Norepinephrine induces cardiac heat shock protein 70 and delayed cardioprotection in the rat through alpha 1 adrenoceptors

Objective: Previous studies have demonstrated that norepinephrine (NE) confers immediate cardioprotection against ischemia and reperfusion injuries. The present study tests the hypothesis that in vivo treatment with NE induces delayed cardioprotection against postischemic dysfunction in the rat heart which is associated with expression of c-fos and heat shock protein (HSP) 70 in the myocardium. Methods: Rats were treated with NE (3.1 μmol/kg, ip) and hearts isolated and perfused with a modified Langendorff technique 2 or 24 h after injection. Left ventricular developed pressure (LVDP) and left ventricular end-diastolic pressure (LVEDP) were recorded during 25 min normothermic global ischemia and 40 min reperfusion. Total RNA was extracted from left ventricular tissue at various time points and Northern hybridization was applied to detect c-fos and HSP70 mRNAs. Expression and distribution of c-fos and HSP72 proteins in the myocardium were examined by immunohistochemical staining. Results: In vivo NE treatment improved postischemic recovery of both LVDP and LVEDP in the hearts isolated at 24 h after treatment but not in those isolated at 2 h. LVDP was 68.9 ± 4.8 mmHg in NE 24 h group at the end of reperfusion in comparison to 43.6 ± 2.9 mmHg in saline control group ( P < 0.01). Pretreatment with prazosin abolished NE-induced cardioprotection while propranolol pretreatment had no effect. Northern analysis demonstrated rapid and transient increases in c-fos and HSP70 mRNAs in the myocardium after NE treatment. Accumulation of c-fos protein was observed at 3 h and increased amount of HSP72 protein was demonstrated at 24 h in the myocardium. Pretreatment of rats with prazosin eliminated NE-induced increase in cardiac HSP70 mRNA. Conclusions: The results suggest that in vivo treatment with NE upregulates the expression of c-fos and HSP70 in the myocardium and induces delayed protection against postischemic myocardial dysfunction in the isolated rat heart. Induction of both the expression of cardiac HSP70 and the delayed cardioprotection by NE appears to be mediated by α 1 adrenoceptors.