We recently reported that long-term treatment with
pioglitazone restored cardiac Akt phosphorylation in response to
hyperthermia (HT) and subsequent cardiac
heat-shock protein 72 (HSP72) expression, in heredity
insulin resistance rats via improvement of
insulin sensitivity. Because
adrenomedullin (AM) promotes Akt phosphorylation and attenuates
myocardial ischemia/
reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against
ischemia/reperfusion injury in this model. At 16 wk of age, male
insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a
phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in
insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released
creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a
phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against
ischemia/reperfusion injury. This intervention was effective even in
insulin-resistant hearts.