STUDIES ON THE MECHANISM OF 5-HT1 RECEPTOR-INDUCED SMOOTH-MUSCLE CONTRACTION IN DOG SAPHENOUS-VEIN

1 We have investigated the mechanism of smooth muscle contraction evoked by activation of 5-HT 1-like receptors in dog isolated saphenous vein. 2 In the presence of the 5-HT2 receptor antagonist, ritanserin (0.1-mu-M), concentration-effect curves (10 nM-300-mu-M) for 5-hydroxytryptamine (5-HT)-induced smooth muscle contraction were biphasic. This could be attributed to a direct action on 5-HT1 -like receptors at low concentrations of 5-HT (10 nM-10-mu-M) and an indirect (through the release of noradrenaline from sympathetic neurones) activation of postjunctional alpha-adrenoceptors at higher 5-HT concentrations. In contrast, concentration-effect curves (100 nM-100-mu-M) for sumatriptan-induced contractions were not biphasic, and were due solely to activation of 5-HT1 -like receptors. 3 Smooth muscle contractions evoked either by low concentrations of 5-HT or by sumatriptan were abolished by removal of extracelluar calcium and were markedly inhibited, but not abolished, by the calcium channel blocker, verapamil (1-30-mu-M). In contrast, contractions evoked by high concentrations of 5-HT were markedly less sensitive to removal of extracellular calcium or to verapmil. 4 5-HT and sumatriptan also inhibted (to a maximum of about 50%) prostaglandin E2 (PGE2, 5-mu-M)-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. This effect was mimicked by the alpha(2)-adrenoceptor agonist, azepexole (B-HT933) but not by the alpah(1)-adrenoceptor agonist, methoxamine. 5 In contrast to mediation of smooth muscle contraction, the 5-HT1 -like receptor-mediated inhibition of PGE2-stimulated cyclic AMP formation evoked by 5-HT or sumatriptan was not attenuated by removal of extracellular calcium or by verapamil (1-mu-M). 6 A directly-acting inhibitor of adenylyl cyclase, 2',3'-dideoxyadenosine (1 mM) inhibited PGE2-stimulated cyclic AMP formation but did not produce smooth muscle contraction. 7 These results suggest that contractile responses of dog isolated saphenous vein arising through activation of 5-HT1 -like receptors are associated with both an influx of extracellular calcium ions (to a large extent via voltage-dependent channels) and an inhibition of adenylyl cyclase. However, although these two responses are coupled to the same receptor, they appear to be independent.