs like SR 141716 may represent a novel class of cognition-enhancing drugs, we wanted to check whether the function of the CB[SUB1] receptor is preserved during ageing. 2 Hippocampal and striatal slices from 2- to 3- and 24- to 28-month-old C57BL/6J mice were preincubated with [[SUP3]H]-noradrenaline ([[SUP3]H]-NA) and superfused. 3 The cannabinoid receptor agonist WIN 55,212-2 inhibited, and Sr 141716 facilitated, the electrically (3Hz) evoked tritium overflow in hippocampal slices (preincubated with [SUP3]H]-choline) from young and aged mice to the same extent. The evoked overflow per se was less by 33% in slices from aged animals. 4 WIN 55,212-2 and SR 141716 did not affect, but the muscarinic receptor agonist exotremorine inhibited, the evoked (3 Hz) overflow in striatal slices (preincubated with [[SUP3]H]-choline) from young and aged mice to the same extent. The evoked overflow per se t ended to be less in slices from aged animals. 5 The evoked (0.3 Hz) overflow in hippocampal slics (preincubated with [[SUP3]H]-NA) was not affected by WIN 55,212-2 and SR 141716, but was inhibited by histamine (via H[SUB3] receptors) in slices from young mice and, to a somewhat less extent, in slices from aged mice. The evoked overflow per se did not differ between age groups. 6 In conclusion, the function of CB[SUB1] receptor involved in the tonic inhibition of hippocampal acetylcholine release is preserved in aged mice. [ABSTRACT FROM AUTHOR]

The modulation of dopamine release from the guinea-pig retina was studied using maximally effective concentrations of 10 agonists acting on G[sub i]-, G[sub s]- or G[sub q]-proteincoupled receptors (PCRs). Retinal discs were preincubated with [³H]noradrenaline and superfused; tritium overflow was evoked electrically. The following compounds acting on G[sub i]-PCRs reduced the tritium overflow, which represents quasi-physiological dopamine release under the experimental conditions of our study: the dopamine and α[sub 2]-adrenoceptor agonist B-HT 920 by 95%, the muscarinic agonist oxotremorine by 96%, melatonin by 94%, the cannabinoid agonist WIN 55,212-2 by 71% and histamine by 66%. Tritium overflow was not affected by serotonin or by agonists acting on G[sub s]-PCRs (ACTH[sub 1-24] and the β-adrenoceptor agonist procaterol) and G[sub q]-PCRs (angiotensin II and bradykinin). The effects of B-HT 920, oxotremorine and melatonin were studied in more detail using appropriate antagonists. The inhibitory effect of a submaximally active concentration of B-HT 920 was counteracted by the dopamine D[sub 2/3] antagonist haloperidol but not affected by the α[sub 2]-adrenoceptor antagonist phentolamine. The muscarinic antagonist atropine shifted to the right the concentration-response curve of oxotremorine (pA[sub 2] 8.7) and the melatonin MT[sub 2] antagonist 4-P-PDOT produced a rightward shift of the concentration-response curve of melatonin (pA[sub 2] 10.6). Melatonin was also studied in superfused brain slices (from the guinea-pig) preincubated with [³H]noradrenaline. The electrically evoked tritium overflow in cerebrocortical, hippocampal and hypothalamic slices (representing quasi-physiological noradrenaline release) and in striatal slices (representing quasiphysiological dopamine release) was not affected by melatonin at a concentration that causes the maximum effect in retinal discs. In conclusion, dopamine release in the guinea-pig retina... [ABSTRACT FROM AUTHOR]

We have previously shown that cannabinoid CB 1 and CB 2 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 β 1 -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.)