nNOS-dependent reactivity of cerebral arterioles in Type 1 diabetes

Abstract

Our goals were to determine whether Type 1 diabetes (T1D) alters neuronal nitric oxide synthase (nNOS) dependent reactivity of cerebral arterioles and to identify a potential role for oxidative stress in T1D-induced impairment in nNOS-dependent responses of cerebral arterioles. Rats were injected with vehicle (sodium citrate buffer) or streptozotocin (50 mg/kg IP) to induce T1D. Two to three months later, we measured functional responses of cerebral arterioles to nNOS-dependent (NMDA and kainate) and -independent (nitroglycerin) agonists in nondiabetic and diabetic rats before and during inhibition of oxidative stress using tempol (100 μM). In addition, we measured superoxide anion production under basal conditions, during stimulation with NMDA and kainate, and during treatment with tempol. We found that nNOS-dependent, but not -independent, vasodilatation was impaired in diabetic compared to nondiabetic rats. In addition, treatment of the cerebral microcirculation with tempol restored impaired nNOS-dependent vasodilatation in diabetic rats towards that observed in nondiabetic rats. Further, the production of superoxide anion (lucigenin chemiluminescence) was increased in parietal cortical tissue of diabetic rats under basal conditions. Application of NMDA and kainate did not increase superoxide anion production in nondiabetic or diabetic rats. However, tempol decreased basal production of superoxide anion in diabetic rats. Our findings suggest that T1D impairs nNOS dependent dilatation of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide anion.

Cerebrovascular Complications of Diabetes: Focus on Stroke

“…These include nitric oxide production by nitric oxide synthase, activation of potassium channels leading to the hyperpolarization of vascular smooth muscle, and beta-adrenergic stimulation of adenylate cyclase. 72 Diabetes induces alterations in these dilator pathways that lead to impaired reactivity and contribute to the pathogenesis of stroke. 50 Studies investigating T1D effects on the vasculature using STZ-induced models predominate the literature; however, there are some reports in genetic models of T2D.…”

“…50,73,74,75,76 Its cause is multifactorial and has been attributed to increased oxidative stress, 74, 77,78,79 disturbances in NO synthesis and production, 72, 75,80 impairment of vascular smooth muscle ion channels, 81,82,83 and inhibition of Rho-kinase activity. 74 …”

Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes

“…[1][2][3][4][5][6][7][8][9][10] Many mechanisms have been proposed to account for impaired eNOSand nNOS-dependent responses of cerebral arteries/ arterioles during diabetes, including the production of a cyclooxygenase constrictor substance, 9 activation of protein kinase C 11,12 and an increase in oxidative stress via activation of multiple cellular pathways. 8,[13][14][15][16][17] Activation of nitric oxide synthases (NOS) has the ability to produce nitric oxide and superoxide. 18,19 The production of nitric oxide requires arginine as a substrate and several cofactors [nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), calcium and tetrahydrobiopterin (BH 4 )] for normal activity.…”

Cerebrovascular complications of diabetes: focus on cognitive dysfunction

“…Causes of vascular dysfunction are multifactorial, with increased oxidative stress (130–132), disturbances in NO synthesis and production (133), ion channel impairment in VSMCs (134,135), as well as stimulation of Rho-kinase activity contributing to this dysfunction (132). Cerebrovascular dysfunction in diabetes has been shown in experimental models to have enhanced constriction, reduced dilatory function and impaired myogenic tone, which contribute to a global reduction in CBF (136).…”

“…Cerebral arteries express decreased dilator responses to acetylcholine, adenosine 5’-diphosphate, and beta-adrenergic receptor activation (131,133). Impairment of NOS-dependent reactivity has been rescued through treatment of enalapril (145), apocynin (131), tempol (146), chronic ETA receptor blockade (147), and poly (ADP-ribose) polymerase (PARP) inhibition (146). The duration of diabetes has been seen to impact vessel function and reactivity to vasoactive agents.…”