Potentiation of responses to sympathetic nerve stimulation and vasoconstrictor agents by SK&F 103829 in the feline mesenteric circulation.
1. The amplification of vasoconstrictor effects of several agonists and sympathetic nerve stimulation, caused by 5-HT2 receptor activation, was studied in the autoperfused mesenteric circulation of anaesthetized cats. To produce long lasting and selective 5-HT2 receptor stimulation we used SK&F 103829 (2,3,4,5 tetrahydro-8[methyl-sulphonyl]-1H3-benzazepin-7-ol methensulphonate). We assessed that SK&F 103829 was a strong contractile partial agonist in isolated preparations of rat tail artery and calf pulmonary artery. 2. The intrinsic activity of SK&F 103829 with respect to 5-hydroxytryptamine (5-HT) was 0.8 in rat tail artery and 0.6 in calf pulmonary artery. SK&F 103829-induced contractile responses were surmountably antagonized by ketanserin with a potency expected from its affinity for 5-HT2 receptors. SK&F 103829 surmountably antagonized the effects of 5-HT in rat tail artery with a pKp of 5.8. 3. Concentrations of SK&F 103829 causing greater than threshold constrictions enhanced vasoconstrictor responses of sympathetic nerve stimulation, noradrenaline, angiotensin II, methoxamine and alpha, beta-methylene ATP in the mesenteric arterial bed. Increases in mesenteric arterial pressure by noradrenaline, observed in the presence of prazosin, were also potentiated by SK&F 103829. 4. Ketanserin prevented both the constrictor effect of SK&F 103829 and the SK&F 103829-evoked potentiation of the responses to noradrenaline and angiotensin II in the mesenteric arterial bed. Ketanserin, however, failed to abolish (once established) the SK&F 103829-evoked potentiation of the constrictor effects caused by both noradrenaline and angiotensin II. 5. Short lasting constrictor effects of 5-HT were reversed to dilator effects by SK&F 103829 in both the mesenteric arterial and venous bed, thereby revealing the existence of vasodilator 5-HT receptors.6. The main finding is consistent with a sensitization of the mesenteric arterial bed to vasoconstrictor responses mediated through alpha 1- and alpha2-adrenoceptors, angiotensin II receptors and purinoceptors by SK&F 103829-evoked activation of 5-HT2 receptors. This property, together with the direct constrictor effect of the mesenteric arterial bed suggest that SK&F 103829 can reduce portal venous flow thereby being a useful therapeutic principle for the treatment of portal hypertension.
SmithKline Beecham Pharmaceuticals, Welwyn, Herts.
E M
EM
Taylor
A J
AJ
Kaumann
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D002417:Cattle; D005260:Female; D066298:In Vitro Techniques; D007422:Intestines / Q000098:blood supply / Q000187:drug effects; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001552:Benzazepines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; C078977:SK&F 103829; D007650:Ketanserin