PT  - JOURNAL ARTICLE
AU  - Kristy D. Lake
AU  - David R. Compton
AU  - Karoly Varga
AU  - Billy R. Martin
AU  - George Kunos
TI  - Cannabinoid-Induced Hypotension and Bradycardia in Rats Is Mediated by CB<sub>1</sub>-Like Cannabinoid Receptors
DP  - 1997 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1030--1037
VI  - 281
IP  - 3
4099  - http://jpet.aspetjournals.org/content/281/3/1030.short
4100  - http://jpet.aspetjournals.org/content/281/3/1030.full
SO  - J Pharmacol Exp Ther1997 Jun 01; 281
AB  - Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and Δ9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-Δ9-THC dimethylheptyl (+)-11-OH-Δ9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-Δ9-THC dimethylheptyl ≥ (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol > THC > anandamide ≥ (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-Δ9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear. The American Society for Pharmacology and Experimental Therapeutics