Cannabinoids cause central sympathoexcitation and bradycardia in rabbits.
Systemically administered cannabinoids elicit marked cardiovascular effects, and the role of the central and the peripheral nervous system in these effects is not clarified. The aim of this study was to characterize the actions of cannabinoids on cardiovascular regulatory centers in conscious rabbits. A catheter for administration of drugs into the cisterna cerebellomedullaris and an electrode for recording renal sympathetic nerve activity were implanted under halothane anesthesia. Experiments were carried out later in conscious animals. Two cannabinoid receptor agonists were injected intracisternally: the aminoalkylindole WIN55212-2 (0.1, 1, and 10 microg kg(-1)) and the bicyclic Delta(9)-tetrahydrocannabinol analog CP55940 (0.1, 1, and 10 microg kg(-1)). WIN55212-2 and CP55940 dose dependently increased renal sympathetic nerve activity and the plasma noradrenaline concentration and also lowered the heart rate. The highest doses of WIN55212-2 and CP55940 increased blood pressure. In contrast, intracisternal injection of WIN55212-3 (0.1, 1, and 10 microg kg(-1)), an enantiomer of WIN55212-2 with very low affinity for cannabinoid binding sites, had no effects. The CB(1) cannabinoid receptor antagonist SR141716A (0.5 mg kg(-1), i.v. ) attenuated the effects of intracisternally administered WIN55212-2 (0.1, 1, and 10 microg kg(-1)). The results indicate that cannabinoids, acting directly on cardiovascular regulatory centers, elicit sympathoactivation and bradycardia. These effects were likely mediated by CB(1) cannabinoid receptors, because they were elicited by two cannabinoid agonists belonging to different chemical classes (WIN55212-2 and CP55940), but not by the inactive enantiomer WIN55212-3, and because they were attenuated by the CB(1) cannabinoid receptor antagonist SR141716A.
Niederhoffer
N
N
Institut für Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg, Germany.
Szabo
B
B
D000818:Animals; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular; D007668:Kidney / Q000294:innervation; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000097:blood; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D013237:Stereoisomerism; D013564:Sympathetic Nervous System / Q000187:drug effects*
D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant; D009638:Norepinephrine