Inhibitory Effect of Frusemide on Sympathetic Vasoconstrictor Responses: Dependence on a Renal Hormone and the Vascular Endothelium

Abstract

1. Mesenteric perfusion pressure was measured in the in situ mesentery perfused at a constant rate with blood drawn from the carotid artery of the same anaesthetized rat. Increases in perfusion pressure were produced by mesenteric periarterial electrical stimulation. These responses were measured before and 30 min after the administration of frusemide (5 mg/kg i.v.) to the rat. Loss of volume due to the frusemide-induced diuresis was prevented by a urinary bladder-venous extracorporeal circuit. 2. Responses to stimulation were reduced after frusemide and were not increased by the subsequent administration of indomethacin (2 mg/kg i.v.). This indomethacin treatment rapidly and completely prevented the fall in blood pressure produced by i.v. arachidonic acid. 3. In rats where the renal papilla had been ablated by treatment with bromoethylamine (200 mg/kg i.p.) 5 weeks previously, frusemide administration did not reduce sympathetic responses in the in situ blood-perfused mesentery. 4. A segment of rat tail artery, cannulated at both ends was mounted in an organ bath and perfused with blood withdrawn from, and returned to, an anaesthetized rat. Increases in perfusion pressure produced by periarterial electrical stimulation of this ex vivo blood perfused tail artery segment were reduced by frusemide administration to the anaesthetized rat. 5. When the endothelium was removed from the tail artery segment, frusemide administration did not lead to any reduction of vasoconstrictor responses. 6. Frusemide may lead to the release of a non-prostanoid hormone from the renal medulla which results in inhibition of peripheral sympathetic vasoconstrictor responses. The release of the hormone may involve intra-renal prostaglandins. The final antivasoconstrictor effect requires an intact vascular endothelium.

Mechanisms behind the Relaxing Effect of Furosemide on the Isolated Rabbit Ear Artery

“…The relaxation of vascular smooth muscle observed in vivo after the intravenous administration of furosemide seems to be dependent on the release of vasoactive compounds from the kidney. There is evidence indicating that (1) lack of renal function (Gerkens et al 1987a;Gerkens & Smith 1984);…”

“…(2) administration of a prostaglandin synthesis inhibitor (Johnston et al 1983) and (3) chemical destruction of the renal medulla (Gerkens 1987;Gerkens et al 1987b) may abolish the vascular response to furosemide. The exact nature of the compounds which are believed to mediate this indirect effect of furosemide and the mechanism by which they act have not been clarified.…”

“…Since the endothelium derived relaxing factor (EDRF) was first described, a lot of substances have been recognized as endothelium-dependent vasodilators (Furchgott 1984). Gerkens (1987) showed in an ex vivo experiment with a blood perfused rat tail artery that the effect of furosemide on the response to periarterial electrical stimulation was endothelium-dependent. But there is no report on the role of the endothelium in the vasorelaxant effect of furosemide in isolated vessel segments.…”

Interactions Between Furosemide and the Renal Sympathetic Nerves

“…Furthermore, this response was abolished after removal of the endothelium from the tail artery segment (Gerkens 1987;Gerkens et al 1988). Since prostaglandin-mediated vasodilation is endothelium-independent, Gerkens and coworked formed the hypothesis that furosemide stimulates renal prostaglandin synthesis which in turn causes release of a renomedullary antihypertensive hormone to the circulation (Gerkens 1987). The final renomedullary hormone is not yet defined, but circumstantial evidence suggest that a renomedullary lipid (medullipin I) is released from the renal medulla in response to increased renal perfusion pressure, and that the active hepatic metabolite (medullipin 11) has vasodilatory, sympathoinhibitory, and diuretic-natriuretic actions (Muirhead et al 1983;Karlstrom et al 1988Karlstrom et al & 1989Christy et al 1993;Thomas et al 1994).…”

“…injection of furosemide in the donor rat. Furthermore, this response was abolished after removal of the endothelium from the tail artery segment (Gerkens 1987;Gerkens et al 1988). Since prostaglandin-mediated vasodilation is endothelium-independent, Gerkens and coworked formed the hypothesis that furosemide stimulates renal prostaglandin synthesis which in turn causes release of a renomedullary antihypertensive hormone to the circulation (Gerkens 1987).…”