The overall goal of Project III is to investigate the ionic mechanisms underlying the effects of volatile anesthetics and anesthetic-induced preconditioning (APC) on cardiac electrophysiology. APC mimics ischemic preconditioning (IPC) as quantified by reduction in infarct size, but whether it also provides protection from cardiac arrhythmias during myocardial ischemia and reperfusion is not well established. The experiments proposed in Project In will characterize cardiac rhythm in APC rats using the Langendorff isolated heart methodology, and investigate the underlying ionic mechanisms using the patch clamp technique. Though activation of the sarcolemmal KATPchannel, hypothesized to occur during APC, can profoundly affect cardiac electrophysiology, the intracellular signaling pathways thought to mediate APC, for example, PKC (protein kinase C), PTK (protein tyrosine kinase), and MAPK (mitogen-activated protein kinase) pathways, also modulate the voltage-gated channels. The key question is whether these changes in signal transduction have a """"""""delayed"""""""" effect on the ion channels to coincide with the time course of APC. The general hypothesis to be tested in this proposal is that volatile anesthetics produce cardioprotective antiarrhythmic effects by facilitating the actions of the kinase-dependent pathways potentiated or triggered by APC on the voltage-gated ion channels, specifically the fast Na, L-type Ca and transient outward K channels. This will be tested by utilizing rats post-APC and various genetic strains of rats with differential sensitivity to APC. The following aims and hypotheses will be pursued:
Aim I : To characterize the effects of APC on cardiac rhythm using the Langendorff isolated heart.
Aim II : To characterize the effects of volatile anesthetics on the cardiac action potential in ventricular myocytes isolated from normal and APC rat hearts.
Aim III : To characterize the modulation of I(Na), I(Ca),L and I(to) in ventricular myocytes isolated from normal and APC rat hearts. Functional protection, particularly with regard to suppression of arrhythmias associated with myocardial ischemia and reperfusion, has yet to be clearly established. The experiments designed in this proposal will characterize the role of ion channels other than the sarcolemmal K(ATP) channel in contributing to the antiarrhythmic effects of APC.
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