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Sex differences in the mechano‐energetic effects of genistein on stunned rat and guinea pig hearts

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Clinical and Experimental Pharmacology and Physiology

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Although the phytoestrogen genistein (Gen) is considered protective in cardiovascular diseases, its direct effects on stunned hearts after transient ischemia‐reperfusion (I/R) are unknown. Here we studied the effects of 20 μM Gen on the mechano‐calorimetric behavior during I/R of rat and guinea pig hearts to evaluate the energetics of Ca2+ homeostasis. Isolated beating hearts were perfused with control Krebs solution inside a calorimeter with or without perfusion of Gen before a transient period of I/R. Left ventricular pressure development (P) and total heat rate (Ht) were continuously measured. At 37 °C, Gen did not change post‐ischemic contractile recovery (PICR), but it increased the relaxation rate. However, PICR was reduced in hearts of male rats and guinea pigs at 30 °C. Total muscle economy (P/Ht) showed the same behavior as P at each temperature. Inhibition of phosphatases with orthovanadate during Gen perfusion prevented a decrease in PICR in male rat hearts, suggesting that this effect is due to tyrosine kinase inhibition. Reperfusing ischemic hearts with 10 mM caffeine‐36 mM Na+‐Krebs induced contracture dependent on the sarcoreticular Ca2+ content. Contracture relaxation depends on mitochondrial Ca2+ uptake and Gen reduced the relaxation rate. Moreover, Gen prevented the increase in Rhod‐2 fluorescence (free [Ca2+]m) of rat cardiomyocytes. In guinea pig hearts, Gen maintained ischemic preconditioning, but was reduced by 5‐hydroxydecanoate, suggesting the participation of mitochondrial ATP‐dependent K channels. Results suggest that Gen acts on several mechanisms that regulate myocardial calcium homeostasis and energetics during I/R, which differ in a temperature‐ and sex‐dependent manner. This article is protected by copyright. All rights reserved.