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1 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
* To whom correspondence should be addressed. E-mail: kmm{at}interchange.ubc.ca.
Studies in streptozotocin (STZ) induced diabetic rats have demonstrated cardiovascular abnormalities such as depressed mean arterial blood pressure (MABP) and heart rate (HR), endothelial dysfunction and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60mg/kg STZ via the tail vein. One, 3, 9 or 12-weeks following STZ injection, MABP, HR and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin-2 (AT II) were constructed in the presence of 1400W (N- [-3(Aminomethyl) Benzyl] acetamidine, dihydrochloride), a specific inhibitor of iNOS. Depressed MABP, HR and impairment of endothelial function were observed as early as 3 weeks after induction of diabetes. Acute inhibition of iNOS with 1400W (3mg/kg iv) restored the attenuated pressor responses to both MTX and AT II without affecting the basal MABP and HR. Immunohistochemical and western blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine (NT) with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction.
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