Abstract
BackgroundMitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro.MethodsMale Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate.ResultsIn control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups.ConclusionThis study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection.
Highlights
Ischemic heart disease is the leading cause of death worldwide, accounting for about 11% of all deaths globally [1]
This study shows that in male rats protein kinase G-dependent opening of mitochondrial BKCa (mBKCa) channels plays a pivotal role in sildenafil-induced cardioprotection
The cardioprotective effects of sildenafil are thought to be mediated by opening of mitochondrial ATP-sensitive potassium channels [14], enhanced expression of endothelial nitric oxide synthase (NOS) and inducible NOS [5], and activation of protein kinase C and protein kinase G (PKG) [15]
Summary
Ischemic heart disease is the leading cause of death worldwide, accounting for about 11% of all deaths globally [1]. Reperfusion itself induces injury that accounts for up to 50% of the final size of a myocardial infarction and paradoxically reduces the beneficial effects of a restored coronary blood flow [2]. The cardioprotective effects of sildenafil are thought to be mediated by opening of mitochondrial ATP-sensitive potassium (mito-KATP) channels [14], enhanced expression of endothelial nitric oxide synthase (NOS) and inducible NOS [5], and activation of protein kinase C and PKG [15]. Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro
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