Neuronal nitric oxide synthase expression is lower in areas of the nucleus tractus solitarius excited by skeletal muscle reflexes in hypertensive rats

Abstract

Murphy MN, Mizuno M, Downey RM, Squiers JJ, Squiers KE, Smith SA. Neuronal nitric oxide synthase expression is lower in areas of the nucleus tractus solitarius excited by skeletal muscle reflexes in hypertensive rats. Am J Physiol Heart Circ Physiol 304: H1547-H1557, 2013. First published April 5, 2013; doi:10.1152/ajpheart.00235.2012.-The functions of the skeletal muscle exercise pressor reflex (EPR) and its mechanically sensitive component are augmented in hypertension producing exaggerated increases in blood pressure during exercise. Afferent information from the EPR is processed in the nucleus tractus solitarius (NTS). Within the NT, nitric oxide (NO), produced via L-arginine oxidation by neuronal nitric oxide synthase (nNOS), buffers the pressor response to EPR activation. Therefore, EPR overactivity may manifest as a decrease in NO production due to reductions in nNOS. We hypothesized that nNOS protein expression is lower in the NTS of spontaneously hypertensive (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. Further, we examined whether nNOS is expressed with FOS, a marker of neuronal excitation induced by EPR activation. The EPR and mechanoreflex were intermittently activated for 1 h via hindlimb static contraction or stretch, respectively. These maneuvers produced significantly greater pressor responses in SHR during the first 25 min of stimulation. Within the NTS, nNOS expression was lower from Ϫ14.9 to Ϫ13.4 bregma in SHR compared with WKY. For example, at Ϫ14.5 bregma the number of NTS nNOS-positive cells in SHR (13 Ϯ 1) was significantly less than WKY (23 Ϯ 2). However, the number of FOS-positive cells after muscle contraction in this area was not different (WKY ϭ 82 Ϯ 18; SHR ϭ 75 Ϯ 8). In both groups, FOS-expressing neurons were located within the same areas of the NTS as neurons containing nNOS. These findings demonstrate that nNOS protein expression is lower within NTS areas excited by skeletal muscle reflexes in hypertensive rats.hypertension; exercise; nucleus tractus solitarius PHYSICAL ACTIVITY INDUCES increases in arterial blood pressure (ABP), heart rate (HR), and sympathetic nerve activity (20,32). In hypertension, exercise evokes abnormally exaggerated elevations in each of these variables (2, 9, 27). This places hypertensive patients at a greater risk for the occurrence of an adverse cardiovascular and/or cerebrovascular event during or immediately after a bout of exercise (6, 21). As a result, the intensity and duration of exercise prescription at a level that is both safe and therapeutically effective are often limited. Thus determining the cause of the cardiovascular hyperexcitability manifest in hypertension is clinically important.Exercise-induced autonomic changes in the cardiovascular system are mediated by the central command, the arterial baroreflex and the exercise pressor reflex (EPR; Refs. 4,18,19). Of these, recent evidence in both the animal and human literature suggests that the EPR contributes significantly to the abnormally accentuated circulatory response to ...

Dynamic exercise training prevents exercise pressor reflex overactivity in spontaneously hypertensive rats

“…Heart weight-tobody weight ratio as well as heart weight-to-tibial length ratio were significantly greater in SHR than WKY as previously reported (42,43,47,60). Further, exercise training significantly increased these ratios in both WKY and SHR.…”

“…Consistent with our previous studies, EPR function was abnormally heightened in untrained SHR compared with WKY (26,42,43,47,60). This characteristic EPR overactivity has been shown to manifest not only in SHR but also in other models of the disease such as prenatally programmed hypertension (41,44) and angiotensin II-induced hypertension (24).…”

“…Within the medulla, the production of nitric oxide (NO) within the nucleus tractus solitarius (NTS), the site most critical for processing EPR sensory signals, buffers reflex-induced increases in SNA (56). It has been demonstrated that expression of neuronal NO synthase (NOS), necessary for the production of NO, is reduced throughout a large portion of the NTS in hypertensive rats (47). This could compromise NO production within the NTS of hypertensive animals reducing its sympathetic buffering capacity.…”

GABA_B Receptor Gene Transfer Into the Nucleus Tractus Solitarii Induces Chronic Blood Pressure Elevation in Normotensive Rats

“…A third possibility is that enhanced GBR expression in the NTS of SHR may be caused by other neural modulators, such as nitric oxide (NO) or reactive oxygen species (ROS). It has been reported that NO production in the NTS of SHR is reduced as compared with WKY rats (16), and enhanced NO production in this brain area by overexpression of eNOS lowers blood pressure in SHR (17). On the other hand, ROS generation in the NTS is increased in SHR.…”

The exercise pressor reflex in hypertension

“…Evidence suggests that centrally-derived nitric oxide inhibits sympathetic outflow 109,110) . Using immunohistochemical and western blotting techniques, we showed that the expression of at least one isoform of nitric oxide synthase protein (i.e., neural nitric oxide synthase) is lowered throughout a large portion of the NTS in hypertensive compared to normotensive rats 111) . From such investigation, we further demonstrated that reducing the endogenous production of nitric oxide within the NTS generates overactive muscle mechanoreflex activity in normotensive rats similar to that exhibited in hypertensive animals 112) .…”