Inducible Nitric Oxide Synthase as a Possible Target in Hypertension

Abstract

Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derived from three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relatively small amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associated with iNOS activity may have detrimental consequences to the cardiovascular system and contribute to hypertension. In this article, we reviewed current literature and found mounting evidence indicating that increased iNOS expression and activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO produced by iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress and endothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete with eNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhanced production of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute to hypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on different animal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosative stress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potential pharmacological target in hypertension.

Metabolomic signature of arterial stiffness in male patients with peripheral arterial disease

“…7 These results are intriguing, as arginine increases endothelial NO production. 24 However, in our study, there were no differences in arginine or citrulline levels between the PAD patients and the controls. Differences between the results of the studies could be explained by the fact that arginine metabolism is mainly related to coronary rather than peripheral atherosclerosis.…”

The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells

“…In this study, we have identified Ang-(1-7) as a novel player in preventing the pro-inflammatory activation of human VSMC. More specifically, Ang-(1-7) attenuated the induction of iNOS, a NO-generating enzyme that is found over-activated in a series of vascular diseases running with low grade inflammation, such as atherosclerosis, hypertension or diabetic vasculopathy (Shimokawa and Tsutsui, 2010; Di Pietro et al, 2013; Oliveira-Paula et al, 2014). …”

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

“…NO signaling in the brain may be pro-or antihypertensive depending on the NOS isoform that generates this gas molecule and the site of action (4,35). Unlike endothelial NOS (eNOS) and neuronal NOS (nNOS), which constitutively express in endothelial cells or other specific neurons (10, 29), brain iNOS is rarely expressed in normal physiological conditions, and its expression could be dramatically enhanced in pathogenesis condition or under oxidative stress (29). The NO produced by iNOS functions as a neuronal neuromodulator and can regulate the release of neurotransmitters and alter neuronal activity (34).…”