Modulation of nitric oxide improves cyclosporin A-induced hypertension in rats and primates

Abstract

Cyclosporin-induced hypertension is a major complication of immunosuppression in transplant recipients but its pathophysiology is only partly understood. Cyclosporin reduces endothelium-dependent vasodilation and increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of: (1) nitric oxide enhancement with L-arginine administration and antagonism with N-nitro-L-arginine; and (2) chronic endothelin receptor blockade with the non-peptide endothelin receptor antagonist, bosentan, in two animal models of cyclosporin-induced hypertension. Cyclosporin, administered daily to female Wistar rats (10 mg/kg per day for 30 days, s.c.) and to marmosets (30 mg/kg per day for 20 days, p.o.) significantly elevated tail cuff systolic blood pressure (BP). L-arginine (250 mg/kg, in saline, i.p.), N-nitro-L-arginine (25 mg/kg, in saline, i.p.), bosentan (100 mg/kg, in arabic gum, p.o.) or vehicle were given daily to the rats during the last week of cyclosporin treatment. Marmosets received L-arginine (300 mg/kg, in water, p.o.), bosentan (100 mg/kg/day in arabic gum, p.o.) or vehicle for the last 7 days of cyclosporin treatment. L-arginine, but not saline alone significantly lowered BP in the cyclosporin-hypertensive rats from 129 ± 2 mm Hg to 122 ± 3 mm Hg (P < 0.05), and cyclosporin-hypertensive marmosets from 156 ± 2 mm hg to 139 ± 4 mm hg (P < 0.01). nola significantly increased systolic bp in cyclosporin-treated (from 133 ± 2 mm hg at week 3 to 142 ± 3 mm hg, P < 0.05) and control rats (from 124.0 ± 2 mm hg to 134 ± 2 mm hg, P < 0.05) indicating that nitric oxide synthesis in cyclosporin-hypertensive rats could be further antagonised. bosentan, but not arabic gum alone, also lowered bp in the cyclosporin-hypertensive rats from 134 ± 1 mm hg to 122 ± 3 mm hg (P < 0.01), and cyclosporin-hypertensive marmosets from 156 ± 2 mm hg to 139 ± 4 mm hg (P < 0.01). these results support the roles of both increased endothelin synthesis and decreased nitric oxide activity in the pathogenesis of cyclosporin a-induced hypertension.