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(Circulation. 1999;99:1242-1248.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Effects of Hypertension, Diabetes Mellitus, and Hypercholesterolemia on Endothelin Type B Receptor–Mediated Nitric Oxide Release From Rat Kidney

Masao Kakoki, MD; Yasunobu Hirata, MD; Hiroshi Hayakawa, MD; Akihiro Tojo, MD; Daisuke Nagata, MD; Etsu Suzuki, MD; Kenjiro Kimura, MD; Atsuo Goto, MD; Kazuya Kikuchi, PhD; Tetsuo Nagano, PhD; Masao Omata, MD

From the Second Department of Internal Medicine, Faculty of Medicine (M.K., Y.H., H.H., A.T., D.N., E.S., K. Kimura, A.G., M.O.), and Faculty of Pharmaceutical Sciences (K. Kikuchi, T.N.), University of Tokyo, Tokyo, Japan.

Correspondence to Yasunobu Hirata, MD, The Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail hirata-2im{at}h.u-tokyo.ac.jp

Background—Although endothelin-1 is a potent vasoconstrictor peptide, stimulation of endothelin type B receptor (ETBR) causes bidirectional changes in vascular tone, ie, vasodilation and vasoconstriction. Roles of ETBR in pathological conditions are largely unknown.

Methods and Results—We studied the effect of BQ-3020, a highly selective ETBR agonist, on renal vascular resistance and nitric oxide (NO) release in the isolated, perfused kidney of rats with hypertension, diabetes mellitus, and hypercholesterolemia. Immunohistochemistry of endothelial NO synthase and ETBR was also examined. Infusion of BQ-3020 at concentrations of 10^-10 mol/L reduced renal perfusion pressure in Dahl salt-resistant (R) rats but increased renal perfusion pressure in Dahl salt-sensitive (S) rats (10^-10 mol/L: -10.3±0.6% versus 11.2±1.5%, R versus S; P<0.01). BQ-3020 caused a dose-dependent release of NO in both R and S rats, although the level of NO release in S rats was lower, as detected by chemiluminescence (10^-10 mol/L: 10.7±0.7 versus 3.1±0.4 fmol/min per gram of kidney, R versus S; P<0.01). Similar effects of BQ-3020 were observed in streptozotocin-induced diabetic rats and diet-induced hypercholesterolemic rats. Expression of endothelial NO synthase decreased in S rats but not in diabetic or hypercholesterolemic rats. In contrast, expression of ETBR in the endothelium was decreased in all 3 disease models compared with that in the vascular smooth muscle cell.

Conclusions—These results suggest that impaired NO release in response to stimulation of ETBR is due, at least in part, to a decrease in endothelial ETBR and may play a role in vascular dysfunction usually associated with arteriosclerosis-related diseases.

Key Words: immunohistochemistry • diabetes mellitus • hypertension • hypercholesterolemia • angiotensin

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