Basu A K, Ghosh S, Mohanty P K, Watlington C O
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Hypertension. 1994 Oct;24(4):480-5. doi: 10.1161/01.hyp.24.4.480.
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 beta-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 the augmentation of blood pressure by cyclosporine is mediated by a further increase in renal CYP3A activity. Accordingly, we assessed the effect of troleandomycin administration on cyclosporine-induced systolic blood pressure increase and renal and hepatic microsomal CYP3A activity in SHR. Cyclosporine (5 mg/kg SC) given daily in 11-week-old SHR resulted in substantial augmentation of blood pressure after 6 days. This blood pressure increase was attenuated by troleandomycin (40 mg/kg) given either during or after development of hypertension. Cyclosporine increased renal (60%) but decreased hepatic (25%) microsomal CYP3A activity in SHR. In contrast, cyclosporine failed to produce any detectable increase in either blood pressure or renal CYP3A activity in WKY rats. Troleandomycin completely inhibited renal CYP3A activity measured after cyclosporine treatment of SHR, which correlated with its attenuation of the cyclosporine-induced blood pressure increase. These findings suggest that renal CYP3A could play an important role in acute cyclosporine-induced hypertension.
支持3A族细胞色素P-450（CYP3A）活性具有高血压生成作用的证据是，CYP3A的选择性抑制剂三乙酰竹桃霉素可降低自发性高血压大鼠（SHR）的血压和体内皮质酮6β-羟基化水平。与Wistar-Kyoto（WKY）大鼠相比，SHR的肾CYP3A活性显著增加。环孢素可使SHR的收缩压和肾总细胞色素P-450急性升高。我们检验了环孢素引起血压升高是由肾CYP3A活性进一步增加介导的这一假说。因此，我们评估了三乙酰竹桃霉素给药对环孢素诱导的SHR收缩压升高以及肾和肝微粒体CYP3A活性的影响。在11周龄的SHR中每日皮下注射环孢素（5 mg/kg），6天后血压大幅升高。在高血压发生期间或之后给予三乙酰竹桃霉素（40 mg/kg）可减弱这种血压升高。环孢素使SHR的肾微粒体CYP3A活性增加（60%），但使肝微粒体CYP3A活性降低（25%）。相比之下，环孢素未能使WKY大鼠的血压或肾CYP3A活性产生任何可检测到的升高。三乙酰竹桃霉素完全抑制了环孢素处理后的SHR的肾CYP3A活性，这与其减弱环孢素诱导的血压升高相关。这些发现表明，肾CYP3A可能在急性环孢素诱导的高血压中起重要作用。
