5-Hydroxytryptamine2 receptors coupled to phospholipase C in rat aorta: modulation of phosphoinositide turnover by phorbol ester.
In rat aorta, 5-hydroxytryptamine (5-HT) stimulated phosphoinositide (PI) turnover and contraction (EC50 = 10 +/- 3 microM); these two responses were highly correlated (r = 0.95; P less than .01). We have characterized the inhibitory potency of a variety of 5-HT-antagonists against the stimulation of PI turnover elicited by 5-HT. Classic 5-HT2 antagonists mianserin, ketanserin, metergoline and pizotifen were found to inhibit this response in the low nanomolar range; amitryptiline and haloperidol were 10- to 20-fold less potent. The alpha-1 receptor antagonist, prazosin, was inactive in micromolar concentrations. The potency of the 5-HT2 antagonists was correlated with their ability to displace [3H] ketanserin binding from rat frontal cortex membranes (r = 0.90; P less than .05). The tumor promoter phorbol dibutyrate was found to inhibit 5-HT-stimulated PI turnover at low nanomolar concentrations whereas the biologically inactive substance 4-alpha-phorbol was ineffective. Pretreatment of rat aorta with phorbol dibutyrate at concentrations that inhibited 5-HT-induced PI turnover also attenuated the aortic contraction induced by 5-HT in the presence of a calcium channel blocker nitrendipine. Our results suggest that phorbol esters may desensitize 5-HT2-receptor-mediated PI turnover and contraction of rat aorta, possibly via an activation of protein kinase C.
D000818:Animals; D001013:Aorta, Thoracic; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D010738:Type C Phospholipases