Metoprolol Ameliorates Cyclosporine A–induced Hypertension and Nephrotoxicity in Rats

Abstract

Despite their clinical relevance as important cardiovascular modulators, there are few studies regarding the potential protective effect of β-blockers against immunosuppressive-induced cardiovascular side effects. This study investigated the possible ameliorating effect of β1-blocker, metoprolol (MTP), against both hypertensive and nephrotoxic effects of cyclosporine A (CSA). Compared with vehicle (olive oil)-treated rats, chronic treatment with CSA (20 mg·kg·d subcutaneous, for 14 days) increased systolic blood pressure, elevated renal function indices and plasma renin activity, impaired renovascular responsiveness of isolated perfused rat kidneys to endothelium-dependent vasodilations induced by carbachol. These effects were abolished upon concurrent administration of MTP (5 mg·kg·d for 14 days, intraperitoneal). The possibility that alterations in the antioxidant and/or circulating cytokine levels contributed to the CSA-MTP interaction was also investigated. MTP abrogated the oxidative (superoxide dismutase, catalase), lipid peroxidation (malondialdyde), and elevated the cytokine (TNF-α and TGF-β) effects of CSA. Histologically, CSA caused tubular brush border loss and isometric vacuolization clustered in the proximal tubule; this effect disappeared in rats cotreated with MTP. The use of a nonhypotensive dose of MTP (1.25 mg/kg) countered in part endothelium dysfunction altered oxidative stress parameters and cytokine levels in CSA-treated rats. Collectively, MTP abrogates both the hypertensive and the nephrotoxic effects of CSA via ameliorating endothelium dysfunction, oxidative stress, and upregulated cytokine levels caused by CSA. The demonstration of nephroprotection by the low dose of MTP suggests that its renal effect may be partially unrelated to its hemodynamic activity.