Inhibition of iNOS augments cardiovascular action of noradrenaline in streptozotocin-induced diabetes

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Abstract
Objective: The aim was to determine if inducible nitric oxide synthase (iNOS) contributes to depressed cardiovascular function at the acute phase of streptozotocin-induced diabetes. Methods: Male Wistar rats were injected with streptozotocin [60 mg/kg, intravenously (i.v.)] or the vehicle (0.9% NaCl) and were studied 3 weeks later. Results: The diabetic and control rats had similar mean arterial pressure (MAP) and total peripheral resistance (TPR). Noradrenaline (NA) increased in vivo left ventricular contractility (LV +dP/dt), MAP and TPR in both groups; however, the responses were markedly less in the diabetic than control rats. Acute administration of 1400W (selective inhibitor of iNOS; 3 mg/kg followed by 3 mg/kg/h, i.v.) did not alter responses to NA in the control rats, but augmented the influence of NA on MAP, TPR and LV +dP/dt in the diabetic rats. At this time, reverse transcription–polymerase chain reaction (RT-PCR) products (RNA) of iNOS were present in the hearts of the diabetic but not control rats. The activity of iNOS was threefold higher in the hearts of the diabetic rats relative to the controls, and the increase was inhibited by 1400W. Furthermore, immunostaining (proteins) of iNOS and nitrotyrosine (NT; marker of peroxynitrite) were identified in the hearts of the diabetic but not control rats. In contrast, the RT-PCR products of eNOS, activity of eNOS and immunostaining of eNOS were of similar intensity in the hearts of both groups. Conclusions: Activation of iNOS contributes to depressed cardiovascular contractile function to NA at the acute phase of streptozotocin-induced diabetes. Selective inhibition of iNOS partially restored cardiovascular responses to NA.

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