Angiotensin II Inhibits Neuronal Nitric Oxide Synthase Activation Through the ERK1/2-RSK Signaling Pathway to Modulate Central Control of Blood Pressure

Abstract

Rationale: Angiotensin (Ang) II exerts diverse physiological actions in both the peripheral and central neural systems. It was reported that the activity of Ang II is higher in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and that angiotensin type-1 receptors are colocalized with NAD(P)H oxidase in the neurons of the NTS, resulting in the induction of local reactive oxygen species production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain unclear. Objective: The aim of this study was to investigate the possible signaling pathways involved in Ang II-mediated blood pressure regulation in the NTS. Methods and Results: Male SHRs were treated with losartan or tempol for 2 weeks, after which systolic blood pressure was observed to decrease significantly. Dihydroethidium staining showed many cells with high reactive oxygen species in the NTS of SHRs. The addition of losartan or tempol decreased the numbers of reactive oxygen species-positive cells in the NTS. The systemic administration of losartan or tempol reduced the systolic blood pressure and increased NO production. Immunoblotting and immunohistochemical analysis further showed that inhibition of Ang II activity by losartan or tempol significantly increased the expression extracellular signal-regulated kinase (ERK)1/2, ribosomal protein S6 kinase (RSK), and also increased neuronal NO synthase (nNOS) phosphorylation. RSK was also found to bind directly to nNOS and induce phosphorylation at the Ser1416 position. Conclusions: Taken together, these results suggest that the ERK1/2-RSK-nNOS signaling pathway may play a significant role in Ang II-mediated central blood pressure regulation. (Circ Res. 2010;106:788-795.)Key Words: angiotensin II Ⅲ nucleus tractus solitarii Ⅲ neuronal nitric oxide synthase Ⅲ ribosomal protein S6 kinase Ⅲ reactive oxygen species T he nucleus tractus solitarii (NTS), which is located in the dorsal medulla of the brain stem, is the primary site of termination of the vagus and glossopharyngeal nerves. The NTS participates in cardiovascular, gastric, and gustatory control. Our previous studies demonstrated that several neuromodulators are involved in cardiovascular control of the NTS, including ATP, 1 adenosine, 2 neuropeptide Y, 3 angiotensin (Ang) II, 4 NO, 5 carbon monoxide, 6 and insulin. 7 Ang II is a powerful vasoconstrictor in the peripheral blood system that exerts effects on the central nervous system, regulating fluid balance and the secretion of aldosterone. Hyperactivity of Ang II has been shown to play a major role in hypertension. 8,9 Ang II is produced from enzymatic cleavage of angiotensinogen by renin and then by angiotensin converting enzyme. These pathological and physiological actions of Ang II are mediated through its type 1 receptor (AT 1 R). 10 Recent evidence suggests that hyperactivity of the brain renin-angiotensin system may play a critical role in mediating hypertension in spontaneously hypertensive rats (SHRs). 11 Significant differences in AT 1...

Caffeine Intake Improves Fructose-Induced Hypertension and Insulin Resistance by Enhancing Central Insulin Signaling

“…28 In a previous study, we showed that angiotensin II induces superoxide generation, which impairs NO production in the NTS. 10 The depressor effect of NO in the NTS occurs through the inhibition of sympathetic nervous activity. 30 Our findings extend previous observations that central insulin resistance in the NTS might participate in a superoxide-dependent pathway via the impairment of NO production to produce hypertension of fructose-fed rats.…”

“…Furthermore, NO has important modulatory functions in the NTS, including the modulation of arterial BP and sympathetic nerve activity. 10 In previous experiments, we demonstrated that insulin microinjected into the NTS induces a depressor effect and initiates an interaction between insulin and phosphatidylinositol 3-kinase Abstract-Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide.…”

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit

“…In particular, previous studies have demonstrated that several neuromodulators, including angiotensin II acting on AT 1 receptors, are involved in cardiovascular regulation within the NTS (Arnold et al, 2010;Cheng et al, 2010Cheng et al, , 2012Kasparov et al, 1998;Mosqueda-Garcia et al, 1990). Accordingly, high levels of ACE (Rogerson et al, 1995) and high densities of AT 1 receptors have been found at the level of the NTS in the rabbit (Aldred et al, 1993) as well as in many other mammals including humans (Paul et al, 2006;Premer et al, 2013;Wright and Harding, 2011).…”

Angiotensin-II Induced Reactive Oxygen Species: Implications in Neurogenic Hypertension

“…But recently, Wen et al [36] found nNOS increased after inhibition of Ang II downstream of AT 1 R or depletion of ROS in the NTS of SHR S which suggests nNOS might be one of the downstream targets of Ang II that is involved in NO production and that modulates blood pressure function in the NTS of SHRs. They also observed that ROS accumulation inhibited ERK1/2 activation in the NTS and induced hypertension.…”