Isoproterenol mimics calcium preconditioning-induced protection against ischemia.
We tested the hypothesis that a transient increase in intracellular calcium concentration ([Ca2+]i) before 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 after I/R. Pretreatment with 0.1 micromol/l Iso caused a sudden increase in left ventricular contractility, a significant decrease in lactate dehydrogenase release, preservation of ATP content, and left ventricular function compared with nontreated I/R hearts. Administration of verapamil during Iso treatment blunted the salutary effects of Iso on I/R and pretreatment with BAY K 8644, an 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 a 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.
Miyawaki
H
H
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Ohio 45267-0529, USA.
Ashraf
M
M
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011493:Protein Kinase C; D007545:Isoproterenol; D002118:Calcium