Renal hemodynamic control by endothelin and nitric oxide under angiotensin II blockade in man

Abstract

To investigate whether endothelin-A receptors and nitric oxide modulate renal hemodynamics in man under angiotensin II receptor-1 blockade, 6 healthy volunteers, on a 240 mmol Na diet, underwent 4 separate renal hemodynamic measurements, in 3 of which endothelin-A blocker BQ-123 0.2 nmol · kg · min-1 was infused for 90 minutes after pretreatment with either placebo, telmisartan 1 mg · kg · day-1 for 3 days, or telmisartan as well, but with co-infusion of both BQ-123 and NG-nitro-L-arginine methylester 0.5 μg · kg · min-1. A fourth infusion was made with NG-nitro-L-arginine methylester alone. No change followed infusion of either NG-nitro-L-arginine methylester alone or BQ-123 alone. With BQ-123 after telmisartan, renal blood flow rose from 916+56 mL · min-1 · 1.73 m2 to 1047±51.2 (P<0.001), and renal vascular resistances fell from 89±7 mm Hg · min · L-1 to 74±4 (P<0.001). These changes were fully abolished by the co-infused NG-nitro-L-arginine methylester. Infusion of BQ-123, devoid of renal hemodynamic effects at baseline, produces significant renal vasodilation when angiotensin II receptors are blocked, indicating an increasing renal hemodynamic role of endothelin-A-receptor activity. Because such a vasodilation is prevented by nonvasoconstricting microdoses of NG-nitro-L-arginine methylester, nitric oxide-endothelin balance controls substantially renal hemodynamics under angiotensin II blockade. These findings are consistent with a rationale of the association of endothelin-A blockers with angiotensin II blockers or angiotensin-converting enzyme inhibitors in treating nitric oxide-deficient conditions such as arterial hypertension, heart failure, and chronic renal diseases.