Studies of the role of membrane lipid order in the effects of delta 9- tetrahydrocannabinol on adenylate cyclase activation in heart

CJ Hillard, JJ Pounds, DR Boyer and AS Bloom

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.

The studies in this report were carried out to investigate the effects of delta 9-tetrahydrocannabinol (delta 9-THC) on cardiac membrane adenylate cyclase activity and to determine the role of changes in membrane lipid order in these effects. delta 9-THC and its psychoactive metabolite, 11-OH-delta 9-THC, increased isoproterenol (ISO) stimulation of adenylate cyclase in rat cardiac ventricular membranes. Cannabidiol, cannabinol and (+)-delta 9-THC were all without effect, indicating that this effect of delta 9-THC is stereoselective and specific for cannabinoids with psychoactive potency. delta 9-THC also increased glucagon stimulation of adenylate cyclase. The enhancement of both ISO and glucagon-stimulated adenylate cyclase was due to an increase in the Vmax of these agonists with no significant change in Kact. delta 9-THC did not affect basal adenylate cyclase activity or the activation of the enzyme by forskolin, guanine nucleotides or fluoride ion. Those cannabinoids which increased ISO-stimulated adenylate cyclase activity also decreased the break temperature of the Arrhenius plot; evidence that the effects of delta 9-THC involve changes in membrane phospholipid order. The effects of the cannabinoids on cardiac membrane phospholipid order were investigated directly using diphenylhexatriene fluorescence polarization. delta 9-THC and 11-OH- delta 9-THC alone decreased the break temperature of the diphenylhexatriene temperature profile, i.e., decreased the temperature of the lipid phase separation. This effect of delta 9-THC was stereoselective.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 252, Issue 3, pp. 1075-1082, 03/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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