Abstract
BackgroundThe current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels.MethodsMale Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR).ResultsUnder normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%).ConclusionFasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection.
Highlights
Rho-kinase, a ubiquitously expressed serine-threonine protein kinase that is involved in diverse cellular functions, may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke and heart failure [1]
The detailed mechanisms are unclear, it has been suggested that the loss of cardioprotection by hyperglycemia might be associated with several mechanisms, namely, generation of large quantities of reactive oxygen species (ROS), inhibition of protective signaling mechanisms, downregulation of endothelial nitric synthase, reduced activation and availability of protective molecules, coronary vascular endothelial dysfunction, and/or impairment in the function of mitochondrial KATP (m-KATP) channels [11,12,13,17,18]
Hemodynamic data for heart rate (HR) and mean blood pressure (MBP) are shown in Infarct size There were no significant differences in left ventricle (LV) weight, area at risk (AAR) weight or the ratio of AAR to total LV mass among the groups (Table 3)
Summary
Rho-kinase, a ubiquitously expressed serine-threonine protein kinase that is involved in diverse cellular functions, may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke and heart failure [1]. Some reports showed that fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, had beneficial effects in ischemic heart disease. A double-blind placebo-controlled trial showed that fasudil increased the [6]. It is not clear whether mitochondrial KATP (m-KATP) channels mediate the Rho-kinase inhibitor-induced PostC. The effect of hyperglycemia on the Rho-kinase inhibitor-induced myocardial protection against ischemic reperfusion injury is unknown. The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels
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