Isoproterenol mimics calcium preconditioning-induced protection
against ischemia.
Miyawaki, Hiroshi, Muhammad Ashraf.
Department of Pathology and Laboratory Medicine, University of
Cincinnati Medical Center, Cincinnati, Ohio 45267-0529
APStracts 3:0368H, 1996.
We tested the hypothesis that a transient increase in intracellular
calcium ([Ca2+]i) prior to prolonged ischemia triggers the activation
of protein kinase C (PKC) resulting in significant protection against
ischemic injury. Ca2+ preconditioning (3 cycles of 1 min Ca2+
depletion and 5 min Ca2+ repletion) and pharmacological intervention
with isoproterenol (ISO) were employed to increase the Ca2+ influx.
Langendorff-perfused rat hearts were subjected to 40 min of global
ischemia followed by 30 min of reperfusion (I/R). A significant
functional recovery and minimal biochemical changes were observed in
Ca2+ preconditioned hearts following ischemia and reperfusion.
Pretreatment with 0.1 [mu]mol/L ISO caused a sudden increase in left
ventricular contractility, a significant decrease in LDH release,
preservation of ATP content and left ventricular function as compared
to non treated-I/R hearts. Administration of verapamil during ISO
-treatment blunted the salutary effects of ISO on I/R, and
pretreatment with BAY K 8644, L-type Ca2+ channel opener, mimicked
ISO-induced protection. Addition of propranolol or specific PKC
inhibitors (chelerythrine or bisindolylmaleimide) during ISO infusion
completely abolished the beneficial effects of ISO. These results
demonstrate that (1) treatment with low dose of ISO provides
significant protection against ischemic injury, (2) transient
elevation of [Ca2+]i is a strong activator of PKC, and (3) PKC plays
a crucial role in the subcellular mechanisms of protection by
activating second messenger signals during ISO-induced
preconditioning.
Received 23 February 1996; accepted in final form 19 August 1996.
APS Manuscript Number H180-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 19 September 1996