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1.
Hypertension ; 75(4): 1072-1081, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32063060

RESUMO

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; P<0.05), mechanoreflex (21±13 versus 51±20%; P<0.05), and metaboreflex (40±20 versus 88±39%; P<0.01) activation in T1DM rats evoked significant increases in renal sympathetic nerve activity as well as mean arterial pressure. The response of group IV afferents to mechanical (18±24 versus 61±45 spikes; P<0.01) and chemical (0.3±0.4 versus 1.6±0.8 Hz; P<0.01) stimuli were significantly greater in T1DM than control. T1DM rats showed markedly increased pPKCα levels in dorsal root ganglia compared with control. These data suggest that in T1DM, abnormally muscle reflex-evoked increases in sympathetic activity mediate exaggerations in blood pressure. Further, sensitization of muscle afferents, potentially via PKC activation, may contribute to this abnormal circulatory responsiveness.

2.
3.
J Physiol ; 597(20): 5049-5062, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468522

RESUMO

KEY POINTS: Insulin is known to activate the sympathetic nervous system centrally. A mechanical stimulus to tissues activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we report the novel finding that insulin augments the mechanical responsiveness of thin fibre afferents not only at dorsal root ganglion, but also at muscle tissue levels. Our data suggest that sympathoexcitation is mediated via the insulin-induced mechanical sensitization peripherally. The present study proposes a novel physiological role of insulin in the regulation of mechanical sensitivity in somatosensory thin fibre afferents. ABSTRACT: Insulin activates the sympathetic nervous system, although the mechanism underlying insulin-induced sympathoexcitation remains to be determined. A mechanical stimulus to tissues such as skin and/or skeletal muscle, no matter whether the stimulation is noxious or not, activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion (DRG) neurons of these afferents. Accordingly, we investigated whether insulin augments whole-cell current responses to mechanical stimuli in small DRG neurons of normal healthy mice. We performed whole-cell patch clamp recordings using cultured DRG neurons and observed mechanically-activated (MA) currents induced by mechanical stimuli applied to the cell surface. Local application of vehicle solution did not change MA currents or mechanical threshold in cultured DRG neurons. Insulin (500 mU mL-1 ) significantly augmented the amplitude of MA currents (P < 0.05) and decreased the mechanical threshold (P < 0.05). Importantly, pretreatment with the insulin receptor antagonist, GSK1838705, significantly suppressed the insulin-induced potentiation of the mechanical response. We further examined the impact of insulin on thin fibre muscle afferent activity in response to mechanical stimuli in normal healthy rats in vitro. Using a muscle-nerve preparation, we recorded single group IV fibre activity to a ramp-shaped mechanical stimulation. Insulin significantly decreased mechanical threshold (P < 0.05), although it did not significantly increase the response magnitude to the mechanical stimulus. In conclusion, these data suggest that insulin augments the mechanical responsiveness of small DRG neurons and potentially sensitizes group IV afferents to mechanical stimuli at the muscle tissue level, possibly contributing to insulin-induced sympathoexcitation.

4.
Am J Physiol Regul Integr Comp Physiol ; 317(2): R270-R279, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091155

RESUMO

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14-16 wk) in combination with two low doses (35 mg/kg week 1, 25 mg/kg week 2) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.

5.
Front Physiol ; 10: 95, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814955

RESUMO

Central command (CC) and the exercise pressor reflex (EPR) regulate blood pressure during exercise. We previously demonstrated that experimental stimulation of the CC and EPR pathways independently contribute to the exaggerated pressor response to exercise in hypertension. It is known that CC and EPR modify one another functionally. Whether their interactive relationship is altered in hypertension, contributing to the generation of this potentiated blood pressure response, remains unknown. To address this issue, the pressor response to activation of the CC pathway with and without concurrent stimulation of the EPR pathway, and vice versa, was examined in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. In decerebrated, paralyzed animals, activation of the CC pathway was evoked by electrical stimulation of the mesencephalic locomotor region (MLR; 20-50 µA in 10-µA steps). Electrical stimulation of the sciatic nerve (SN, 3, 5, and 10 × motor threshold; MT) was used to activate hindlimb afferents known to carry EPR sensory information. In both WKY and SHR, the algebraic sum of the pressor responses to individual stimulation of the MLR and SN were greater than when both inputs were stimulated simultaneously. Although the blood pressure response to a constant level of SN stimulation was not significantly affected by concurrent MLR stimulation at variable intensities, the pressor response to a constant level of MLR simulation was significantly attenuated by concurrent SN stimulation in WKY but not in SHR. These findings suggest the interactive relationship between CC and the EPR is inhibitory in nature in both WKY and SHR. However, the neural occlusion between these central and peripheral pressor mechanisms is attenuated in hypertension.

6.
J Am Heart Assoc ; 8(7): e010161, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30905258

RESUMO

Background Increased blood pressure ( BP ) variability and nondipping status seen on 24-hour ambulatory BP monitoring are often observed in autonomic failure ( ATF ). Methods and Results We assessed BP variability and nocturnal BP dipping in 273 patients undergoing ambulatory BP monitoring at Southwestern Medical Center between 2010 and 2017. SD , average real variability, and variation independent of mean were calculated from ambulatory BP monitoring. Patients were divided into a discovery cohort (n=201) and a validation cohort (n=72). ATF was confirmed by formal autonomic function test. In the discovery cohort, 24-hour and nighttime average real variability, SD , and variation independent of mean did not differ significantly between ATF (n=25) and controls (n=176, all P>0.05). However, daytime SD, daytime coefficient of variation, and daytime variation independent of mean of systolic BP ( SBP ) were all significantly higher in patients with ATF than in controls in both discovery and validation cohorts. Nocturnal BP dipping was more blunted in ATF patients than controls in both cohorts (both P<0.01). Using the threshold of 16 mm Hg, daytime SD SBP yielded a sensitivity of 77% and specificity of 82% in detecting ATF in the validation cohort, whereas nondipping status had a sensitivity of 80% and specificity of 44%. The area under the receiver operator characteristic of daytime SD SBP was greater than the area under the receiver operator characteristic of nocturnal SBP dipping (0.79 [0.66-0.91] versus 0.73 [0.58-0.87], respectively). Conclusions Daytime SD of SBP is a better screening tool than nondipping status in detecting autonomic dysfunction.

7.
Circulation ; 139(11): 1422-1434, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30612451

RESUMO

BACKGROUND: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. METHODS: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. RESULTS: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P=0.01) and increased sedentary time ( P=0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparγ, in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. CONCLUSIONS: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Ácidos Graxos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fosfatos/efeitos adversos , Fósforo na Dieta/efeitos adversos , Animais , Linhagem Celular , Metabolismo Energético/genética , Exercício , Tolerância ao Exercício/genética , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Fosfatos/administração & dosagem , Fosfatos/metabolismo , Fósforo na Dieta/administração & dosagem , Fósforo na Dieta/metabolismo , Comportamento Sedentário
9.
Am J Physiol Heart Circ Physiol ; 313(4): H788-H794, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28733447

RESUMO

Exaggerated heart rate (HR) and blood pressure responses to exercise in hypertension are mediated, in part, by overactivity of the exercise pressor reflex (EPR). The mechanisms underlying this EPR dysfunction have not been fully elucidated. Previous studies have shown that stimulation of mineralocorticoid receptors (MRs) with exogenous administration of aldosterone in normal, healthy rats reproduces the EPR overactivity characteristic of hypertensive animals. Conversely, the purpose of this study was to examine whether antagonizing MR with spironolactone (SPIR) or eplerenone (EPL) in decerebrated hypertensive rats ameliorates abnormal EPR function. Changes in mean arterial pressure (MAP) and HR induced by EPR or muscle mechanoreflex (a component of EPR) activation were assessed in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) fed normal chow (NC) or a customized diet containing either SPIR or EPL for 3 wk. SHRs treated with SPIR or EPL had significantly attenuated MAP responses to EPR (NC: 45 ± 7 mmHg, SPIR: 26 ± 4 mmHg, and EPL: 24 ± 5 mmHg, P = 0.02) and mechanoreflex (NC: 34 ± 9 mmHg, SPIR: 17 ± 3 mmHg, and EPL: 15 ± 3 mmHg, P = 0.03) activation. SHRs treated with SPIR or EPL also showed significantly attenuated HR responses to EPR (NC: 17 ± 3 beats/min, SPIR: 9 ± 1 beats/min, and EPL: 9 ± 2 beats/min, P = 0.01) and mechanoreflex (NC: 15 ± 3 beats/min, SPIR: 6 ± 1 beats/min, and EPL: 7 ± 1 beats/min, P = 0.01) activation. Wistar-Kyoto rats treated with SPIR did not demonstrate significant differences in MAP or HR responses to EPR or mechanoreflex activation. The data suggest that antagonizing MRs may be an effective strategy for the treatment of EPR overactivity in hypertension.NEW & NOTEWORTHY Exaggerated cardiovascular responses to exercise in hypertensive patients are linked with overactive exercise pressor reflexes (EPRs). Administration of low-dose mineralocorticoid receptor antagonists (spironolactone or eplerenone) effectively ameliorates abnormal EPR function in hypertension. Effective treatment of EPR overactivity may reduce the cardiovascular risks associated with physical activity in hypertension.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Estado de Descerebração , Eplerenona , Frequência Cardíaca/efeitos dos fármacos , Masculino , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reflexo/efeitos dos fármacos , Espironolactona/análogos & derivados , Espironolactona/farmacologia
10.
Am J Physiol Regul Integr Comp Physiol ; 312(6): R851-R863, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28381455

RESUMO

During both dynamic (e.g., endurance) and static (e.g., strength) exercise there are exaggerated cardiovascular responses in hypertension. This includes greater increases in blood pressure, heart rate, and efferent sympathetic nerve activity than in normal controls. Two of the known neural factors that contribute to this abnormal cardiovascular response are the exercise pressor reflex (EPR) and functional sympatholysis. The EPR originates in contracting skeletal muscle and reflexly increases sympathetic efferent nerve activity to the heart and blood vessels as well as decreases parasympathetic efferent nerve activity to the heart. These changes in autonomic nerve activity cause an increase in blood pressure, heart rate, left ventricular contractility, and vasoconstriction in the arterial tree. However, arterial vessels in the contracting skeletal muscle have a markedly diminished vasoconstrictor response. The markedly diminished vasoconstriction in contracting skeletal muscle has been termed functional sympatholysis. It has been shown in hypertension that there is an enhanced EPR, including both its mechanoreflex and metaboreflex components, and an impaired functional sympatholysis. These conditions set up a positive feedback or vicious cycle situation that causes a progressively greater decrease in the blood flow to the exercising muscle. Thus these two neural mechanisms contribute significantly to the abnormal cardiovascular response to exercise in hypertension. In addition, exercise training in hypertension decreases the enhanced EPR, including both mechanoreflex and metaboreflex function, and improves the impaired functional sympatholysis. These two changes, caused by exercise training, improve the muscle blood flow to exercising muscle and cause a more normal cardiovascular response to exercise in hypertension.


Assuntos
Artérias/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/inervação , Exercício , Hipertensão/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Reflexo , Vasoconstrição , Adaptação Fisiológica , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Frequência Cardíaca , Humanos , Contração Muscular , Músculo Esquelético/metabolismo , Fluxo Sanguíneo Regional
11.
Am J Physiol Regul Integr Comp Physiol ; 311(1): R39-48, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27170660

RESUMO

An increasing number of studies have linked high dietary phosphate (Pi) intake to hypertension. It is well established that the rise in sympathetic nerve activity (SNA) and blood pressure (BP) during physical exertion is exaggerated in many forms of hypertension, which are primarily mediated by an overactive skeletal muscle exercise pressor reflex (EPR). However, it remains unknown whether high dietary Pi intake potentiates the EPR-mediated SNA and BP response to exercise. Accordingly, we measured renal SNA (RSNA) and mean BP (MBP) in normotensive Sprague-Dawley rats fed a normal Pi diet (0.6%, n = 13) or high Pi diet (1.2%, n = 13) for 3 mo. As previously reported, we found that resting BP was significantly increased by 1.2% Pi diet in both conscious and anesthetized animals. Activation of the EPR by electrically induced hindlimb contraction triggered greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (126 ± 25 vs. 42 ± 9%; 44 ± 5 vs. 14 ± 2 mmHg, respectively, P < 0.01). Activation of the muscle mechanoreflex, a component of the EPR, by passively stretching hindlimb muscle also evoked greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (109 ± 27 vs. 24 ± 7%, 38 ± 7 vs. 8 ± 2 mmHg, respectively, P < 0.01). A similar response was produced by hindlimb intra-arterial capsaicin administration to stimulate the metaboreflex arm of the EPR. Thus, our data demonstrate a novel action of dietary Pi loading in augmenting EPR function through overactivation of both the muscle mechanoreflex and metaboreflex.


Assuntos
Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Dieta , Hipertensão/induzido quimicamente , Fosfatos/toxicidade , Esforço Físico/efeitos dos fármacos , Animais , Capsaicina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/inervação , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fosfatos/sangue , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos
12.
Am J Physiol Heart Circ Physiol ; 310(1): H123-31, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26545711

RESUMO

The sympathetic and pressor responses to exercise are exaggerated in hypertension. However, the underlying mechanisms causing this abnormality remain to be fully elucidated. Central command, a neural drive originating in higher brain centers, is known to activate cardiovascular and locomotor control circuits concomitantly. As such, it is a viable candidate for the generation of the augmented vascular response to exercise in this disease. We hypothesized that augmentations in central command function contribute to the heightened cardiovascular response to exercise in hypertension. To test this hypothesis, changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to electrical stimulation of mesencephalic locomotor region (MLR; 20-50 µA in 10-µA steps evoking fictive locomotion), a putative component of the central command pathway, were examined in decerebrate, paralyzed normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Tibial nerve discharge during MLR stimulation significantly increased in an intensity-dependent manner in both WKY and SHR but was not different between groups. Stimulation of the MLR evoked significantly larger increases in RSNA and MAP with increasing stimulation intensity in both groups. Importantly, the increases in sympathetic and pressor responses to this fictive locomotion were significantly greater in SHR compared with WKY across all stimulation intensities (e.g., at 50 µA, ΔRSNA: WKY 153 ± 31%, SHR 287 ± 42%; ΔMAP: WKY 87 ± 9 mmHg, SHR 139 ± 7 mmHg). These findings provide the first evidence that central command may be a critical contributor to the exaggerated rise in sympathetic activity and blood pressure during exercise in hypertension.


Assuntos
Pressão Arterial , Sistema Cardiovascular/fisiopatologia , Hipertensão/fisiopatologia , Rim/inervação , Mesencéfalo/fisiopatologia , Atividade Motora , Esforço Físico , Sistema Nervoso Simpático/fisiopatologia , Animais , Barorreflexo , Estado de Descerebração , Modelos Animais de Doenças , Estimulação Elétrica , Potenciais Evocados , Masculino , Pressorreceptores/fisiopatologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Simpatectomia , Fatores de Tempo
16.
Am J Physiol Heart Circ Physiol ; 309(5): H762-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26163445

RESUMO

Cardiovascular responses to exercise are exaggerated in hypertension. We previously demonstrated that this heightened cardiovascular response to exercise is mediated by an abnormal skeletal muscle exercise pressor reflex (EPR) with important contributions from its mechanically and chemically sensitive components. Exercise training attenuates exercise pressor reflex function in healthy subjects as well as in heart failure rats. However, whether exercise training has similar physiological benefits in hypertension remains to be elucidated. Thus we tested the hypothesis that the EPR overactivity manifest in hypertension is mitigated by exercise training. Changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to muscle contraction, passive muscle stretch, and hindlimb intra-arterial capsaicin administration were examined in untrained normotensive Wistar-Kyoto rats (WKYUT; n = 6), exercise-trained WKY (WKYET; n = 7), untrained spontaneously hypertensive rats (SHRUT; n = 8), and exercise-trained SHR (SHRET; n = 7). Baseline MAP after decerebration was significantly decreased by 3 mo of wheel running in SHRET (104 ± 9 mmHg) compared with SHRUT (125 ± 10 mmHg). As previously reported, the pressor and renal sympathetic responses to muscle contraction, stretch, and capsaicin administration were significantly higher in SHRUT than WKYUT. Exercise training significantly attenuated the enhanced contraction-induced elevations in MAP (SHRUT: 53 ± 11 mmHg; SHRET: 19 ± 3 mmHg) and RSNA (SHRUT: 145 ± 32%; SHRET: 57 ± 11%). Training produced similar attenuating effects in SHR during passive stretch and capsaicin administration. These data demonstrate that the abnormally exaggerated EPR function that develops in hypertensive rats is significantly diminished by exercise training.


Assuntos
Hipertensão/fisiopatologia , Esforço Físico , Reflexo , Animais , Pressão Sanguínea , Masculino , Contração Muscular , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/fisiologia
17.
Hypertension ; 66(3): 627-33, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26195483

RESUMO

The sympathetic and pressor responses to exercise are exaggerated in hypertension. Evidence suggests that an overactive exercise pressor reflex (EPR) contributes to this abnormal responsiveness. The mechanisms underlying this EPR overactivity are poorly understood. An increasing body of evidence suggests that aldosterone and excessive salt intake play a role in regulating resting sympathetic activity and blood pressure in hypertension. Therefore, each is a good candidate for the generation of EPR dysfunction in this disease. The purpose of this study was to examine whether excessive salt intake and chronic administration of aldosterone potentiate EPR function. Changes in mean arterial pressure and renal sympathetic nerve activity induced by EPR stimulation were examined in vehicle and aldosterone-treated (4 weeks via osmotic mini-pump) Sprague-Dawley rats given either water or saline (elevated salt load) to drink. When compared with vehicle/water-treated rats, stimulation of the EPR by muscle contraction evoked significantly greater increases in mean arterial pressure in vehicle/saline, aldosterone/water, and aldosterone/saline-treated animals (14±3, 29±3, 37±6, and 44±7 mm Hg/kg, respectively; P<0.01). A similar renal sympathetic nerve activity response profile was likewise produced (39±11%, 87±15%, 110±20%, and 151±25%/kg, respectively; P<0.01). The pressor and sympathetic responses to the individual activation of the mechanically and chemically sensitive components of the EPR were also augmented by both saline and aldosterone. These data provide the first direct evidence that both aldosterone and high salt intake elicit EPR overactivity. As such, each represents a potential mechanism by which sympathetic activity and blood pressure are augmented during exercise in hypertension.


Assuntos
Aldosterona/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Condicionamento Físico Animal , Reflexo/efeitos dos fármacos , Cloreto de Sódio na Dieta/administração & dosagem , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Barorreflexo/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
Am J Physiol Heart Circ Physiol ; 307(2): H242-51, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24816260

RESUMO

Functional sympatholysis is impaired in hypertensive animals and patients. Exercise training (ET) improves functional sympatholysis through a nitric oxide (NO)-dependent mechanism in normotensive rats. However, whether ET has similar physiological benefits in hypertension remains to be elucidated. Thus we tested the hypothesis that the impairment in functional sympatholysis in hypertension is reversed by ET through a NO-dependent mechanism. In untrained normotensive Wistar-Kyoto rats (WKYUT; n = 13), untrained spontaneously hypertensive rats (SHRUT; n = 13), and exercise-trained SHR (SHRET; n = 6), changes in femoral vascular conductance (FVC) were examined during lumbar sympathetic nerve stimulation (1, 2.5, and 5 Hz) at rest and during muscle contraction. The magnitude of functional sympatholysis (Δ%FVC = Δ%FVC muscle contraction - Δ%FVC rest) in SHRUT was significantly lower than WKYUT (1 Hz: -2 ± 4 vs. 13 ± 3%; 2.5 Hz: 9 ± 3 vs. 21 ± 3%; and 5 Hz: 12 ± 3 vs. 26 ± 3%, respectively; P < 0.05). Three months of voluntary wheel running significantly increased maximal oxygen uptake in SHRET compared with nontrained SHRUT (78 ± 6 vs. 62 ± 4 ml·kg(-1)·min(-1), respectively; P < 0.05) and restored the magnitude of functional sympatholysis in SHRET (1 Hz: 9 ± 2%; 2.5 Hz: 20 ± 4%; and 5 Hz: 34 ± 5%). Blockade of NO synthase (NOS) by N(G)-nitro-l-arginine methyl ester attenuated functional sympatholysis in WKYUT but not SHRUT. Furthermore, NOS inhibition significantly diminished the improvements in functional sympatholysis in SHRET. These data demonstrate that impairments in functional sympatholysis are normalized via a NO mechanism by voluntary wheel running in hypertensive rats.


Assuntos
Terapia por Exercício , Artéria Femoral/inervação , Hipertensão/terapia , Músculo Esquelético/irrigação sanguínea , Óxido Nítrico/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Artéria Femoral/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Contração Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Consumo de Oxigênio , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Corrida , Fatores de Tempo
20.
Exp Physiol ; 98(9): 1337-48, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23771911

RESUMO

NEW FINDINGS: What is the central question of this study? Does increasing NO production within the nucleus tractus solitarii (NTS) affect mechanoreflex function in normotensive and hypertensive rats?What is the main finding and its importance? Dialysis of 1 µm l-arginine, an NO precursor, within the NTS significantly attenuated the pressor response to muscle stretch in normotensive and hypertensive rats. In contrast, 10 µm l-arginine had no effect in normotensive animals, while increasing and decreasing the pressor and tachycardic responses to stretch, respectively, in hypertensive rats. This suggests that increasing NO within the NTS using lower doses of l-arginine can partly normalize mechanoreflex overactivity in hypertensive rats, whereas the effects of larger doses are equivocal. The blood pressure response to exercise is exaggerated in hypertension. Recent evidence suggests that an overactive skeletal muscle mechanoreflex contributes significantly to this augmented circulatory responsiveness. Sensory information from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) of the medulla oblongata. Normally, endogenously produced nitric oxide within the NTS attenuates the increase in mean arterial pressure (MAP) induced by mechanoreflex stimulation. Thus, it has been suggested that decreases in NO production in the NTS underlie the generation of mechanoreflex dysfunction in hypertension. Supporting this postulate, it has been shown that blocking NO production within the NTS of normotensive rats reproduces the exaggerated pressor response elicited by mechanoreflex activation in hypertensive animals. What is not known is whether increasing NO production within the NTS of hypertensive rats mitigates mechanoreflex overactivity. In this study, the mechanoreflex was selectively activated by passively stretching hindlimb muscle before and after the dialysis of 1 and 10 µm l-arginine (an NO precursor) within the NTS of decerebrate normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Stretch induced larger elevations in MAP in SHRs compared with WKY rats. In both groups, dialysis of 1 µm l-arginine significantly attenuated the pressor response to stretch. However, at the 10 µm dose, l-arginine had no effect on the MAP response to stretch in WKY rats, while it enhanced the response in SHRs. The data demonstrate that increasing NO availability within the NTS using lower doses of l-arginine partly normalizes mechanoreflex dysfunction in hypertension, whereas higher doses do not. The findings could prove valuable in the development of treatment options for mechanoreflex overactivity in this disease.


Assuntos
Arginina/farmacologia , Hipertensão/fisiopatologia , Mecanotransdução Celular/efeitos dos fármacos , Reflexo de Estiramento/efeitos dos fármacos , Núcleo Solitário/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Masculino , Mecanorreceptores/fisiologia , Microdiálise , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
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