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Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

The blood pressure response to exercise is exaggerated in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2DM is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2DM rats. Additionally, TRPV1 and protein kinase C (PKC) protein levels in dorsal root ganglia (DRG) subserving skeletal muscle were assessed. For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or high fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2DM). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic neve activity in decerebrated T2DM than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2DM was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high glucose environment. T2DM showed significantly increased phospholyrated-TRPV1 and −PKCα levels in DRG neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early-stage T2DM with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. KEY POINTS: Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.

Patients with diabetes display heightened blood pressure response to exercise but the underlying mechanism are remains to be elucidated. There is no direct evidence that insulin resistance (hyperinsulinemia or hyperglycemia) impact neural cardiovascular control during exercise. We propose a novel paradigm in which hyperinsulinemia or hyperglycemia significantly influence neural regulatory pathways controlling the circulation during exercise in diabetes.

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

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.

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.

Numerous studies have demonstrated that sympathetic nervous system overactivation during exercise in hypertensive rodents and humans is due, in part, to an exaggerated reflex response known as the exercise pressor reflex. Our prior studies have implicated a key role of mineralocorticoid receptor activation in mediating an augmented exercise pressor reflex in spontaneously hypertensive rats, which is mitigated by blockade with eplerenone. However, the effect of eplerenone on exercise pressor reflex has not been assessed in human hypertension. Accordingly, the authors performed a randomized crossover study to compare the effects of eplerenone to another antihypertensive drug from a different class amlodipine on sympathetic nerve activity (SNA) in 14 patients with uncomplicated hypertension. The authors found that amlodipine unexpectedly augmented the increase in SNA during the second minute of isometric handgrip, which persisted into the post‐exercise circulatory arrest period (∆ SNA, from rest of 15 ± 2 vs. 9 ± 2 vs. 10 ± 2 bursts/min, amlodipine vs. baseline vs. eplerenone, respectively, p

An increasing number of studies have reported a deleterious role of inorganic phosphate (Pi) in promoting hypertension. Previously, we have shown high Pi diet-induced excessive pressor and sympathetic responses to muscle contraction in otherwise normal rats, which were primarily mediated by an overactive exercise pressor reflex (EPR), a reflex arising from contracting muscle. However, the mechanism underlying these abnormalities generated by excess Pi intake remains unclear. Dietary Pi is known to increase release of bone-derived fibroblast growth factor (FGF) 23 to regulate Pi homeostasis. Evidence suggests that FGF23 and FGF receptors (FGFRs) are also present in the central nervous system. The aim of this study was to determine the role of brain FGFRs in mediating augmented EPR activity induced by dietary Pi excess. Accordingly, we assessed cerebrospinal fluid FGF23 levels in Sprague-Dawley rats fed either a normal 0.6% Pi diet (NP) or a high 1.2% Pi diet (HP) for 12 weeks. To determine the role of central FGFRs in mediating the EPR, we measured mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction before and after intracerebroventricular (ICV) administration of either a selective FGFR4 inhibitor BLU9931 or a FGFR1/2/3 inhibitor AZD4547 in decerebrate NP and HP animals. Cerebrospinal fluid FGF23 levels were significantly higher in HP rats compared to NP rats (8.3±0.9 vs. 7.2±0.8 pM, P

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 P P P P

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 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.

The cardiovascular response to physical exercise is abnormally exaggerated in hypertension. Since such responses potentially increase the risk for adverse cardiovascular events, it is clinically important to elucidate the cause of this cardiovascular hyper-excitability in this disease. Even if blood pressure is normal at rest, individuals displaying a heightened blood pressure response to exercise are more likely to develop future hypertension. Therefore, early detection of this abnormal circulatory response to physical activity could lead to the early treatment as well as prevention of hypertension. Much evidence suggests that the abnormal exercise pressor reflex (EPR; a reflex originating in exercising skeletal muscle) significantly contributes to the generation of the enhanced circulatory responses in this disease. In addition, it has been demonstrated that the EPR dysfunction is mediated by both mechanically-sensitive fibers associated with the muscle mechanoreflex and chemically-sensitive fibers associated with the muscle metaboreflex. This review focuses on the underlying mechanisms for this overactive EPR function in hypertension. Specifically, updates on our current understanding of the EPR in this disease as well as experimental models used to examine this reflex are presented.

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.

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 P

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.

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.

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.

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.

Exercise training has beneficial effects on cardiovascular diseases such as hypertension. However, the underlying mechanisms remain to be elucidated. The purpose of this study was to examine whether regular exercise reduces abnormally exaggerated skeletal muscle mechanoreflex function in hypertension. Changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to stimulation of the muscle mechanoreflex were assessed in untrained normotensive Wistar-Kyoto rats (WKYUT; n = 6), exercise trained WKY (WKYET; n = 7; housed in cage with running wheel for 3 months), untrained spontaneously hypertensive rats (SHRUT; n = 3) and exercise trained SHR (SHRET; n = 7). There was no difference between WKYUT and WKYET in RSNA (40±11 vs. 47±11 %, respectively) and MAP (7.5±4.0 vs. 8.0±4.2 mmHg, respectively) responses to stimulating the mechanoreflex by passively stretching hindlimb muscles. Voluntary wheel running (3 months) significantly attenuated sympathetic responses to mechanoreflex stimulatio...

Exercise is a beneficial treatment for hypertension. However, hypertensive patients frequently exhibit a dangerous, exaggerated rise in mean arterial pressure (MAP) during physical activity. Evidence suggests that the skeletal muscle exercise pressor reflex (EPR) plays a primary role in evoking this potentiated responsiveness, although the mechanisms remain largely undetermined. Studies suggest that mineralcorticoid receptors (MR) can contribute significantly to hypertension. Whether MR activation mediates EPR overactivity is unknown. Changes in MAP in response to EPR activation (via electrically-induced hindlimb muscle contraction) were assessed in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additional SHR were fed (3 weeks) either normal chow (NC) or a customized diet containing the mineralcorticoid receptor antagonists spironolactone (SPIR, 50 mg/kg/day) or eplerenone (EPL, 100 mg/kg/day). The MAP response to EPR activation was markedly larger in SHR (37±8 mmHg) compared ...

Our previous study in patients with mild essential hypertension demonstrated that moderate level rhythmic handgrip (RHG) at 30% maximal voluntary contraction (MVC), which typically had no effect on...