Differences in regional vascular sensitivity to endothelin‐1 between spontaneously hypertensive and normotensive Wistar‐Kyoto rats

Abstract

1 The systemic and regional haemodynamic effects of porcine endothelin-1 (endothelin) have been measured in anaesthetized spontaneously hypertensive (SH) rats rendered areflexic by ganglion blockade; comparisons were made with age-matched Wistar-Kyoto (WKY) control animals. 2 In both SH and WKY rats endothelin (0.1-1 nmol kg-1 i.v.) elicited an initial, short-lived (<2 min), fall in blood pressure which was associated with substantial increases in hindquarter and carotid vascular conductances. Both the blood pressure falls and the peripheral vasodilator responses were greater in SH than in WKY rats. 3 The initial depressor effects of endothelin were followed by marked and sustained increases in blood pressure associated with constriction in carotid, hindquarter, renal and mesenteric vascular beds. Vasoconstrictor responses were quantitatively similar in the two rat strains. 4 Pretreatment with indomethacin (5mgkg-t i.p. or i.v.) did not alter the responses to endothelin, 1 nmol kg-1, in SH rats. 5 The regional haemodynamic effects of intravenously administered acetylcholine (0.01-1 pg kg-), nitroprusside (0.3-lOpgkg-') and angiotensin II (0.01-0.1 ugkg-1) were similar in SH and WKY rats. 6 Endothelin (10-10-3 x 10 -8M) contracted aortic rings from both SH rats and WKY control animals. Removal of the endothelium enhanced significantly the sensitivity of tissues from both WKY and SH rats to endothelin; the increase in sensitivity was greater in tissues from SH than WKY rats. 7 The results demonstrate qualitative similarities in the complex haemodynamic effects of endothelin in SH rats and WKY control animals. However, the SH rats display substantially greater vasodilator responses to endothelin than WKY. Eicosanoid generation is not the mechanism of the vasodilator action of endothelin in SH rats under the conditions of our experiments.

Evidence from receptor antagonists of an important role for ETB receptor‐mediated vasoconstrictor effects of endothelin‐1 in the rat kidney

“…However, indomethacin was ineffective against higher concentrations of SX6c and did not significantly alter the response to ET-1. Consistent with an earlier report (Wright & Fozard, 1990), indomethacin had no effect on haemodynamic and renal responses to ET-1 or SX6c in vivo.…”

Role of endothelium in endothelin-evoked contractions in the rat aorta.

“…6 ' 7 Because this effect is more pronounced in arteries from hypertensive than those from normotensive animals, all the experiments of the present study were performed in the presence of nitro-L-arginine, a noncompetitive inhibitor of nitric oxide synthase. 13 Inhibitors of this enzyme also potentiate endotheliumdependent contractions in SHR aorta, most likely by preventing a chemical interaction between nitric oxide and endothelium-derived contracting factor.…”

Is endothelin involved in the pathogenesis of hypertension?

“…75 - 81 The release of atrial natriuretic peptides evoked by endothelin is larger in atria from SHR than WKY rats, although this probably does not contribute to the depressor effect of endothelin in the hypertensive strain. 81 - 82 Judging from the endothelium-dependent relaxations that they cause in the aorta of the SHR compared with the WKY rat, the ability to release EDRF in response to ET-1 and ET-3 is certainly not curtailed in the SHR. 38 A greater release of EDRF would help to explain why removal of the endothelium causes a greater potentiation of the contractile response to endothelin in the aorta of the SHR than that of the WKY rat, 38 -83 although this phenomenon is not observed in all types of spontaneous hypertension.…”