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) rece ptor 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 t herefore investigated whether plasma renin activity and renin release are r egulated by the ETA receptor, Experiments were made in conscious, chronical ly instrumented dogs receiving either saline or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the adminis tration 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) w ere 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 E TA receptor blockade did not alter renin release at resting renal perfusion pressure (78 +/- 25 versus 71 +/- 39 U/min) but strongly enhanced the sens itivity of pressure-dependent renin release <80 mm Hg approximate to 2.2-fo ld. In conclusion, selective ETA receptor blockade is associated with a sti mulation of the circulating renin-angiotensin system, which results from bo th a sensitization of pressure-dependent renin release and a larger proport ion of blood pressure values falling into the low pressure range, where ren in release is stimulated. These findings strengthen the view that ET and th e 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.