Interactions of nifedipine with the renovascular effects of endothelin in humans
Kaasjager, K.A.; van Rijn, H.J.; Koomans, H.A.; Rabelink, T.J.
Journal of Pharmacology and Experimental Therapeutics 275(1): 306-311
1995
ISSN/ISBN: 0022-3565 PMID: 7562563 Document Number: 441274
Infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes mild hypertension, strong sodium retention and renal vasoconstriction. Animal studies have shown that part of these effects depend upon activation of voltage-dependent calcium channels. However, it is unknown whether hemodynamic effects of endothelin-1 in humans, once established, can be reversed by calcium channel blockers. We therefore studied in healthy subjects whether coinfusion of nifedipine, after 60 min of endothelin-1 infusion, could reverse these effects. During endothelin-1 infusion alone, plasma endothelin increased from 2.9 +- 0.2 to 8.0 +- 0.6 pmol/l (P lt .05). Blood pressure rose by apprxeq 6 mm Hg at the end of the endothelin-1 infusion (P lt .05). Endothelin-1 caused a marked increase in renal vascular resistance by apprxeq 34% (P lt .05) and in filtration fraction by apprxeq 25% (P lt .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 lt .05). During coinfusion of nifedipine, plasma endothelin levels increased 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. However, nifedipine could not reverse the endothelin-induced increase of filtration fraction, indicating that the effects of endothelin-1 and nifedipine in the renal microcirculation do not overlap completely. Because calcium channel blockers have a preferentially preglomerular effect, this suggests that endothelin-1 maintained vasoconstriction of the efferent arteriole in the kidney during nifedipine. These observations are the first to show that nifedipine can be used in humans to reverse endothelin-induced reductions in renal blood flow, which is of relevance for pathological conditions which are characterized by elevated plasma levels of endothelin and strong renal vasoconstriction.