Potentiation of responses to sympathetic nerve stimulation and vasoconstrictor agents by SK&F 103829 in the feline mesenteric circulation.

Abstract

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.

• Authors: E M Taylor, A J Kaumann
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 111 Issue 1 Pg. 264-70 (Jan 1994) ISSN: 0007-1188 [Print] England
• PMID: 8012704 (Publication Type: Journal Article)

Chemical References

• Benzazepines
• Receptors, Serotonin
• Serotonin Receptor Agonists
• Vasoconstrictor Agents
• SK&F 103829
• Ketanserin

Topics

• Animals
• Benzazepines (pharmacology)
• Blood Pressure (drug effects)
• Cats
• Cattle
• Female
• In Vitro Techniques
• Intestines (blood supply, drug effects)
• Ketanserin (pharmacology)
• Male
• Mesenteric Arteries (drug effects, innervation, physiology)
• Muscle Contraction (drug effects)
• Muscle, Smooth, Vascular (drug effects)
• Rats
• Receptors, Serotonin (drug effects, metabolism)
• Regional Blood Flow (drug effects)
• Serotonin Receptor Agonists (pharmacology)
• Sympathetic Nervous System (physiology)
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)