Inducible nitric oxide synthase depresses cardiac contractile function in Zucker diabetic fatty rats

Cardiac contractile dysfunction is a common occurrence in type 2 diabetes. The aim was to examine if inducible nitric oxide synthase (iNOS) causes cardiac dysfunction in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. ZDF and Zucker lean control rats (20 week old) were studied at 6 h after recovery from halothane anaesthesia and surgery that involved insertions of catheters into the iliac arteries, iliac veins and the left ventricle via the right carotid artery. Protein expression and activity of iNOS in the hearts were measured by immunostaining and arginine-citrulline conversion assay, respectively. Both groups had similar baseline left ventricular developed pressure and maximum rate of rise of left ventricular pressure (+dP/dt), but heart rate and rate pressure product were lower in the ZDF than control rats. Dobutamine dose-dependently increased left ventricular developed pressure, +dP/dt, heart rate and rate pressure product in both groups, but the responses were less in the diabetic than control rats. The activity and protein expression of iNOS and nitrotyrosine were higher in the hearts of the diabetic than control rats. Selective inhibition of iNOS by 1400 W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the effects of dobutamine on left ventricular developed pressure and rate pressure product in the diabetic rats. The results indicate that activation of iNOS contributed to left ventricular contractile dysfunction in the ZDF rats, and this was partially reversed by selective inhibition of the activity of iNOS.