(Circulation. 1995;91:1229-1235.)
© 1995 American Heart Association, Inc.
Articles |
Direct Measurements of Endothelium-Derived Nitric Oxide Release by Stimulation of Endothelin Receptors in Rat Kidney and Its Alteration in Salt-Induced Hypertension
From the Second Department of Internal Medicine (Y.H., H.H., E.S., K. Kimura, M.O.) and Faculty of Pharmaceutical Sciences (K. Kikuchi, T.N., M.H.), University of Tokyo, Japan.
Correspondence to Yasunobu Hirata, MD, the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Background Stimulation of endothelin subtype B (ETB) receptors has been proposed to induce release of endothelium-derived nitric oxide (EDNO).
Methods and Results To obtain direct evidence of its release and its alteration in deoxycorticosterone acetate (DOCA)-salt hypertension, EDNO released from renal vessels by ET stimulation was assayed by a highly sensitive chemiluminescence method. Kidneys were isolated from DOCA-salt and control rats, and renal perfusion pressure (RPP) and EDNO (by hydrogen peroxide–luminol chemiluminescence) in the perfusate were monitored simultaneously during perfusion of ET-1, ET-3, an ETA receptor antagonist (BQ-123), and an ETB receptor agonist (BQ-3020). In control rats, ET-1 and ET-3 dose-dependently increased both RPP and NO release. Although the vasoconstricting effects of ET-1 were greater, their NO-releasing effects were comparable. The increase in NO release by ETs was inhibited by NG-monomethyl-L-arginine. After 10-6 mol/L BQ-123 treatment, ET-1 decreased RPP and increased NO release in control kidneys. DOCA-salt rats responded to these agents with much less NO release. BQ-3020 at up to 10-10 mol/L caused vasodilation (RPP, 10-11 mol/L, -5.4±1.7%, P<.01) associated with increased NO release in control kidneys (+9.0±2.7 fmol · min-1 · g-1 kidney wt, P<.01). However, in DOCA-salt kidneys, BQ-3020 caused renal vasoconstriction (RPP, +5.4±2.4%, P<.01 versus control) and a much smaller NO release (+1.1±0.4 fmol · min-1 · g-1 kidney wt, P<.01 versus control). Northern blot analysis revealed that renal ETB mRNA was significantly decreased in DOCA-salt rat kidneys compared with controls (0.36±0.13 versus 1.00±0.23, P<.05).
Conclusions These results suggest that ET-1 and ET-3 release EDNO via ETB receptors in renal vessels. ETB-mediated NO release was reduced in DOCA-salt rats, which may modulate renal function and thus blood pressure regulation in DOCA-salt hypertensive rats.
Key Words: endothelium-derived factors • endothelin • hypertension • kidney
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