iNOS inhibition causes myocardial abnormalities through an AKT dependent pathway

Increased expression of inducible nitric oxide synthase (iNOS) during periods of cardiac stress has shown to be both beneficial and detrimental to cardiac contractile performance depending on the stress condition. However, if iNOS plays a role in the maintenance of normal cardiac function remains to be established. This study was designed to determine whether chronic iNOS inhibition has an effect on cardiac function and whether this effect worked through the AKT pathway, considering the relationship between Akt and NOS activity. Male C57 or AKT2(−/−) mice were injected with the iNOS specific inhibitor 1400W (2mg/kg/d) or saline for 7 days. Chronic administration of 1400W significantly decreased heart weight and liver weight in wild type but not AKT2(−/−) mice. Edge detection of single myocyte function revealed a significant decrease of peak shortening, shortening/relengthening velocities, and an increased systolic duration in the 1400W administered animals, all of which were ablated in AKT2(−/−) mice. Chronic iNOS inhibition caused decreased insulin and glucose tolerance in wild type but was masked in AKT2(−/−) animals. Nonetheless, AKT2(−/−) mice alone display an insulin resistant phenotype. Taken together, these data show that iNOS does play a role in maintaining normal cardiac function through AKT and helps maintain glucose homeostasis in healthy animals. NIH P20 RR016474