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Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.

ABSTRACT: Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB.Langendorff-perfused isolated rat hearts were subjected to 2 hours intermittent cold (10°C) CP (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 minutes for 1 minute. Hearts were treated with rottlerin 1 ?mol/L (CP+R) (n=7) or without rottlerin (CP) (n=9), and the BK(Ca++) channel inhibitor paxilline 100 nmol/L was supplied in the CP. Hearts constantly perfused with KHB served as controls (n=6). Baseline parameters of cardiac function were similar between groups. CP resulted in reduced cardiac function (left ventricular diastolic pressure, 39 ± 3.8%; ± dP/dt, 32 ± 4.4%, -41 ± 5.1% decrease compared to baseline). Treatment with rottlerin 1 ?mol/L significantly improved CP-induced cardiac function (left ventricular diastolic pressure, 20 ± 5.9%; ± dP/dt, 5.2 ± 4.5%, -11.6 ± 4.7% decrease versus baseline; P<0.05 CP+R versus CP). Rottlerin also caused a significant increase in coronary flow postreperfusion (CP, 34 ± 4.2% decrease from baseline; CP+R, 26 ± 9.6% increase over baseline; P=0.01). Independent of vascular effects, CP significantly decreased isolated myocyte contraction, which was restored by rottlerin treatment. The BK(Ca++) channel inhibitor greatly reduced the majority of beneficial effects associated with rottlerin.Rottlerin significantly improves cardiac performance after CP arrest through improved cardiomyocyte contraction and coronary perfusion.

SUBMITTER: Clements RT

PROVIDER: S-EPMC3358121 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.

Clements Richard T RT Cordeiro Brenda B Feng Jun J Bianchi Cesario C Sellke Frank W FW

Circulation 20110901 11 Suppl

<h4>Background</h4>Cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to complex injurious stimuli that can result in cardiomyocyte and vascular contractile abnormalities. Rottlerin, originally identified as a delta-protein kinase C inhibitor, has a number of known additional effects that may be beneficial in the setting of CP/CPB. We tested the hypothesis that rottlerin mitigates deleterious effects associated with CP/CPB.<h4>Methods and results</h4>Langendorff-perfused isolat ...[more]

PMID: 21911819

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Project description:The intracellular fibroblast growth factors (iFGF/FHFs) bind directly to cardiac voltage gated Na+ channels, and modulate their function. Mutations that affect iFGF/FHF-Na+ channel interaction are associated with arrhythmia syndromes. Although suspected to modulate other ionic currents, such as Ca2+ channels based on acute knockdown experiments in isolated cardiomyocytes, the in vivo consequences of iFGF/FHF gene ablation on cardiac electrical activity are still unknown. We generated inducible, cardiomyocyte-restricted Fgf13 knockout mice to determine the resultant effects of Fgf13 gene ablation. Patch clamp recordings from ventricular myocytes isolated from Fgf13 knockout mice showed a ~25% reduction in peak Na+ channel current density and a hyperpolarizing shift in steady-state inactivation. Electrocardiograms on Fgf13 knockout mice showed a prolonged QRS duration. The Na+ channel blocker flecainide further prolonged QRS duration and triggered ventricular tachyarrhythmias only in Fgf13 knockout mice, suggesting that arrhythmia vulnerability resulted, at least in part, from a loss of functioning Na+ channels. Consistent with these effects on Na+ channels, action potentials in Fgf13 knockout mice, compared to Cre control mice, exhibited slower upstrokes and reduced amplitude, but unexpectedly had longer durations. We investigated candidate sources of the prolonged action potential durations in myocytes from Fgf13 knockout mice and found a reduction of the transient outward K+ current (Ito). Fgf13 knockout did not alter whole-cell protein levels of Kv4.2 and Kv4.3, the Ito pore-forming subunits, but did decrease Kv4.2 and Kv4.3 at the sarcolemma. No changes were seen in the sustained outward K+ current or voltage-gated Ca2+ current, other candidate contributors to the increased action potential duration. These results implicate that FGF13 is a critical cardiac Na+ channel modulator and Fgf13 knockout mice have increased arrhythmia susceptibility in the setting of Na+ channel blockade. The unanticipated effect on Ito revealed new FGF13 properties and the unexpected lack of an effect on voltage-gated Ca2+ channels highlight potential compensatory changes in vivo not readily revealed with acute Fgf13 knockdown in cultured cardiomyocytes.

Dataset Information

Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.

Publications

Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts.

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