Iseproterenol 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 μmol/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.