Role of Neural NO Synthase (nNOS) Uncoupling in the Dysfunctional Nitrergic Vasorelaxation of Penile Arteries from Insulin-Resistant Obese Zucker Rats

Abstract

ObjectiveErectile dysfunction (ED) is considered as an early sign of vascular disease due to its high prevalence in patients with cardiovascular risk factors. Endothelial and neural dysfunction involving nitric oxide (NO) are usually implicated in the pathophysiology of the diabetic ED, but the underlying mechanisms are unclear. The present study assessed the role of oxidative stress in the dysfunctional neural vasodilator responses of penile arteries in the obese Zucker rat (OZR), an experimental model of metabolic syndrome/prediabetes.Methods and ResultsElectrical field stimulation (EFS) under non-adrenergic non-cholinergic (NANC) conditions evoked relaxations that were significantly reduced in penile arteries of OZR compared with those of lean Zucker rats (LZR). Blockade of NO synthase (NOS) inhibited neural relaxations in both LZR and OZR, while saturating concentrations of the NOS substrate L-arginine reversed the inhibition and restored relaxations in OZR to levels in arteries from LZR. nNOS expression was unchanged in arteries from OZR compared to LZR and nNOS selective inhibition decreased the EFS relaxations in LZR but not in OZR, while endothelium removal did not alter these responses in either strain. Superoxide anion production and nitro-tyrosine immunostaining were elevated in the erectile tissue from OZR. Treatment with the NADPH oxidase inhibitor apocynin or acute incubation with the NOS cofactor tetrahydrobiopterin (BH4) restored neural relaxations in OZR to levels in control arteries, while inhibition of the enzyme of BH4 synthesis GTP-cyclohydrolase (GCH) reduced neural relaxations in arteries from LZR but not OZR. The NO donor SNAP induced decreases in intracellular calcium that were impaired in arteries from OZR compared to controls.ConclusionsThe present study demonstrates nitrergic dysfunction and impaired neural NO signalling due to oxidative stress and nNOS uncoupling in penile arteries under conditions of insulin resistance. This dysfunction likely contributes to the metabolic syndrome-associated ED, along with the endothelial dysfunction also involving altered NO signalling.

Diminished Neurogenic Femoral Artery Vasoconstrictor Response in a Zucker Obese Rat Model: Differential Regulation of NOS and COX Derivatives

“…Under these same conditions of insulin resistance, modified neural NO-mediated relaxant responses due to oxidative stress have been reported in penile arteries [14]. The present results suggest that oxidative stress may be involved in the changes that limit the activity of endothelial NO, due to the inhibitory effect of SOD in femoral arteries from obese animals with an intact endothelium but not in denuded preparations.…”

Regulation of obesity and insulin resistance by nitric oxide

“…Indeed, the ratio of BH 4 to BH 2 is critical in preventing glucose-induced NOS3 uncoupling [210] and replenishment of BH 4 pools via either providing sepiapterin or by inducing pathways that increase biopterin synthesis or maintain BH 4 in its reduced state have proven effective in multiple pathological scenarios (for review, see [201, 202, 211-213]). Uncoupling of NOS does not appear to be a factor unique to NOS3, however, as NOS1 was shown to be uncoupled in penile arteries of obese rats, leading to nitrergic dysfunction, which was corrected by increasing BH 4 levels [214]. …”

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

“…Impaired NO signaling because of nNOS uncoupling and oxidative stress was recently observed in the cerebral artery of Zucker obese rats 53 and in penile arteries under conditions of insulin resistance. 54 PIN was demonstrated in a recent study 55 to decrease the catalytically active dimeric nNOS via ubiqutin-dependent proteolytic degradation of the enzyme in the brain. Whether this modification of nNOS activity by PIN contributes to ROS generation under the condition of MetS awaits further investigation.…”