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

Cyclosporin-induced hypertension is a major complication of immunosuppression In transplant recipients but its pathophysiology is only partly understood. Cyclosporin reduces endotheliun-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 nan-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 (250mg/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 mmHg 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.