Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt; Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Lebanon.
Biomed Pharmacother. 2018 May;101:889-897. doi: 10.1016/j.biopha.2018.03.026. Epub 2018 Mar 22.
We recently reported that exposure to cyclosporine (CSA) plus diclofenac causes hypertension and impairs left ventricular (LV) and cardiac autonomic functions in female rats. Here, we tested the hypothesis that these effects could be mitigated by facilitated heme oxygenase (HO) signaling. Experiments were performed in female rats to assess the effects of 10-day treatment with CSA (25 mg/kg/day)/diclofenac (1 mg/kg/day) regimen on cardiovascular functions in absence and presence of maneuvers that upregulate HO or its enzymatic products. The CSA/diclofenac-induced hypertension and impairment in cardiac sympathovagal balance (i.e. reduced low-frequency/high-frequency spectral ratio) were blunted upon concurrent treatment with hemin (HO-1 inducer), tricarbonyldichlororuthenium (II) dimer (CORM-2, carbon monoxide-releasing molecule), or bilirubin. While none of the latter treatments affected the CSA/diclofenac-evoked decrease in isovolumic relaxation constant (Tau, a measure of diastolic function), the increased LV contractility (dP/dt) and attenuated reflex bradycardia in CSA/diclofenac-treated rats was abolished by bilirubin only. Paradoxically, the CSA/diclofenac-evoked attenuation in reflex tachycardia was improved in presence of hemin or CORM-2, but not bilirubin. The favorable hemin effects were abrogated after inhibition of HO (ZnPP) or nitric oxide synthase (NOS, l-NAME). These finding highlights NOS-dependent modulatory roles for HO and its enzymatic products in improving the worsened cardiovascular profile in CSA/diclofenac-treated female rats.
我们最近报道，环孢素（CSA）加双氯芬酸暴露会导致雌性大鼠高血压，并损害左心室（LV）和心脏自主功能。在这里，我们测试了这样一种假设，即这些作用可以通过促进血红素加氧酶（HO）信号来减轻。在雌性大鼠中进行实验，以评估 CSA（25mg/kg/天）/双氯芬酸（1mg/kg/天）方案 10 天治疗对心血管功能的影响，以及在增强 HO 或其酶产物的操作存在和不存在的情况下。CSA/双氯芬酸引起的高血压和心脏交感神经迷走神经平衡受损（即低频/高频频谱比降低），在同时用血红素（HO-1 诱导剂）、三羰基二氯钌（II）二聚体（CORM-2，一氧化碳释放分子）或胆红素治疗时减弱。虽然这些治疗方法都不会影响 CSA/双氯芬酸引起的等容松弛常数（Tau，舒张功能的一种衡量标准）的降低，但 CSA/双氯芬酸治疗大鼠的 LV 收缩性增加（dP/dt）和反射性心动过缓减弱仅被胆红素消除。矛盾的是，在 CSA/双氯芬酸治疗大鼠中，反射性心动过速的 CSA/双氯芬酸诱导的衰减在血红素或 CORM-2 存在的情况下得到改善，但在胆红素存在的情况下没有改善。有利的血红素作用在 HO（ZnPP）或一氧化氮合酶（NOS，l-NAME）抑制后被消除。这些发现强调了 HO 和其酶产物在改善 CSA/双氯芬酸治疗的雌性大鼠心血管状况恶化方面的 NOS 依赖性调节作用。
