Stimulation of the renin-angiotensin system by endothelin subtype A receptor blockade in conscious dogs

Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ETA/B) or selective endothelin subtype A (ETA) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ETA receptor, Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99 +/- 7 versus 81 +/- 6 bpm; P < 0.05) and renal blood flow (327 +/- 40 versus 278 +/- 36 mL/min; P < 0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93 +/- 5 versus 105 +/- 7 mm Hg), These changes were associated with a 2-fold increase in plasma renin activity (0.74 +/- 0.12 versus 0.37 +/- 0.10 ng angiotensin I per milliliter per hour; P < 0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ETA receptor blockade did not alter renin release at resting renal perfusion pressure (78 +/- 25 versus 71 +/- 39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg approximate to 2.2-fold. In conclusion, selective ETA receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These findings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both presser systems.