Contribution of the endothelin system to the renal hypoperfusion associated with experimental congestive heart failure

The objective of this study was to define further the local activation of e ndothelin-1 (ET-1) and the ETA receptor as well as the functional consequen ces of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instru mented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ven tricular dysfunction (fractional shortening 34 +/- 2% vs. 46 +/- 3%; p less than or equal to 0.05) and dilatation (LVEDd 13.6 +/- 0.3 vs. 11.5 +/- 0.4 mm; p less than or equal to 0.05), decreased mean arterial pressure (59.4 +/- 2.9 vs. 74.6 +/- 3.7 mm Hg; p less than or equal to 0.05), increased he art rate (236 +/- 11 vs. 216 +/- 8 beats/min; p less than or equal to 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 k Hz; 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 r evealed an unchanged expression of ETA receptor messenger RNA (0.79 +/- 0.0 5 vs. 0.77 +/- 0.04 arbitrary units; NS) in renal tissue, whereas expressio n of prepro-ET-1 was below the range of detection. In CHF, selective ETA-re ceptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increase d 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, unaltere d gene expression, and functional integrity of the renal ETA receptor in CH F. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an impor tant strategy to attenuate renal hypoperfusion in CHF.