© 2004 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism
Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK
* Corresponding author. Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 9HN, UK. Tel.: +44-116-252-3302; fax: +44-116-252-5045. nbs{at}le.ac.uk
Objective: We have used isolated myocytes to investigate the effects of diazoxide on sarcolemmal KATP channel (sarcoKATP) activity and action potential failure during metabolic inhibition, and the role of these channels in protection of functional recovery on reperfusion. Materials and methods: Isolated adult rat ventricular myocytes were exposed to metabolic inhibition (NaCN and iodoacetate) and reperfusion. Functional recovery was assessed from the ability of cells to contract on electrical stimulation and to recover calcium homeostasis, measured with fura-2. Action potentials and KATP currents were measured using patch clamp. Results: Pretreatment with diazoxide (100 µM, 5 min) increased the proportion of cells that recovered contractile function after MI and reperfusion from 16.8±2.4% to 65.0±2.2% (p<0.001) and the proportion of cells in which [Ca2+]i recovered to <250 nM. Pretreatment also accelerated action potential and contractile failure during MI. In cell-attached patches, MI activated sarcoKATP channels after 224±11 s, and diazoxide pretreatment decreased this to 145±24 s (p<0.01). However, diazoxide present in the patch pipette did not accelerate sarcoKATP channel activation. Intracellular Mg2+ rose earlier in diazoxide-pretreated cells. The sarcoKATP blocker HMR 1883 delayed action potential failure and reduced diazoxide protection. Conclusions: Diazoxide pretreatment increases recovery of function and [Ca2+]i following reperfusion. Protection is coupled with early action potential failure, due to early activation of sarcoKATP channels during metabolic inhibition (MI), which is likely to involve an indirect effect of diazoxide.
KEYWORDS K-ATP channel; Ischemia; Myocytes; Preconditioning; Rat
Time for primary review 26 days
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