REGULATION OF THE URINARY-EXCRETION OF ENDOTHELIN IN THE RAT

The regulation of the urinary excretion of endothelin (U(ET)V) and its clinical significance has not yet been established. The present study was designed to examine the effect of angiotensin II (A-II), arginine vasopressin (AVP), and nifedipine on U(ET)V. Anesthetized Munich-Wistar rats were infused with low (50 ng/kg/min) and high (500 ng/kg/min) doses of A-II for 30 min. Both doses significantly increased U(ET)V, from nondetectable (ND) levels to 155 +/- 54 (P < .03) and 450 +/- 86 fg/min (P < .001), respectively. This effect was accompanied by a significant increase in urine flow (UV), from 6 +/- 1 to 67 +/- 12 and 89 +/- 10 muL/min, and in mean arterial pressure (MAP), from 139 +/- 4 to 187 +/- 5 and 217 +/- 3 mm Hg. Infusions of A-II with its nonspecific antagonist, saralasin, resulted in a further increase in U(ET)V to 647 +/- 126 and 782 +/- 117 fg/min (P < .002), respectively. However, infusion of A-II with its specific antagonist, losartan, completely blocked its stimulatory effect on U(ET)V. Infusion of AVP, 10 or 100 mU/kg/h, produced increases in MAP, from 134 +/- 3 to 165 +/- 7 and 203 +/- 4 mm Hg, and in UV from 6 +/- 1 to 37 +/- 6 and 97 +/- 17 muL/min, comparable to A-II, but AVP did not have a marked effect on U(ET)V. Infusion of 0.1 or 1.0 mg/kg/h of nifedipine increased U(ET)V, from ND levels to 84 +/- 36 and 146 +/- 40 fg/min (P < .006), respectively, despite a significant decrease in MAP, from 139 +/- 8 to 118 +/-3 and 107 +/- 3 mm Hg (P <.05), respectively. Pretreatment of rats with captopril, 1 mg/kg/h, prevented the nifedipine-induced increase in U(ET)V. Our data suggest that A-II is a major regulator of urinary endothelin excretion. The effect was independent of urinary flow or blood pressure. The effect of nifedipine on U(ET)V was abolished by captopril, suggesting its mediation via reflex activation of the renin-angiotensin axis.