Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

Abstract

Abstract —Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ET A/B ) or selective endothelin subtype A (ET A ) 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 ET A receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ET A 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 ET A 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 ≈2.2-fold. In conclusion, selective ET A 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 find-ings 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 pressor systems.