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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.

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.

Manfred Göthert, who had served Naunyn-Schmiedeberg’s Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca2+ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT3 receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT3 receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today’s pharmacology.

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.

Background LY393558 is a combined antagonist of serotonin (5-HT) 5-HT1B 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.

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.

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.

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.

Although β1-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 (KDs). 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 > [KDs], 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.

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 β1-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.

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.

Muscarinic M2 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 with 3H-choline. 3H-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.

The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. We discuss pleiotropic effects of cannabinoids on the cardiovascular system mediated via numerous neuronal and non-neuronal mechanisms both in normotension and in hypertension. The final results are dependent on the model of hypertension, age, sex, the cannabinoid ligands used or the action via endocannabinoid metabolites. More experimental and clinical studies are needed to clarify the role of endocannabinoids in hypertension, not only in the search for new therapeutic strategies but also in the context of cardiovascular effects of cannabinoids and the steadily increasing legalization of cannabis use for recreational and medical purposes. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Presynaptic receptors are sites at which transmitters, locally formed mediators or hormones inhibit or facilitate the release of a given transmitter from its axon terminals. The interest in the identification of presynaptic receptors has faded in recent years and it may therefore be justified to give an overview of their occurrence in the autonomic and central nervous system; this review will focus on presynaptic receptors in human tissues. Autoreceptors are presynaptic receptors at which a given transmitter restrains its further release, though in some instances may also increase its release. Inhibitory autoreceptors represent a typical example of a negative feedback; they are tonically activated by the respective endogenous transmitter and/or are constitutively active. Autoreceptors also play a role under pathophysiological conditions, e.g. by limiting the massive noradrenaline release occurring during congestive heart failure. They can be used for therapeutic purposes; e.g., the α2-adrenoceptor antagonist mirtazapine is used as an antidepressant and the inverse histamine H3 receptor agonist pitolisant has been marketed as a new drug for the treatment of narcolepsy in 2016. Heteroreceptors are presynaptic receptors at which transmitters from adjacent neurons, locally formed mediators (e.g. endocannabinoids) or hormones (e.g. adrenaline) can inhibit or facilitate transmitter release; they may be subject to an endogenous tone. The constipating effect of the sympathetic nervous system or of the antihypertensive drug clonidine is related to the activation of inhibitory α2-adrenoceptors on postganglionic parasympathetic neurons. Part of the stimulating effect of adrenaline on the sympathetic nervous system during stress is related to its facilitatory effect on noradrenaline release via β2-adrenoceptors.

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-HT1B, 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.

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-HT3 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.

Muscarinic M

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 (0.75 Hz, 1 ms, 50 V, 5 impulses) of the preganglionic sympathetic nerve fibres innervating the blood vessels more strongly increased DBP in normotensive than in DOCA–salt rats. Phenylephrine (0.01 μmol/kg) induced similar increases in DBP in both groups. The cannabinoid receptor agonist CP55940 (0.01–1 μmol/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 (3 μmol/kg). AM251 enhanced the neurogenic vasopressor response during S4 by itself in hypertensive rats only. URB597 (3 μmol/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.

The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. We discuss pleiotropic effects of cannabinoids on the cardiovascular system mediated via numerous neuronal and non-neuronal mechanisms both in normotension and in hypertension. The final results are dependent on the model of hypertension, age, sex, the cannabinoid ligands used or the action via endocannabinoid metabolites. More experimental and clinical studies are needed to clarify the role of endocannabinoids in hypertension, not only in the search for new therapeutic strategies but also in the context of cardiovascular effects of cannabinoids and the steadily increasing legalization of cannabis use for recreational and medical purposes. LINKED ARTICLES: This article is part of a themed section on 8

The G

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 M2-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.

The Gi/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.

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 3H-noradrenaline and hippocampal slices with 3H-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’.