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-HT1-like receptors in dog isolated saphenous vein. 2. In the presence of the 5-HT2 receptor antagonist, ritanserin (0.1 microM), concentration-effect curves (10 nM-300 microM) 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 microM) 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 microM) 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 extracellular calcium and were markedly inhibited, but not abolished, by the calcium channel blocker, verapamil (1-30 microM). In contrast, contractions evoked by high concentrations of 5-HT were markedly less sensitive to removal of extracellular calcium or to verapamil. 4. 5-HT and sumatriptan also inhibited (to a maximum of about 50%) prostaglandin E2 (PGE2, 5 microM)-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 alpha 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 microM).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.
Sumner
M J
MJ
Pharmacology Division, Glaxo Group Research Ltd., Ware, Hertfordshire.
Feniuk
W
W
McCormick
J D
JD
Humphrey
P P
PP
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects / Q000201:enzymology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D013449:Sulfonamides / Q000494:pharmacology; D018170:Sumatriptan; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D005576:Colforsin; D012701:Serotonin; D018170:Sumatriptan; D000242:Cyclic AMP; D015232:Dinoprostone; D002118:Calcium