Kah. Kaasjager et al., INTERACTIONS OF NIFEDIPINE WITH THE RENOVASCULAR EFFECTS OF ENDOTHELIN IN HUMANS, The Journal of pharmacology and experimental therapeutics, 275(1), 1995, pp. 306-311
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.