Molecular changes in nNOS protein expression within the ventrolateral medulla following transient focal ischemia affect cardiovascular functions (original) (raw)
Related papers
Brain Research, 2006
The enzyme nitric oxide synthase (NOS) which is necessary for the production of nitric oxide from L-arginine exists in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Our previous studies have demonstrated the roles of nNOS and eNOS within the rostral (RVLM) and caudal ventrolateral medulla (CVLM) in modulating cardiovascular responses during static skeletal muscle contraction via altering localized glutamate and GABA levels (Brain Res. 977 (2003) 80-89; Neuroscience Res. 52 (2005) 21-30). In this study, we investigated the role of iNOS within the RVLM and CVLM on cardiovascular responses and glutamatergic/GABAergic neurotransmission during the exercise pressor reflex. Bilateral microdialysis of a selective iNOS antagonist, aminoguanidine (AGN; 1.0 microM), for 60 min into the RVLM attenuated increases in mean arterial pressure (MAP), heart rate (HR), and extracellular glutamate levels during a static muscle contraction. Levels of GABA within the RVLM were increased. After 120 min of discontinuation of the drug, MAP and HR responses and glutamate/GABA concentrations recovered to baseline values during a subsequent muscle contraction. In contrast, bilateral application of AGN (1.0 microM) into CVLM potentiated cardiovascular responses and glutamate concentration while attenuating levels of GABA during a static muscle contraction. All values recovered after 120 min of discontinuation of the drug. These results demonstrate that iNOS within the ventrolateral medulla plays an important role in modulating cardiovascular responses and glutamatergic/GABAergic neurotransmission that regulates the exercise pressor reflex.
Reperfusion Alterations in Nitric Oxide Synthase Isoforms in Acute Lower Limb Ischemia and
2000
Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle. J. Appl. Physiol. 85(4): 1362-1367, 1998.-The effect of nitric oxide synthase (NOS) inhibition and endothelin-A (ET A )receptor blockade on neural sympathetic control of vascular tone in the gastrocnemius muscle was examined in anesthetized dogs under conditions of constant flow. Muscle perfusion pressure (MPP) was measured before and after NOS inhibition (N -nitro-L-arginine methyl ester; L-NAME) and ET Areceptor blockade [cyclo-(D-Trp-d-Asp-Pro-D-Val-Leu); BQ-123]. Zero and maximum sympathetic nerve activities were achieved by sciatic nerve cold block and stimulation, respectively. In group 1 (n ϭ 6), MPP was measured 1) before nerve cold block, 2) during nerve cold block, and 3) during nerve stimulation. Measurements under these conditions were repeated after L-NAME and then BQ-123. The same protocol was followed in group 2 (n ϭ 6) except that the order of L-NAME and BQ-123 was reversed. MPP and muscle vascular resistance (MVR) increased after L-NAME and then decreased to control values after BQ-123. MVR decreased after BQ-123 alone and, with the addition of L-NAME, increased to a level not different from that observed during the control period. MVR fell during nerve cold block. This response was not affected by administration of L-NAME followed by BQ-123, but it was attenuated by administration of BQ-123 before L-NAME. The constrictor response during sympathetic nerve stimulation was enhanced by L-NAME; no further effect was observed with BQ-123, nor was the response affected when BQ-123 was given first. These findings indicate that endothelin contributes to 1) basal vascular tone in skeletal muscle and 2) the increase in skeletal muscle vascular resistance after NOS inhibition. Finally, nitric oxide ''buffers'' the degree of constriction in skeletal muscle vasculature during maximal sympathetic stimulation. endothelin; nitric oxide; vascular resistance 1364 ENDOTHELIAL MODULATION OF SKELETAL MUSCLE VASCULAR TONE by 10.
The Journal of …, 2002
Nitric oxide (NO) attenuates a-adrenergic vasoconstriction in contracting rodent skeletal muscle, but it is unclear if NO plays a similar role in human muscle. We therefore hypothesized that in humans, NO produced in exercising skeletal muscle blunts the vasoconstrictor response to sympathetic activation. We assessed vasoconstrictor responses in the microcirculation of human forearm muscle using near-infrared spectroscopy to measure decreases in muscle oxygenation during reflex sympathetic activation evoked by lower body negative pressure (LBNP). Experiments were performed before and after NO synthase inhibition produced by systemic infusion of N G-nitro--arginine methyl ester (-NAME). Before -NAME, LBNP at _20 mmHg decreased muscle oxygenation by 20 ± 2 % in resting forearm and by 2 ± 3 % in exercising forearm (n = 20), demonstrating metabolic modulation of sympathetic vasoconstriction. As expected, -NAME increased mean arterial pressure by 17 ± 3 mmHg, leading to baroreflex-mediated supression of baseline muscle sympathetic nerve activity (SNA). The increment in muscle SNA in response to LBNP at _20 mmHg also was attenuated after -NAME (before, +14 ± 2; after, +8 ± 1 bursts min _1 ; n = 6), but this effect of -NAME was counteracted by increasing LBNP to _40 mmHg (+19 ± 2 bursts min _1). After -NAME, LBNP at _20 mmHg decreased muscle oxygenation similarly in resting (_11 ± 3 %) and exercising (_10 ± 2 %) forearm (n = 12). Likewise, LBNP at _40 mmHg decreased muscle oxygenation both in resting (_19 ± 4 %) and exercising (_21 ± 5 %) forearm (n = 8). These data advance the hypothesis that NO plays an important role in modulating sympathetic vasoconstriction in the microcirculation of exercising muscle, because such modulation is abrogated by NO synthase inhibition with -NAME.
Nitric Oxide, 2009
While the unequivocal pattern of endothelial nitric oxide (NO) synthase (eNOS) inhibition in cardiovascular control has been recognised, the role of NO produced by neuronal NOS (nNOS) remains unclear. The purpose of the present study was to describe the cardiovascular effects of NO production interference by inhibition of nNOS with 7-nitroindazole (7-NI). Wistar rats (10 weeks old) were used: control and experimental rats were administered 7-NI 10 mg/kg b.w./day in drinking water for 6 weeks. Systolic blood pressure (BP) was measured by the tail-cuff plethysmographic method. Isolated thoracic aortas (TAs) were used to study vasomotor activity of the conduit artery in vitro. The BP response of anaesthetised animals was used to follow the cardiovascular-integrated response in vivo. Geometry of the TA was measured after perfusion fixation (120 mm Hg) by light microscopy. Expression of eNOS was measured in the TA by immunoblot analysis. Although 6 weeks of nNOS inhibition did not alter systolic BP, the heart/body weight ratio was decreased. Relaxation of the TA in response to acetylcholine (10 À9-10 À5 mol/L) was moderately inhibited. However, no difference in the BP hypotensive response after acetylcholine (0.1, 1, 10 lg) was observed. The contraction of TA in response to noradrenaline (10 À10-10 À5 mol/L), and the BP pressor response to noradrenaline (0.1, 1 lg) was attenuated. The inner diameter of the TA was increased, and the wall thickness, wall cross-sectional area, and wall thickness/inner diameter ratio were decreased. The expression of eNOS in the TA was increased. In summary, cardiac and TA wall hypotrophy, underlined by decreased contractile efficiency, were observed. The results suggested that two constitutive forms of NOS (nNOS, eNOS) likely participate in regulation of cardiovascular tone by different mechanisms.
Physiological Genomics, 2000
Lau, Kim S., Robert W. Grange, Eiji Isotani, Ingrid H. Sarelius, Kristine E. Kamm, Paul L. Huang, and James T. Stull. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol. Genomics 2: 21–27, 2000.—Nitric oxide (NO) from Ca2+-dependent neuronal nitric oxide synthase (nNOS) in skeletal muscle fibers may modulate vascular tone by a cGMP-dependent pathway similar to NO derived from NOS in endothelial cells (eNOS). In isolated fast-twitch extensor digitorum longus (EDL) muscles from control mice, cGMP formation increased ∼166% with electrical stimulation (30 Hz, 15 s). cGMP levels were not altered in slow-twitch soleus muscles. The NOS inhibitor Nω-nitro-l-arginine abolished the contraction-induced increase in cGMP content in EDL muscles, and the NO donor sodium nitroprusside (SNP) increased cGMP content ∼167% in noncontracting EDL muscles. SNP treatment but not electrical stimulation increased cGMP formation in muscles from nNOS...
Frontiers in Physiology, 2016
Resistance training is one of the most common kind of exercise used nowadays. Long-term high-intensity resistance training are associated with deleterious effects on vascular adjustments. On the other hand, is unclear whether low-intensity resistance training (LI-RT) is able to induce systemic changes in vascular tone. Thus, we aimed to evaluate the effects of chronic LI-RT on endothelial nitric oxide (NO) bioavailability of mesenteric artery and cardiovascular autonomic modulation in healthy rats. Wistar animals were divided into two groups: exercised (Ex) and sedentary (SED) rats submitted to the resistance (40% of 1RM) or fictitious training for 8 weeks, respectively. After LI-RT, hemodynamic measurements and cardiovascular autonomic modulation by spectral analysis were evaluated. Vascular reactivity, NO production and protein expression of endothelial and neuronal nitric oxide synthase isoforms (eNOS and nNOS, respectively) were evaluated in mesenteric artery. In addition, cardiac superoxide anion production and ventricle morphological changes were also assessed. In vivo measurements revealed a reduction in mean arterial pressure and heart rate after 8 weeks of LI-RT. In vitro studies showed an increased acetylcholine (ACh)-induced vasorelaxation and greater NOS dependence in Ex than SED rats. Hence, decreased phenylephrine-induced vasoconstriction was found in Ex rats. Accordingly, LI-RT increased the NO bioavailability under basal and ACh stimulation conditions, associated with upregulation of eNOS and nNOS protein expression in mesenteric artery. Regarding autonomic control, LI-RT increased spontaneous baroreflex sensitivity, which was associated to reduction in both, cardiac and vascular sympathetic modulation. No changes in cardiac superoxide anion or left ventricle morphometric parameters after LI-RT were observed. In summary, these results suggest that RT promotes beneficial vascular adjustments favoring augmented endothelial NO bioavailability and reduction of sympathetic vascular modulation, without evidence of cardiac overload.
Hypertension, 2011
Neurohumoral activation, a hallmark in heart failure (HF), is linked to the progression and mortality of HF patients. Thus, elucidating its precise underlying mechanisms is of critical importance. Besides its classical peripheral vasodilatory actions, the gas nitric oxide (NO) is a pivotal neurotransmitter in the central nervous system (CNS) control of the circulation. While accumulating evidence supports a contribution of blunted NO function to neurohumoral activation in HF, the precise cellular sources, and NO synthase (NOS) isoforms involved, remain unknown. Here, we used a multidisciplinary approach to study the expression, cellular distribution and functional relevance of the endothelial NOS isoform (eNOS) within the hypothalamic paraventricular (PVN) nucleus in Sham and HF rats. Our results show high expression of eNOS in the PVN (mostly confined to astroglial cells), which contributes to constitutive NO bioavailability, as well as tonic inhibition of presympathetic neuronal activity and sympathoexcitatory outflow from the PVN. A diminished eNOS expression and eNOS-derived NO availability was found in the PVN of HF rats, resulting in turn in blunted NO inhibitory actions on neuronal activity and sympathoexcitatory outflow. Taken together, our study supports blunted CNS eNOS-derived NO as a pathophysiological mechanism underlying neurohumoral activation in HF.
Nitric oxide : biology and chemistry, 2018
Nitric oxide (NO), an intercellular signaling molecule is relevant for circulatory autonomic control. Brain NO synthase (NOS) and NO levels were downregulated in pathological conditions, but rescued after exercise training. We hypothesized that exercise training was also able to improve NO modulation within the hypothalamic paraventricular nucleus (PVN) of healthy rats. Male Wistar rats were submitted to two 4-weeks protocols: i) swimming training (T) or kept sedentary (S), ii) l-arginine (62,5 mg/mL, 1 mL/day p. o.) or vehicle supplementation. Rats underwent stereotaxic surgery (PVN bilateral guide cannulas) and chronic catheterization of artery/vein. Arterial pressure (AP), heart rate (HR) and baroreflex sensitivity were recorded in conscious rats at rest and following a selective nNOS inhibitor (Nw-Propyl-l-Arginine, 4 nmol/100 nL) within the PVN. Rats were deeply anesthetized for brain perfusion/harvesting after respiratory arrest. In separate groups (T and S, l-arginine and Veh...
Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice
American Journal of Physiology-heart and Circulatory Physiology, 2002
Flow-induced dilation was examined in isolated coronary arteries of endothelial nitric oxide (NO) synthase knockout mice (eNOS-KO) and wild-type (WT) mice. The basal tone of arteries (percentage of passive diameter) was significantly greater in eNOS-KO than in WT mice; their flow-induced dilations, however, were similar. Endothelial removal eliminated the dilations in vessels of both strains of mice. In arteries of WT mice, N-nitro-L-arginine methyl ester (L-NAME) (10 Ϫ4 M) or indomethacin (10 Ϫ5 M) alone, inhibited flow-induced dilation by ϳ50%, whereas their simultaneous administration abolished the responses. In arteries of eNOS-KO mice, flow-induced dilation was inhibited by ϳ40% with L-NAME. The residual portion (60%) of the response was eliminated by the additional administration of indomethacin. 7-Nitroindazole (10 Ϫ4 M) attenuated flow-induced dilation by ϳ40% in arteries of eNOS-KO mice, but did not affect responses in those of WT mice. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (3 ϫ 10 Ϫ5 M) inhibited the L-NAME/7-nitroindazole-sensitive portion of the responses in arteries of eNOS-KO mice. Immunohistochemical evidence confirms the presence of neuronal NOS (nNOS) in the arterial endothelium of eNOS-KO mice. In conclusion, nNOSderived NO, via activation of cGMP, together with prostaglandins, maintains flow-induced dilation in coronary arteries of male eNOS-KO mice.
Acta Physiologica, 2007
Aim: Myocardial infarction (MI) induces a progressive ventricular remodelling leading to a contractility depression. During the acute phase of MI inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production increases in the heart. The aim of this study was to investigate the role of iNOS in the left ventricular contractility at 3 days after MI. Methods: Wistar rats were divided into: sham operated (SHAM, n ¼ 23), infarction (INF, n ¼ 18); sham operated plus the iNOS inhibitor, S-methylisothiourea (SMT) 5 mg kg )1 day )1 , i.p. treatment (SHAM-SMT, n ¼ 26) and infarction plus SMT (INF-SMT, n ¼ 22). Concentration-response curves for isoprenaline, Ca 2+ and frequency-force curve were studied in isolated papillary muscle from left ventricle. Results: After 3 days infarct area was similar between groups. SMT treatment reduced the time to peak tension during frequency-force curve in the infarct group (SHAM ¼ 63 AE 3; SHAM-SMT ¼ 71 AE 3; INF ¼ 90 AE 4; INF-SMT ¼ 79 AE 4 ms, P < 0.05) and increased the maximal response to isoprenaline (SHAM ¼ 0.93 AE 0.11; SHAM-SMT ¼ 1.13 AE 0.1; INF ¼ 0.84 AE 0.16; INF-SMT ¼ 1.49 AE 0.15 g mm )2 , P < 0.05). The response to Ca 2+ was equally reduced in the INF and INF-SMT groups. SMT treatment did not change the reduced post-rest potentiation performed by INF group, but attenuated the plasma nitrite and nitrate (NOx) levels in the INF group without any haemodynamic effect. Conclusion: These finding suggest that at 3 days after MI the iNOS modulates the isolated papillary muscle response to isoprenaline and its inhibition improves the b-adrenergic inotropic responses. Keywords b-adrenergic receptor, inducible nitric oxide synthase, myocardial infarction, papillary muscle.