Captopril prevents chronic hypertension produced by infusion of endothelin-1 in rats.

Abstract

Endothelin-1 (ET-1), a potent vasoconstrictor peptide synthesized by the vascular smooth muscle endothelium, has been previously shown to produce a sustained, salt-sensitive elevation in mean arterial pressure when chronically infused over a 7-day period into male Sprague-Dawley rats. In addition to other physiological actions, ET-1 has been shown to have potent effects on various renal functions, including renin production. Activation of the renin-angiotensin system, therefore, may contribute to the pressor response induced by ET-1. In this investigation, captopril ([2S]-l-[3-mercapto-2-methylpropionyl]-Lproline), a sulfhydryl-containing angiotensin I converting enzyme inhibitor, was chronically administered to endothelin-infused rats to elucidate the role of the renin-angiotensin system in this animal model of hypertension. Rats were catheterized, housed in metabolic cages, and maintained on a fixed 6.0 meq • day" 1 sodium intake throughout the experiment, with daily measurements taken of mean arterial pressure, heart rate, water intake, urine output, and urinary sodium and potassium excretions. Infusion of ET-1 alone at a rate of 5.0 pmol • kg" 1 • min" 1 for 7 days was associated with a significant and sustained increase in mean arterial pressure; concomitant chronic administration of captopril in another group of rats at a rate of 1.0 mg • kg" 1 • hr~' prevented the ET-1-induced hypertension. In an additional study, however, increases in plasma angiotensin II concentration were not observed in rats administered ET-1 alone at 5.0 pmol • kg" 1 • min~'. These results indicate that endothelin-induced hypertension may involve stimulation of the renin-angiotensin system but not an increase in circulating angiotensin II concentration. (Hypertension 1992;19:676-680) KEY WORDS • endothelin • captopril • renin-angiotensin system • chronic hypertension • rat studies S ince the isolation of the endothelial-produced, vasoactive peptide endothelin in 1988, extensive investigations into its biochemical and physiological nature have been performed. Presently, although the biochemical nature of this family of peptides has been extensively described in the available literature, 1 much of the physiology of the endothelins remains to be elucidated. Likewise, the relevance of circulating or endothelial-derived endothelin in cardiovascular physiology or pathophysiology has not been firmly established. Considerable evidence exists, however, that suggests a possible pathophysiological role for circulating endothelin.2 For example, recent reports implicate the endothelin-1 (ET-1) isoform in several diseases, including cerebral ischemia, 3 myocardial infarction, 4 congestive heart failure, 5 hypertension, 6 and hemangioendothelioma (endothelin-secreting tumor), 7 as these clinical situations were associated with significantly elevated plasma levels of endothelin. Alternatively, because this vasoactive peptide is produced ubiquitously throughout the vascular endothelium 8 and other cardiovascular structures, 9 there is also reason ...

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

“…Although some studies have shown that ET infusion in rats causes elevation of blood pressure [82], other studies have demonstrated that ET infusion causes slight or no change [56]. The difference in the results could be related to the activity of the ET batches from different commercial sources.…”

Endothelin mobilizes calcium and enhances glucose uptake in cultured human skeletal myoblasts and L6 myotubes.

“…The action of endothelin (ET), a potent vasoconstrictor of endothelial origin, 911 was used to test this hypothesis. Although the systemic infusion of ET can produce hypertension in the rat, 12 a controversy exists as to whether the circulating levels of this factor are increased in essential hypertension. Moreover, it is uncertain whether elevated levels of ET cause hypertension in humans (reviewed in Reference 7).…”

“…43 -44 Several observations support the idea that the special relation between ET and Ang II plays an important function in the pathophysiology of essential hypertension. First, the ACE inhibitor captopril prevents chronic hypertension produced by the systemic administration of ET in the rat 12 ; second, captopril improves the impaired endothelium-dependent vasodilation in patients with essential hypertension 45 ; and third, Ang II stimulates ET production and augments the contractility of resistance vessels of the spontaneously hypertensive rat to a greater extent than the Wistar-Kyoto rat. 40 Taken together, these observations suggest that at least some forms of essential hypertension are marked by hyperactivity of ET and Ang II or increased sensitivity to these agents of the peripheral circulation.…”

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“…In addition, treatment with an angiotensin converting enzyme (ACE) inhibitor attenuated the reductions in renal blood flow and urinary sodium excretion induced by acute administration of ET-1 (11). Similarly, the hypertension induced by chronic infusion of ET-1 was prevented by an ACE inhibitor (12).…”