The role of endothelin in FK506-induced vascular reactivity changes in rat perfused kidney.
ABSTRACT Tacrolimus (FK506) is an immunosuppressant agent that is widely used in transplanted patients. The aim of this study was to investigate the role of endothelin in the acute effects of FK506 on the vascular reactivity in perfused isolated rat renal and mesenteric vasculature. Left kidney/mesentery of male Wistar rats (230-300 g) were perfused by a constant flow and perfusion pressure was recorded. The responses to noradrenaline and sodium nitroprusside were obtained both in the absence and presence of FK506 (10(-7) M) or polyoxyethylene hydrogenated castor oil 60 (HCO-60 and solvent of the drug at equivalent concentrations). FK506 significantly increased the noradrenaline-induced vasoconstrictor responses in renal, but not in mesenteric vascular beds. Bosentan (10(-5) M), a nonselective endothelin ET-1 receptor antagonist given by perfusion, reversed the increase in noradrenaline responses in the kidney. Sodium nitroprusside-induced vasodilator responses in both renal and mesenteric vascular beds were significantly decreased by FK506. However, in renal vasculature, there was no significant difference between the inhibitory effects of FK506 and HCO-60, although the effect of the solvent was not significantly different from that of the control. While in the mesenteric bed, the solvent significantly inhibited nitroprusside-induced vasodilation, similar to that of FK506. The effect of FK506 on vasodilation in both vascular beds was not reversed by bosentan. Our results indicated that FK506 increased the reactivity of the renal vascular bed to noradrenaline through endothelin ET-1 receptor activation. The mechanism of impaired vasodilation due to FK506 appears to be due to its solvent action and is independent of endothelin release.
- [show abstract] [hide abstract]
ABSTRACT: Cyclosporine immunosuppression for organ transplantation is associated with hypertension and nephrotoxicity. Because the effects of cyclosporine as an immunosuppressant are mediated by the effect of cyclosporine as a phosphatase inhibitor, and phosphatase inhibitors are potent vascular smooth muscle contractile agents, we hypothesized that cyclosporine might induce contraction of the renal artery vascular smooth muscle directly. Strips of bovine renal, carotid, superior mesenteric, or coronary arteries were obtained fresh from an abattoir. The strips were equilibrated in a muscle bath, and the contractile responses to cyclosporine and FK506 were determined. Cyclosporine (50 to 5000 micrograms/ml), but not FK506, induced rapidly developing, sustained contractions of renal and coronary artery smooth muscle. The magnitude of the cyclosporine-induced contractions of carotid and superior mesenteric artery smooth muscles was significantly less. The magnitude of renal artery smooth muscle contractions induced by cyclosporine was enhanced in the presence of an intact endothelium. Although these effects occurred in vitro to relatively high doses of cyclosporine, these data suggest that cyclosporine may selectively induce renal artery smooth muscle contraction through activation of the Ca(2+)-dependent phosphatase (calcineurin) in the smooth muscle, and these contractions may be enhanced by the release of endothelial-derived contracting factors.Surgery 04/1998; 123(4):456-60. · 3.37 Impact Factor
- Acta Physiologica Scandinavica 01/1989; 134(4):573-4. · 2.55 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Cyclosporine A (CSA) stimulated endothelin secretion by a cultured renal epithelial cell line, LLC-PK1. A less nephrotoxic immunosuppressant (FK-506) did not affect endothelin secretion. Putative endothelin converting enzyme inhibitors or specific receptor antagonists may therefore prevent CSA nephrotoxicity.Journal of Cardiovascular Pharmacology 02/1991; 17 Suppl 7:S172-3. · 2.38 Impact Factor