INTERACTIONS OF NIFEDIPINE WITH THE RENOVASCULAR EFFECTS OF ENDOTHELIN IN HUMANS

Infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes mild hypertension, strong sodium retention and renal va soconstriction. Animal studies have shown that part of these effects d epend upon activation of voltage-dependent calcium channels. However, it is unknown whether hemodynamic effects of endothelin-1 in humans, o nce established, can be reversed by calcium channel blockers. We there fore studied in healthy subjects whether coinfusion of nifedipine, aft er 60 min of endothelin-1 infusion, could reverse these effects. Durin g endothelin-1 infusion alone, plasma endothelin increased from 2.9 +/ - 0.2 to 8.0 +/- 0.6 pmol/l (P < .05). Blood pressure rose by approxim ate to 6 mm Hg at the end of the endothelin-1 infusion (P < .05). Endo thelin-1 caused a marked increase in renal vascular resistance by appr oximate to 34% (P (.05) and in filtration fraction by approximate to 2 5% (P < .05). Sodium excretion decreased from a base-line value of 144 +/- 25 to 81 +/- 15 mu mol/min at the end of the endothelin infusion (P < .05). During coinfusion of nifedipine, plasma endothelin levels i ncreased to similar values as found during endothelin-1 infusion alone . Blood pressure increase was prevented, whereas the increase in renal Vascular resistance and antinatriuresis were reversed completely. How ever, nifedipine could not reverse the endothelin-induced increase of filtration fraction, indicating that the effects of endothelin-1 and n ifedipine in the renal microcirculation do not overlap completely. Bec ause calcium channel blockers have a preferentially preglomerular effe ct, this suggests that endothelin-1 maintained vasoconstriction of the efferent arteriole in the kidney during nifedipine. These observation s are the first to show that nifedipine can be used in humans to rever se endothelin-induced reductions in renal blood flow, which is of rele vance for pathological conditions which are characterized by elevated plasma levels of endothelin and strong renal vasoconstriction.