A. Asberg et al., DILTIAZEM MODULATES CYCLOSPORINE-A-INDUCED RENAL HEMODYNAMIC-EFFECTS BUT NOT ITS EFFECT ON PLASMA ENDOTHELIN-1, Clinical transplantation, 12(5), 1998, pp. 363-370
Cyclosporin A (CsA) has been reported to induce major acute renal hypo
perfusion that may be antagonised by calcium channel blockers. The vas
oconstrictive peptide endothelin-1 (ET-1) has been proposed as a media
tor of CsA induced hypoperfusion. We investigated the acute effects of
the new CsA formulation (Sandimmun Neoral(R)) in 8 renal transplant p
atients on triple immunosuppressive therapy before and following slow-
release diltiazem treatment in a dose of 90- 120 mg b.i.d for 4 weeks.
CsA significantly increased mean arterial blood pressure by 6 +/- 2 m
mHg (p < 0.05) during the first 3 h after administration. This effect
was abolished by diltiazem treatment, also reducing blood pressure by
12 +/- 3 mmHg (p < 0.05) 3-9 h after administration. CsA administratio
n induced a maximum reduction in renal blood flow of 20 +/- 8% (p < 0.
05) 5 h after ingestion and a concomitant reduction in glomerular filt
ration rate of 18 +/- 7% (p < 0.05). The filtration fraction increased
by a maximum of 13 +/- 7% (p < 0.05) after 4 h as did the calculated
fractional proximal reabsorption by 14 +/- 4% (p < 0.05). All these ac
ute renal effects were abolished by diltiazem administration. Concurre
nt with the maximum renal hemodynamic effects, plasma ET-1 was elevate
d with a peak increase of about 40% 4-5 h after CsA ingestion, Diltiaz
em treatment had no effect on the increase in plasma ET-1 following Cs
A administration. These findings suggest that CsA induced acute vasoco
nstriction and renal hypoperfusion are mediated by ET-1 and that dilti
azem treatment abolishes these pharmacodynamic effects of CsA despite
persistent increase of plasma ET-1 levels.