Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Abstract

(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 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N- [3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine 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. inducible nitric oxide synthase; nitric oxide; cardiovascular abnormalities CHRONIC HYPERGLYCEMIA has been shown to directly affect the composition and structure of cardiac, vascular, and renal tissues, the progressive modification of which results in a deranged cardiovascular homeostasis (8). Cardiovascular depression, characterized by depressed mean arterial blood pressure (MABP), heart rate (HR), and attenuated pressor responses to vasoactive agents is one of the most notable manifestations of this derangement, particularly in animal models of Type 1 diabetes. Although the exact mechanisms by which diabetes contributes to cardiovascular depression are currently unknown, it is likely that hyperglycemia may initiate this abnormality through the activation of protein kinase C, increased activity of the polyol pathway, formation of nonenzymatic advanced glycosylation end products, oxidative stress, and/or possibly by induction of nitric oxide (NO) synthase (NOS) (19,42).The role of NO in the regulation of hemodynamics under hyperglycemic conditions has been controversial. Despite an impairment of endothelial function and reduced bioavailability of endothelium-derived NO, streptozotocin (STZ)-induced diabetic rats are not hypertensive but instead are normotensive or hypotensive (9,14,18,20,23,31,39,44). In addition, an increased dependence on a functional NO system at the onset of diabetes has been reported to prevent the development of hypertension in STZ diabetic rats (12). It has been suggested that increased NO synthesis m...

Oxidative Stress, Nitric Oxide, and Diabetes

“…Recent reports reveal that decreased expression of eNOS accompanies increased expression of iNOS and nitrotyrosine during the progression of diabetes in rats [81]. This finding suggests that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to depressed responses to vasoactive agents.…”

Oxidative stress is not associated with vascular dysfunction in a model of alloxan-induced diabetic rats

“…This hypothesis is based on the inherent capacity of iNOS to produce greater amounts of NO (in the order of nanomols to micromols) (39) and on the fact that the aorta from our diabetic animals, treated or not, presented increased intensities of immunostaining for iNOS. Therefore, despite a reduction in eNOS immunostaining in the endothelium from the aorta of diabetic rats, which was observed by other authors (40,41), the increase in iNOS immunostaining could have made sufficient NO available to exert its biological effects. These ideas were also defended by Bojunga and cols., who had similar results (42).…”

Dietary coconut kernel protein beneficially modulates NFκB and RAGE expression in streptozotocin induced diabetes in rats

“…It was found that, apart from endothelial cells, NO from sources such as inducible NOS (iNOS) and neuronal NOS (nNOS) may contribute to increased NO in diabetes (Nagareddy et al 2005). Increased expression and activity of iNOS in superior mesenteric arteries (SMA) from 12-14 week STZ-induced diabetic rats were reported earlier (Bardell and MacLeod 2001).…”