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 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.
Bartholomeusz
B
B
Department of Surgery, Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Hardy
K J
KJ
Nelson
A S
AS
Phillips
P A
PA
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002144:Callithrix; D016572:Cyclosporine / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000652:urine; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013599:Systole
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D013449:Sulfonamides; D019335:Nitroarginine; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D000077300:Bosentan