Mechanisms of Ciclosporin A-Induced Vasoconstriction in the Isolated Perfused Rat Kidney

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Abstract
Hypertension is a well-known side effect of ciclosporin A (CsA). In the present study the mechanisms of vasoconstriction in renal vessels were examined in the isolated perfused rat kidney. Kidneys were perfused with constant flow at a temperature of 37 °C with Tyrode’s solution equilibrated with 95% O2/5% CO2. CsA was dissolved in ethanol. 500 and 2000 ng/ml increased resistance of renal vessels by 0.97 ± 0.55 × 105 and 2.29 ± 1.33 × 105 dyn s cm-5, respectively (mean values ± SD, n = 12). The vasoconstriction developed gradually over 4 min. The vasopressor effect of CsA was not changed by saralasin (10-6 M), nifedipine (10-6 M) and ketanserin (10-6 M), but was completely blocked by phentolamine and prazosin (each 10-6M). CsA-induced vasoconstriction was not prevented by perfusion with Ca2+-free solution containing 2 mmol EGTA. Similarly, pretreatment with reserpine to deplete sympathetic nerve endings from catecholamines did not affect CsA-induced vasoconstriction. The findings suggest that CsA-induced vasoconstriction is mediated by stimulation of α1-receptors. Ca2+ influx does not play a role for CsA-induced vasoconstriction. Prolonged perfusion of rat kidneys with the vehicle cremophor EL elicits an irreversible increase in perfusion pressure.

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