Bosentan Ameliorates Cyclosporin A–Induced Hypertension in Rats and Primates

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Abstract
Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134±1 to 122±3 mm Hg ( P <.01) and in the cyclosporine-hypertensive marmosets from 156±2 to 139±4 mm Hg ( P <.01). There were no differential effects on plasma creatinine concentration, endothelin concentration, or end-organ weights. Bosentan had no effect in the vehicle-treated rats. These data provide further evidence to support a role for endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness of endothelin receptor antagonism as a novel treatment in cyclosporine-induced hypertension.