Studies of the role of membrane lipid order in the effects of delta 9-tetrahydrocannabinol on adenylate cyclase activation in heart.
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)
Hillard
C J
CJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Pounds
J J
JJ
Boyer
D R
DR
Bloom
A S
AS
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism* / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D008563:Membrane Lipids; D005576:Colforsin; D013759:Dronabinol; D000262:Adenylyl Cyclases