Effects of thromboxane synthase inhibition on vascular responsiveness in the in vivo rat mesentery

Abstract

The purpose of this investigation was to determine the effects of thromboxane synthase inhibition on vascular responsiveness. To achieve this goal, the effects of thromboxane synthase inhibitors on mesenteric vascular responses to sympathetic nerve stimulation, norepinephrine, and angiotensin II were determined in vivo. In normotensive rats, chronic treatment with the thromboxane synthase inhibitor, UK38,485 (100 mg/kg X d X 7 d), attenuated vascular responses to nerve stimulation and angiotensin II, but not to norepinephrine. Indomethacin treatment (5 mg/kg X three doses) did not attenuate vascular responses, but did prevent chronic UK38,485 administration from attenuating vascular reactivity. A single dose of UK38,485 (100 mg/kg) did not modify vascular responses to nerve stimulation or angiotensin II, even though platelet thromboxane synthase was inhibited completely. In spontaneously hypertensive rats, chronic administration (100 mg/kg X d X 7 d) of either UK38,485, OKY1581, or U-63557A (three structurally distinct thromboxane synthase inhibitors) attenuated vascular responses to nerve stimulation and angiotensin II. Only U-63557A suppressed responses to norepinephrine. Chronic treatment with UK38,485 or U-63557A did not influence vascular reactivity in hypertensive rats treated with indomethacin. Also, chronic administration of lower doses of UK38,485 or U-63557A (30 mg/kg X d X 7 d) did not affect vascular responsiveness in hypertensive rats, despite complete blockade of platelet thromboxane synthase. These data indicate that chronic administration of high doses of thromboxane synthase inhibitors attenuates vascular responses to sympathetic nerve stimulation and angiotensin II, but not usually to norepinephrine. This action may be mediated by endoperoxide shunting within the blood vessel wall.