AUGMENTED ARTERIAL-PRESSURE RESPONSES TO CYCLOSPORINE IN SPONTANEOUSLY HYPERTENSIVE RATS - ROLE OF CYTOCHROME-P-450 3A

Evidence to support a hypertensinogenic role of family 3A cytochrome P -450 (CYP3A) activity is that troleandomycin, a selective inhibitor of CYP3A, decreases both blood pressure and in vivo corticosterone 6 bet a-hydroxylation in spontaneously hypertensive rats (SHR). Renal CYP3A activity is markedly increased in SHR compared with Wistar-Kyoto (WKY) rats. Cyclosporine acutely increases both systolic blood pressure and renal total cytochrome P-450 in SHR. We tested the hypothesis that th e augmentation of blood pressure by cyclosporine is mediated by a furt her increase in renal CYP3A activity. Accordingly, we assessed the eff ect of troleandomycin administration on cyclosporine-induced systolic blood pressure increase and renal and hepatic microsomal CYP3A activit y in SHR. Cyclosporine (5 mg/kg SC) given daily in 11-week-old SHR res ulted in substantial augmentation of blood pressure after 6 days. This blood pressure increase was attenuated by troleandomycin (40 mg/kg) g iven either during or after development of hypertension. Cyclosporine increased renal (60%) but decreased hepatic (25%) microsomal CYP3A act ivity in SHR. In contrast, cyclosporine failed to produce any detectab le increase in either blood pressure or renal CYP3A activity in WKY ra ts. Troleandomycin completely inhibited renal CYP3A activity measured after cyclosporine treatment of SHR, which correlated with its attenua tion of the cyclosporine-induced blood pressure increase. These findin gs suggest that renal CYP3A could play an important role in acute cycl osporine-induced hypertension.