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The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ(9) -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 Δ(9) -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 CB(1) and CB(2) 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) CB(1) 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.

The Bezold-Jarisch reflex is characterized by a sudden bradycardia associated with hypotension induced by the activation of the vanilloid TRPV1 and serotonin 5-HT(3) receptors. This reflex is associated with several health conditions, including myocardial infarction. The aim of the present study was to elucidate the influence of acute experimental myocardial ischemia on the reflex bradycardia induced by anandamide and phenylbiguanide, agonists of the TRPV1 and 5-HT(3) receptors, respectively. In urethane-anesthetized rats, the rapid iv injection of anandamide (0.6 μmol/kg) or phenylbiguanide (0.03 μmol/kg) decreased heart rate (HR) by about 7-10% of the basal values. Myocardial ischemia (MI) was induced by ligation of the left anterior coronary artery. The agonists were injected 5 min before MI (S(1)) and 10, 20 and 30 min thereafter (S(2)-S(4)). MI potentiated the anandamide-induced reflex bradycardia by approximately 105% at S(2) and 70% at S(3) but had no effect at S(4). This amplificatory effect of MI was virtually abolished by the TRPV1 receptor antagonist capsazepine (1 μmol/kg) and was not modified by the cannabinoid CB(1) receptor antagonist rimonabant (0.1 μmol/kg). MI also amplified the reflex bradycardia elicited by phenylbiguanide by approximately 110, 60 and 90% (S(2), S(3) and S(4), respectively), and this effect was sensitive to the 5-HT(3) receptor antagonist ondansetron (3 μmol/kg). In conclusion, our results suggest that acute myocardial ischemia augments the Bezold-Jarisch reflex induced via activation of TRPV1 and 5-HT(3) receptors located on sensory vagal nerves in the heart.

1 Activation by CGP 12177 and cyanopindolol of the human and rat low-affinity state of beta(1)-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(-1)(max)) and decline (-dP dt(-1)(max)), the diastolic blood pressure (DBP) and the mesenteric blood flow (MBF) in pithed and vagotomized rats. 2 CGP 12177 (0.1-100 nmol kg(-1)) and cyanopindolol (1-1000 nmol kg(-1)) dose-dependently enhanced all cardiac parameters. The nonselective beta-adrenoceptor antagonist bupranolol 10 micromol 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 (P0.05), +dP dt(-1)(max) from 5287+/-290 to 2439+/-296 mmHg s(-1) (P0.001) and -dP dt(-1)(max) from -3836+/-301 to -2187+/-443 mmHg s(-1) (P0.05), respectively. The beta(1)-adrenoceptor antagonist CGP 20712A 10 micromol kg(-1) (known to block the low-affinity state of beta(1)-adrenoceptors at high doses) inhibited increases in +/-dP dt(-1)(max) elicited by the highest dose of CGP 12177. 3 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. 4 In conclusion, activation of the low-affinity state of beta(1)-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.

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.

1. Atypical beta-adrenoceptors resistant to propranolol, but blocked by bupranolol, increase contractile force and/or frequency of the heart in humans and rats. We compared the potencies of the enantiomers of bupranolol and examined the possible effects of seven bupranolol analogues including bevantolol (BEV) at this receptor in pithed and vagotomized rats. 2. CGP 12177, an agonist of the atypical beta-adrenoceptor, increased heart rate dose-dependently. Its dose-response curve was shifted to the right by S-(-)-bupranolol 10 micro mol kg(-1) by a factor of 8.4, but not affected by the same dose of R-(+)-bupranolol. 3. Desmethylbupranolol and compounds BK-21, BK-22, BK-23 and BK-25 also increased heart rate dose-dependently. The beta(1)-adrenoceptor antagonist CGP 20712 given in combination with the beta(2)-adrenoceptor antagonist ICI 118,551 (0.1 micro mol kg(-1) each) reduced the positive chronotropic action of the five bupranolol analogues without affecting that of CGP 12177. The potencies of the bupranolol analogues to increase heart rate were correlated (r=0.91, P0.05) with their affinities for beta(1)-adrenoceptor binding sites in rat brain cortex membranes labelled with [(3)H]CGP 12177 (in the presence of ICI 118,551). 4. BK-26 and BEV, 10 micro mol kg(-1) each, had only minor effects on heart rate by themselves and did not antagonize the effect of CGP 12177. However, at 1 micro mol kg(-1), they antagonized the increase in heart rate elicited by the beta(1)-adrenoceptor agonist prenalterol. 5. In conclusion, bupranolol is a stereoselective antagonist at the atypical cardiostimulant beta-adrenoceptor. The effects of the bupranolol analogues are related to the activation or blockade of beta(1)-adrenoceptors, but not of atypical beta-adrenoceptors.

We determined the affinities of eight novel histamine H(3)-receptor ligands (ethers and carbamates) for H(3)-receptor binding sites and their agonistic/antagonistic effects in two functional H(3)-receptor models. The compounds differ from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n-pentyl, 3-methylbutyl and 3,3-dimethylbutyl, respectively. The compounds monophasically inhibited [(3)H]-N(alpha)-methylhistamine binding to mouse cerebral cortex membranes (pK(i) 7.51 - 9.53). The concentration-response curve of histamine for its inhibitory effect on the electrically evoked [(3)H]-noradrenaline overflow from mouse cortex slices was shifted to the right by these compounds (apparent pA(2) 6.61 - 8.00). Only FUB 373 and 407 inhibited the evoked overflow by themselves (intrinsic activities 0.3 and 0.4); these effects were counteracted by the H(3)-receptor antagonist clobenpropit. [(35)S]-GTPgammaS binding to mouse cortex membranes was stimulated by the H(3)-receptor agonist (R)-alpha-methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [(35)S]-GTPgammaS binding (intrinsic activities 0.6 and 0.4). In conclusion, the novel compounds are partial H(3)-receptor agonists (FUB 373 and 407) or H(3)-receptor antagonists; comparison with FUB 335 shows that the transition from antagonist to agonist is caused by a slight structural change. A protonated N atom in the side chain is not necessary for agonism at H(3) receptors, proposing a receptor-ligand interaction different from that of classical agonists.