Abstract
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.
Footnotes
-
Send reprint requests to: Dr. G. Kunos, Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613.
-
↵1 This work was supported by NIH Grants HL-49938 to G.K., DA-09789 to B.R.M. and AHA Virginia Affiliate Grant VA-96-GS7 to K.V. Support for K.D.L. was by NIH training Grant DA07027.
- Abbreviations:
- THC
- Δ9-tetrahydrocannabinol
- CP-55
- 940, (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol
- HU-210
- (-)-11-OH-Δ9-THC dimethylheptyl
- HU-211
- (+)-11-OH-Δ9-THC dimethylheptyl
- WIN-55212-2
- O-502, {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone} JWH-015, (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cyclohexan-1-ol
- O-502
- 4′-(R)-OH-diadduct-Δ9-THC
- O-522
- 4′-(S)-OH-diadduct-Δ9-THC
- SR141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl
- ABN-CBD
- abnormal-cannabidiol
- MAP
- mean arterial blood pressure
- HR
- heart rate
- bpm
- beats per minute
- ED50
- agonist dose producing half-maximal effect, AD50, antagonist dose causing 50% inhibition of agonist response
- Received October 3, 1996.
- Accepted February 19, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|