Superoxide-Dependent Hypertension in Male and Female Endothelin B Receptor

Abstract

Evidence for endothelin (ET) involvement in the control of fluid volume balance and arterial pressure has been derived in part from the observations that rats lacking the ET_B receptor develop hypertension when placed on a high-salt (HS) diet. The present study was designed to determine the effect of superoxide on salt-induced hypertension in male and female ET_B-deficient (sl/sl) and wild-type control (wt) rats. After 14 days on a HS (8% NaCl) diet, female sl/sl rats had significantly elevated arterial pressure (183 ± 2 mm Hg, tail cuff) compared with female wt rats (134 ± 2 mm Hg). The response to a HS diet was lower in male sl/sl rats (166 ± 6 mm Hg) yet was significantly greater than that in male wt controls (135 ± 3 mm Hg). Separate groups of male and female sl/sl and wt rats were given tempol (1 mM in drinking water) during HS treatment. Arterial pressures were 149 ± 5 mm Hg in male and 143 ± 3 mm Hg in female sl/sl rats treated with tempol, values that were similar to those of controls on a normal salt diet. After 14 days, however, male and female sl/ sl rats recovered from the blood pressure–lowering effects of tempol. On Day 15, arterial pressures in female sl/sl rats on a HS diet were 160 ± 6 mm Hg and 177 ± 6 mm Hg in tempol-treated and untreated groups, respectively. In male sl/sl rats, arterial pressures were 155 ± 3 mm Hg and 165 ± 5 mm Hg in tempol-treated and untreated groups, respectively. On Day 15, no differences among groups with or without tempol were observed in plasma thiobarbituric acid–reactive substance (TBARS) concentrations or in urinary excretion of TBARS. Plasma ET-1 concentrations were significantly higher in female vs. male sl/sl rats. These results indicate that the early stages of salt-dependent hypertension produced by ET_B receptor deficiency are dependent on superoxide and that the elevated pressure in the female rats may be due to elevated circulating levels of ET-1.

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References

Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46:325–415, 1994.

Pollock DM. Renal endothelin in hypertension. Curr Opin Nephrol Hypertens 9:157–164, 2000.

Schiffrin EL. Endothelin and endothelin antagonists in hypertension. J Hypertens 16:1891–1895, 1998.

Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M. Salt-sensitive hypertension in endothelin-B receptor–deficient rats. J Clin Invest 105:925–933, 2000.

Elmarakby AA, Dabbs Loomis E, Pollock JS, Pollock DM. ET_A receptor blockade attenuates hypertension and decreases reactive oxygen species in ET_B receptor–deficient rats. J Cardiovasc Pharmacol 44:S7–S10, 2004.

Taylor TA, Gariepy CE, Pollock DM, Pollock JS. Gender differences in ET and NOS systems in ET_B receptor–deficient rats: effect of a high salt diet. Hypertension 41:657–662, 2003.

Pollock DM, Pollock JS. Evidence for endothelin involvement in the response to high salt. Am J Physiol Renal Physiol 281:F144–150, 2001.

Williams JM, Pollock JS, Pollock DM. Arterial pressure response to the antioxidant tempol and ET_B receptor blockade in rats on a high-salt diet. Hypertension 44:770–775, 2004.

Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, Chen AF. Endothelin-1 increases vascular superoxide via endothelin_A-NADPH oxidase pathway in low-renin hypertension. Circulation 107: 1053–1058, 2003.

10.

Callera GE, Touyz RM, Teixeira SA, Muscara MN, Carvalho MH, Fortes ZB, Nigro D, Schiffrin EL, Tostes RC. ET_A receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension. Hypertension 42:811–817, 2003.

11.

Loomis ED, Sullivan JC, Osmond DA, Pollock DM, Pollock JS. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther 315:1058–1064, 2005.

12.

Sedeek MH, Llinas MT, Drummond H, Fortepiani L, Abram SR, Alexander BT, Reckelhoff JF, Granger JP. Role of reactive oxygen species in endothelin-induced hypertension. Hypertension 42:806–810, 2003.

13.

Gariepy CE, Williams SC, Richardson JA, Hammer RE, Yanagisawa M. Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease. J Clin Invest 102:1092–1101, 1998.

14.

Beswick RA, Zhang H, Marable D, Catravas JD, Hill WD, Webb RC. Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension 37:781–786, 2001.

15.

Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-iso-prostaglandin F_2alpha. Hypertension 33:424–428, 1999.

16.

Pollock DM, Rekito A. Hypertensive response to chronic NO synthase inhibition is different in Sprague-Dawley rats from two suppliers. Am J Physiol 275(pt 2):R1719–R1723, 1998.

17.

Elmarakby AA, Loomis ED, Pollock JS, Pollock DM. NADPH oxidase inhibition attenuates oxidative stress but not hypertension produced by chronic ET-1. Hypertension 45:283–287, 2005.

18.

Wedgwood S, Dettman RW, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol 281:L1058–L1067, 2001.

19.

Reinhart GA, Preusser LC, Burke SE, Wessale JL, Wegner CD, Opgenorth TJ, Cox BF. Hypertension induced by blockade of ET_B receptors in conscious nonhuman primates: role of ET_A receptors. Am J Physiol Heart Circ Physiol 283:H1555–H1561, 2002.

Superoxide-Dependent Hypertension in Male and Female Endothelin B Receptor–Deficient Rats

Abstract

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