Abstract
The objective of this study was to define further the local activation of endothelin-1 (ET-1) and the ETA receptor as well as the functional consequences of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instrumented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ventricular dysfunction (fractional shortening 34+/-2% vs. 46+/-3%; p < or = 0.05) and dilatation (LVEDd 13.6+/-0.3 vs. 11.5+/-0.4 mm; p < or = 0.05), decreased mean arterial pressure (59.4+/-2.9 vs. 74.6+/-3.7 mm Hg; p < or = 0.05), increased heart rate (236+/-11 vs. 216+/-8 beats/min; p < or = 0.05) and renal vasoconstriction (vascular resistance 49.65 +/-8.55 vs. 24.61+/-5.85 U; p < 0.05; blood flow velocity, 1.58+/-0.21 vs. 3.63+/-0.31 kHz; p < 0.05). ET-1 concentrations were significantly increased not only in plasma (7.67+/-0.47 vs. 4.56 +/-0.69 pg/ml; p < 0.05) but also in renal tissue (4.8+/-0.5 vs. 3.5 +/-0.64 pg/mg; p < 0.05). Northern analysis revealed an unchanged expression of ETA receptor messenger RNA (0.79+/-0.05 vs. 0.77+/-0.04 arbitrary units; NS) in renal tissue, whereas expression of prepro-ET-1 was below the range of detection. In CHF, selective ETA-receptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increased renal blood flow velocity (3.07+/-0.38 vs. 1.33+/-0.19 kHz; p < 0.05) and reduced renal vascular resistance (29.63+/-6.22 vs. 58.17+/-8.75 U; p < 0.05) without significant effects on mean arterial pressure or heart rate. These studies demonstrate activation of the renal ET system, unaltered gene expression, and functional integrity of the renal ETA receptor in CHF. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an important strategy to attenuate renal hypoperfusion in CHF.
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