ANTIHYPERTENSIVE EFFECTS OF A NOVEL ENDOTHELIN-A RECEPTOR ANTAGONIST IN RATS

被引：59

作者：

BIRD, JE

MORELAND, S

WALDRON, TL

POWELL, JR

机构：

[1] Department of Pharmacology, Bristol-Myers Squibb P., Princeton, NJ

[2] Department of Pharmacology, Bristol-Myers Squibb P., Princeton, NJ 08543-4000

来源：

HYPERTENSION | 1995年 / 25卷 / 06期

关键词：

HYPERTENSION; EXPERIMENTAL; MINERALOCORTICOID; RECEPTORS; ENDOTHELIN; ENDOTHELINS;

D O I：

10.1161/01.HYP.25.6.1191

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

Endothelin is a potent presser agent mediated primarily through activation of endothelin-A receptors on vascular smooth muscle. Surprisingly, there is no consensus in the literature regarding the role of endothelin itself or endothelin-A receptors in hypertension. The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hyper tension. BMS-182874 specifically inhibited the presser response to endothelin-1 (0.3 nmol/kg IV) in Sprague-Dawley rats in a dose-dependent manner (ED(25)=8 mu mol/kg IV) but had no effect on changes in mean arterial pressure brought about by other vasoactive agents. The antihypertensive effects of BMS-182874 were evaluated in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHR), and sodium-deplete SHR. BMS-182874 reduced blood pressure in DOCA-salt hypertensive rats when administered at a dose of 30, 100, or 300 mu mol/kg IV. A maximal decrease of approximately 45 mm Hg was observed after treatment with 100 mu mol/kg IV. Three days of oral or intravenous treatment with BMS-182874 (100 mu mol/kg) elicited a sustained decrease in blood pressure:in the DOCA-salt hypertensive rats. In SHR, BMS-182874 decreased blood pressure by approximately 30 mm Hg, but the antihypertensive effects were similar at doses of 75, 150, and 450 mu mol/kg PO. In sodium-deplete SHR, BMS-182874 did not significantly reduce blood pressure. In summary, BMS-182874 is a specific, orally active endothelin-A receptor antagonist that is efficacious in mineralocorticoid hypertension in rats but has less effect in sodium-replete and sodium-deplete SHR. Thus, endothelin-A receptor activation may play a role in volume-dependent or low-renin hypertension but is unlikely to be important in all hypertensive states.

引用

页码：1191 / 1195

页数：5

共 21 条

[1] Tomobe Y., Miyauchi T., Saito A., Yanagisawa M., Kimura S., Goto K., Masaki T., Effects of endothelin on the renal artery from spontaneously hypertensive and Wistar Kyoto rats, Eur J Pharmacol, 152, pp. 373-374, (1988)
[2] Lippton H., Goff J., Human A., Effects of endothelin in the systemic and renal beds in vivo, Eur J Pharmacol, 155, pp. 197-198, (1988)
[3] Vanhoutte P.M., Is endothelin involved in the pathogenesis of hypertension?, Hypertension, 21, pp. 747-751, (1993)
[4] Luscher T.F., Seo B., Buhler F.R., Potential role of endothelin in hypertension, Hypertension, 21, pp. 752-757, (1993)
[5] Lariviere R., Thibault G., Schiffrin E.L., Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats, Hypertension, 21, pp. 294-300, (1993)
[6] Lariviere R., Day R., Schiffrin E.L., Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats, Hypertension, 21, pp. 916-920, (1993)
[7] Li J.S., Lariviere R., Schiffrin E.L., Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats, Hypertension, 24, pp. 183-188, (1994)
[8] Stein P.D., Hunt J.T., Floyd D.M., Moreland S., Dickinson K.E.J., Mitchell C., Liu E.C.K., Webb M.L., Murugesan N., Dickey J., McMullen D., Zhang R., Lee V.G., Serafino R., Delaney C., Schaeffer T.R., Kozlowski M., The discovery of sulfonamide endothelin antagonists and the development of the orally active ET<sub>A</sub> antagonist, 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide, BMS-182874, J Med Chem, 37, pp. 329-331, (1994)
[9] McMahon E.G., Palomo M.A., Brown M., Bertenshaw S.R., Carter J.S., Effect of phosphoramidon (endothelin converting enzyme inhibitor) and BQ-123 (endothelin receptor subtype a antagonist) on blood pressure in hypertensive rats, Am J Hypertens, 6, pp. 667-673, (1993)
[10] Martel E., Champeroux P., Brisac A.-M., Magnier A., Richard S., Safar M., Pressor responses to endothelin-1 in normotensive and spontaneously hypertensive rats, Neurochem Int, 18, pp. 553-557, (1991)

← 1 2 3 →