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The article focuses on a research which examines the exercise blood flow regulation in heart failure with preserved ejection fraction (HFpEF). Findings of the study demonstrated that alpha adrenergic restraint is a potential mechanism limiting Vo2, a key functional outcome in adults with HFpEF. The findings also highlight new potential mechanisms leading to exercise intolerance in adults with HFpEF. more...

Patients with heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) exhibit severe exercise intolerance that may be due, in part, to inappropriate cardiovascular and hemodynamic adjustments to exercise. Several neural mechanisms and locally released vasoactive substances work in concert through complex interactions to ensure proper adjustments to meet the metabolic demands of the contracting skeletal muscle. Specifically, accumulating evidence suggests that disease-related alterations in neural mechanisms (e.g., central command, exercise pressor reflex, arterial baroreflex, and cardiopulmonary baroreflex) contribute to heightened sympathetic activation and impaired ability to attenuate sympathetic vasoconstrictor responsiveness that may contribute to reduced skeletal muscle blood flow and severe exercise intolerance in patients with HFrEF. In contrast, little is known regarding these important aspects of physiology in patients with HFpEF, though emerging data reveal heightened sympathetic activation and attenuated skeletal muscle blood flow during exercise in this patient population that may be attributable to dysregulated neural control of the circulation. The overall goal of this review is to provide a brief overview of the current understanding of disease-related alterations in the integrative neural cardiovascular responses to exercise in both HFrEF and HFpEF phenotypes, with a focus on sympathetic nervous system regulation during exercise. [ABSTRACT FROM AUTHOR] more...

A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest, but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10 females/8 males) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low (15% maximum contraction) and moderate (30% maximum contraction)-intensity rhythmic handgrip exercise. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1 h, 2 h, and 3 h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (Δ-54 ± 10%), and these responses were attenuated during low (Δ-17 ± 7%)- and moderate (Δ-8 ± 6%)-intensity handgrip exercise. Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3 h postprandial, Δ-47 ± 10%, P = 0.002 vs. preprandial) and blunted attenuation of FVC during low (3 h postprandial, Δ-23 ± 8%, P = 0.001 vs. preprandial)- and moderate (3 h postprandial, Δ-16 ± 6%, P < 0.001 vs. preprandial)-intensity handgrip exercise. The high-fat meal attenuated the magnitude of sympatholysis during low (preprandial, 38 ± 7 vs. 3 h postprandial, 23 ± 8%, P < 0.001)- and moderate (preprandial, 46 ± 11 vs. 3 h postprandial, 31 ± 10%, P < 0.001)-intensity handgrip exercise. The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults. [ABSTRACT FROM AUTHOR] more...

The cardiovascular system must distribute oxygen and nutrients to the body while maintaining appropriate blood pressure. This is achieved through a combination of central and peripheral mechanisms that influence cardiac output and vasomotor tone throughout the vascular system. Furthermore, the capability to preferentially direct blood to tissues with increased metabolic demand (i.e., active hyperemia) is crucial to exercise tolerance. However, the interaction between these systems is difficult to understand without real-life examples. Fortunately, monitoring blood flow, blood pressure, and heart rate during a series of laboratory protocols will allow students to partition the contributions of these central and peripheral factors. The three protocols include 1) reactive hyperemia in the forearm, 2) small muscle mass handgrip exercise, and 3) large muscle mass cycling exercise. In addition to providing a detailed description of the required equipment, specific protocols, and expected outcomes, this report also reviews some of the common student misconceptions that are associated with the observed physiological responses. [ABSTRACT FROM AUTHOR] more...

Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research. [ABSTRACT FROM AUTHOR] more...

Abstract Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P 0.05) and was intensity‐dependent (P more...

Introduction: the aim of the current investigation was to examine if dietary nitrate supplementation would improve vascular control in hypertensive postmenopausal women (PMW). We tested the hypotheses that acute dietary nitrate supplementation would 1) significantly decrease arterial blood pressure (BP) at rest and during exercise, 2) increase limb blood flow during steady-state (SS) exercise, and 3) improve functional sympatholysis during SS exercise. Methods: Ten hypertensive PMW underwent a randomized, double-blind, placebo-controlled trial with a nitrate-rich (NR) or nitrate-poor (NP) supplement. Beat-by-beat BP and heart rate were recorded throughout the trial on the nonexercising limb. Forearm blood flow was measured via ultrasonography on the brachial artery of the exercising limb. All patients performed a resting cold pressor test (CPT) (2 min) and then 7 min of submaximal handgrip exercise with a CPT applied during minutes 5–7. Results: SS systolic (NR, 170 ± 7; NP, 171 ± 37 mm Hg), diastolic (NR, 89 ± 2; NP, 92 ± 2 mm Hg), and mean arterial (NR, 121 ± 4; NP, 123 ± 2 mm Hg) pressures were not different between NP and NR treatment conditions (P > 0.05). During SS exercise, forearm blood flow (NR, 189 ± 8; NP, 218 ± 8 mL·min−1; P = 0.03) in the NR treatment was significantly lower compared with NP. When the CPT was applied during minutes 6–7 of exercise, forearm vascular conductance was reduced by 15% in the NR condition, but only 7% in the NR condition. Conclusions: In summary, an acute NR supplement improved functional sympatholysis by ~50% versus an NP placebo condition. Improvements in functional sympatholysis may have important implications regarding exercise tolerance in hypertensive PMW. [ABSTRACT FROM AUTHOR] more...

Key points: We developed a novel method to study sympatholysis in dogs.We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model.We showed sympatholysis in dogs involving both nNOS‐derived NO‐dependent and NO‐independent mechanisms.We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model.We showed that NO‐independent sympatholysis was not affected in the canine DMD model. The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to the delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma. Sarcolemmal nNOS plays an important role in sympatholysis, a process of attenuating reflex sympathetic vasoconstriction during exercise to ensure blood perfusion in working muscle. Delocalization of nNOS compromises sympatholysis resulting in functional ischaemia and muscle damage in DMD patients and mouse models. Little is known about the contribution of membrane‐associated nNOS to blood flow regulation in dystrophin‐deficient DMD dogs. We tested the hypothesis that the loss of sarcolemmal nNOS abolishes protective sympatholysis in contracting muscle of affected dogs. Haemodynamic responses to noradrenaline in the brachial artery were evaluated at rest and during contraction in the absence and presence of NOS inhibitors. We found sympatholysis was significantly compromised in DMD dogs, as well as in normal dogs treated with a selective nNOS inhibitor, suggesting that the absence of sarcolemmal nNOS underlies defective sympatholysis in the canine DMD model. Surprisingly, inhibition of all NOS isoforms did not completely abolish sympatholysis in normal dogs, suggesting sympatholysis in canine muscle also involves NO‐independent mechanism(s). Our study established a foundation for using the dog model to test therapies aimed at restoring nNOS homeostasis in DMD. Key points: We developed a novel method to study sympatholysis in dogs.We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model.We showed sympatholysis in dogs involving both nNOS‐derived NO‐dependent and NO‐independent mechanisms.We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model.We showed that NO‐independent sympatholysis was not affected in the canine DMD model. [ABSTRACT FROM AUTHOR] more...

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Key points: The arterial baroreflex's operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise. Abstract: We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back‐supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): perindopril (high lipid solubility), captopril (low lipid solubility). Repeated measurements of whole venous blood (n = 8), MSNA (n = 7) and arterial blood pressures (n = 14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady state dynamic exercise. Arterial baroreflex function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance spectroscopy were elevated during exercise and were not altered by ACEi at rest (P ≥ 0.4) or during exercise (P ≥ 0.3). Baseline MSNA and mean arterial pressure were unchanged at rest (P ≥ 0.1; P ≥ 0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P < 0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise‐induced increases in MSNA. [ABSTRACT FROM AUTHOR] more...

Sympathetic vasoconstriction is blunted in exercising muscle (functional sympatholysis) but becomes attenuated with age. We tested the hypothesis that functional sympatholysis is further impaired in chronic obstructive pulmonary disease (COPD) patients. We determined leg blood flow and calculated leg vascular conductance (LVC) during 1) femoral-arterial Tyramine infusion (evokes endogenous norepinephrine release, 1 µmol·min-1·kg leg mass-1), 2) one-legged knee extensor exercise with and without Tyramine infusion [10 W and 20% of maximal workload (WLmax)], 3) ATP (0.05 µmol·min-1·kg leg mass-1) and Tyramine infusion, and 4) incremental ATP infusions (0.05, 0.3, and 3.0 µmol·min-1·kg leg mass-1). We included 10 patients with moderate to severe COPD and 8 age-matched healthy control subjects. Overall, leg blood flow and LVC were lower in COPD patients during exercise (P > 0.05). Tyramine reduced LVC in both groups at 10-W exercise (COPD: -3 ± 1 ml·min-1·mmHg-1 and controls: -3 ± 1 ml·min-1·mmHg-1, P < 0.05) and 20% WLmax (COPD: -4 ± 1 ml·min-1·mmHg-1 and controls: -3 ± 1 ml·min-1·mmHg-1, P < 0.05) with no difference between groups. Incremental ATP infusions induced dose-dependent vasodilation with no difference between groups, and, in addition, the vasoconstrictor response to Tyramine infused together with ATP was not different between groups (COPD: -0.03 ± 0.01 l·min-1·kg leg mass-1 vs. controls: -0.04 ± 0.01 l·min-1·kg leg mass-1, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained. [ABSTRACT FROM AUTHOR] more...

The purpose of this study is to investigate that dipeptidyl peptidase IV (DPPIV) released from skeletal and vascular smooth muscle can increase arteriolar diameter in a skeletal muscle vascular bed by reducing neuropeptide Y (NPY)-mediated vasoconstriction. We hypothesized that the effect of myokine DPP-IV would be greatest in the smallest and least in the largest arterioles. Eight male Sprague Dawley rats (age 7-9 weeks; mass, mean ± SD: 258 ± 41 g) were anesthetized and the gluteus maximus dissected in situ for intravital microscopy analysis of arteriolar diameter of the vascular network. Computational modeling was performed on the diameter measurements to evaluate the overall impact of diameter changes on network resistance and flow distribution. In the first set of experiments, whey protein isolate powder was added to physiological saline solution, put in a heated reservoir, and applied to the preparation to induce release of DPP-IV from the muscle. This resulted in an order-dependent increase in arteriolar diameter, with the largest change in the 6A arterioles (63% more reactive than 1A arterioles; P < 0.05). This effect was abolished by adding the DPP-IV inhibitor, Diprotin A. To test if the DPP-IV released was affecting NPY-mediated vasoconstriction, we applied NPY and whey protein, which resulted in attenuated vasoconstriction. These findings suggest that DPP-IV is released from muscle and has a unique effect on blood flow, which appears to act on NPY to attenuate vasoconstriction. The findings suggest that DPP-IV released from the skeletal or smooth muscle can alter muscle blood flow. [ABSTRACT FROM AUTHOR] more...

Purpose: The aim of this study was to examine whether independent effects exist between contractile work and metabolic demand (VO2m) on vasoconstrictor responsiveness (i.e., functional sympatholysis) under different contraction durations matched for total contractile work in exercising human skeletal muscle.Methods: Ten young men performed rhythmic forearm contractions at 10 and 15% of maximum voluntary contraction (MVC) which consisted of muscle contractions using the same duty cycle but altering the duration of the contraction-relaxation cycles of exercise and included: 1) fast frequency contractions at 10% MVC (FFC10%) using a contraction relaxation cycle at 1:2 s; 2) slow frequency contractions at 10% MVC (SFC10%) at 2:4 s; and 3) SFC at 15% MVC (SFC15%) at 2:4 s. Lower body negative pressure (LBNP) was applied to increase sympathetic vasoconstriction during forearm exercise. Brachial artery diameter and blood velocities (measured via Doppler ultrasound) determined forearm blood flow (FBF), and forearm vascular conductance (FVC) was calculated from FBF (ml min-1) and mean arterial blood pressure.Results: Results revealed that steady-state indices of FBF, FVC, and VO2m were greater (P < 0.05) in FFC10% and SFC15% vs. SFC10%. In addition, the magnitude of vasoconstriction (percent reduction in FVC) in response to reflex increases in sympathetic activity during LBNP was greater with SFC10% vs. FFC10% (-20.6 ± 3.0 vs. -11.1 ± 2.0%; P < 0.05), whereas there was no difference with FFC10% vs. SFC15% (-11.1 ± 2.0 vs. -11.8 ± 1.8%; P = 0.91).Conclusions: Our data indicate that faster work-matched muscle contractions increase blood flow and metabolism, leading to improved functional sympatholysis as compared to slower work-matched muscle contractions in humans. [ABSTRACT FROM AUTHOR] more...

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. [ABSTRACT FROM AUTHOR] more...

Key points Rapid onset vasodilatation (ROV) initiates functional hyperaemia upon skeletal muscle contraction and is attenuated during ageing via α-adrenoreceptor (αAR) stimulation, but it is unknown where this effect predominates in resistance networks., In gluteus maximus muscles of young (4 months) and old (24 months) male C57BL/6 mice, tetanic contraction while observing feed arteries and arterioles initiated ROV, which increased with contraction duration, peaked later in upstream versus downstream vessel branches and was attenuated throughout networks with advanced age., With no effect on muscle force production, inhibiting αARs improved ROV in old mice while activating αARs attenuated ROV in young mice., Modulating ROV through αARs was greater in upstream feed arteries and arterioles compared to downstream arterioles, with α2ARs more effective than α1ARs., ROV is coordinated along resistance networks and modulated differentially between young and old mice via αARs; with advanced age, attenuated dilatation of upstream branches will restrict muscle blood flow., Abstract Rapid onset vasodilatation (ROV) in skeletal muscle is attenuated during advanced age via α-adrenoreceptor (αAR) activation, but it is unknown where such effects predominate in the resistance vasculature. Studying the gluteus maximus muscle (GM) of anaesthetized young (4 months) and old (24 months) male C57BL/6 mice, we tested the hypothesis that attenuation of ROV during advanced age is most effective in proximal branches of microvascular resistance networks. Diameters of a feed artery (FA) and first- (1A), second- (2A) and third- (3A) order arterioles were studied in response to single tetanic contractions (100 Hz, 100-1000 ms). ROV began within 1 s and peaked sooner in 2A and 3A (∼3 s) than in 1A or FA (∼4 s). Relative amplitudes of dilatation increased with contraction duration and with vessel branch order (FA<1A<2A<3A). In old mice, attenuation of ROV was greater in FA and 1A compared to 2A and 3A. With no effect on muscle force production, inhibiting αARs (phentolamine; 10−6 m) improved ROV in FA and 1A of old mice while subthreshold stimulation of αARs in young mice (noradrenaline; 10−9 m) depressed ROV most effectively in FA and 1A. In young mice, stimulating α1ARs (phenylephrine; 10−7 m) and α2ARs (UK 14304; 10−7 m) attenuated ROV primarily in FA. In old mice, inhibiting α2ARs (rauwolscine; 10−7 m) restored ROV more effectively in FA and 1A than did inhibiting α1ARs (prazosin; 10−8 m). We conclude that, with temporal and spatial coordination along resistance networks, attenuation of ROV with advanced age is most effective in proximal branches via constitutive activation of α2ARs. [ABSTRACT FROM AUTHOR] more...

Both obesity and metabolic syndrome are important cardiovascular disease risk factors. In this review, we explore the hypothesis that young obese adults and adults with metabolic syndrome exhibit alterations in blood flow regulation that occur before the onset of overt cardiovascular dysfunction. [ABSTRACT FROM AUTHOR] more...

Appropriate cardiovascular and hemodynamic adjustments are necessary to meet the metabolic demands of working skeletal muscle during exercise. Alterations in the sympathetic and parasympathetic branches of the autonomic nervous system are fundamental in ensuring these adjustments are adequately made. Several neural mechanisms are responsible for the changes in autonomic activity with exercise and through complex interactions, contribute to the cardiovascular and hemodynamic changes in an intensity-dependent manner. This short review is from a presentation made at the Saltin Symposium June 2-4, 2015 in Copenhagen, Denmark. As such, the focus will be on reflex control of the circulation with an emphasis on the work of the late Dr. Bengt Saltin. Moreover, a concerted effort is made to highlight the novel and insightful concepts put forth by Dr. Saltin in his last published review article on the regulation of skeletal muscle blood flow in humans. Thus, the multiple roles played by adenosine triphosphate ( ATP) including its ability to induce vasodilatation, override sympathetic vasoconstriction and stimulate skeletal muscle afferents (exercise pressor reflex) are discussed and a conceptual framework is set suggesting a major role of ATP in blood flow regulation during exercise. [ABSTRACT FROM AUTHOR] more...

Purpose: The effect of acute activation of the sympathetic nervous system on the dynamic response of muscle hyperaemia during exercise at different intensities is not clear. Methods: To explore this, six men performed 16, 5-min bouts of intermittent calf contractions at two intensities (25 and 50 % MVC) and two levels of sympathetic activation (CPT cold pressor test, CON control). Mean arterial pressure (MAP) and leg vascular conductance (LVC leg blood flow/MAP) were measured during rest and contractions (3 s intervals), and dynamic response characteristics of LVC were estimated using curve-fitting and empirical modeling. Results: MAP was ~20 % greater ( P ≤ 0.05) during CPT than CON before and during initial contractions at both intensities. At 25 % MVC, CPT reduced the exercise-induced change in LVC (0.109 vs 0.125 ml 100 mlminmmHg; P < 0.05), an effect attributed to the reduction in the amplitude of the fast growth phase (0.091 vs 0.128 1 ml 100 mlminmmHg; P < 0.05). At 50 % MVC, CPT also blunted the fast growth phase (0.147 vs 0.189 ml 100 mlminmmHg; P < 0.05), but the total change in LVC during exercise was unaffected because of a significant reduction in the amplitude of the rapid decay phase and tendency ( P = 0.1) for a lower amplitude of the slow decay phase. Conclusion: Increased sympathetic constraint of vasodilation persists during initial contractions but is overcome at the high intensity by a mechanism apparently related to hyperaemic decay. [ABSTRACT FROM AUTHOR] more...

Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSµ) which binds spectrin-like repeats within dystrophin’s rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSµ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSµ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD. more...

Blunting of sympathetic vasoconstriction in exercising muscle is well established. Whether it persists during the early post-exercise period is unknown. This study tested the hypothesis that it persists in human skeletal muscle during the first 10 minutes of recovery from exercise. Eight healthy young males (21.4 ±0.8 yrs, SE) performed 7 minutes of forearm rhythmic isometric handgrip exercise at 15% below forearm critical power. In separate trials, a cold pressor test (CPT) of 2 min duration was used to evoke forearm sympathetic vasoconstriction in each of Rest (R), Steady State Exercise (Ex), 2-4 min Post Exercise (PEearly), and 8-10 min Post Exercise (PElate). A 7 min control exercise trial with no CPT was also performed. Exercising forearm brachial artery blood flow, arterial blood pressure, cardiac output, heart rate, forearm deep venous catecholamine concentration and arterialized venous catecholamine concentration were obtained immediately prior to and following the CPT in each trial. CPT resulted in a significant increase in forearm venous plasma norepinephrine concentration in all trials (P=0.007), but no change in arterialized plasma norepinephrine (P=0.32). CPT did not change forearm venous plasma epinephrine (P=0.596) or arterialized plasma epinephrine concentration (P=0.15). As assessed by the %reduction in forearm vascular conductance (FVC) the CPT evoked a robust vasoconstriction at rest that was severely blunted in exercise (R -39.9 ±4.6% vs. Ex 5.5 ±7.4%, P more...

Sympathetic vasoconstriction is normally attenuated in exercising muscle by local changes in muscle metabolites and other substances that reduce vascular responsiveness to α-adrenergic receptor activation. Termed functional sympatholysis, this protective mechanism is thought to optimize muscle blood flow distribution to match perfusion with metabolic demand. Emerging evidence from both animal and human studies indicate that functional sympatholysis is impaired in hypertension and may constitute an important underlying cause of skeletal muscle malperfusion during exercise in this common cardiovascular condition. Findings from studies of animal models of hypertension and patients with essential hypertension will be integrated in this review to provide insight into the underlying mechanisms responsible for inappropriate sympathetic vasoconstriction in exercising muscle and the treatment options that may restore functional sympatholysis and improve muscle perfusion during exercise. [ABSTRACT FROM AUTHOR] more...

Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSβ) which binds spectrin-like repeats within dystrophin's rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSβ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSβ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD. [ABSTRACT FROM AUTHOR] more...

Blunting of sympathetic vasoconstriction in exercising muscle is well-established. Whether it persists during the early post-exercise period is unknown. This study tested the hypothesis that it persists in human skeletal muscle during the first 10min of recovery from exercise. Eight healthy young males (21.4 ± 0.8 yrs, SE) performed 7min of forearm rhythmic isometric handgrip exercise at 15% below forearm critical force (fCF). In separate trials, a cold pressor test (CPT) of 2min duration was used to evoke forearm sympathetic vasoconstriction in each of Rest (R), Steady State Exercise (Ex), 2-4 min Post-Exercise (PEearly), and 8-10min Post-Exercise (PElate). A 7min control exercise trial with no CPT was also performed. Exercising forearm brachial artery blood flow, arterial blood pressure, cardiac output (CO), heart rate (HR), forearm deep venous catecholamine concentration, and arterialized venous catecholamine concentration were obtained immediately prior to and following the CPT in each trial. CPT resulted in a significant increase in forearm venous plasma norepinephrine concentration in all trials (P = 0.007), but no change in arterialized plasma norepinephrine (P = 0.32). CPT did not change forearm venous plasma epinephrine (P = 0.596) or arterialized plasma epinephrine concentration (P = 0.15). As assessed by the %reduction in forearm vascular conductance (FVC) the CPT evoked a robust vasoconstriction at rest that was severely blunted in exercise (R = -39.9 ± 4.6% vs. Ex = 5.5 ± 7.4%, P < 0.001). This blunting of vasoconstriction persisted at PEearly (-12.3 ± 10.1%, P = 0.02) and PElate (-18.1 ± 8.2%, P = 0.03) post-exercise. In conclusion, functional sympatholysis remains evident in human skeletal muscle as much as 10min after the end of a bout of forearm exercise. Persistence of functional sympatholysis may have important implications for blood pressure regulation in the face of a challenge to blood pressure following exercise. [ABSTRACT FROM AUTHOR] more...

Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice (n ≥ 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 µM sodium nitroprusside (pooled values: 1A, 70 ± 3 µm; 2A, 31 ± 3 µm; and 3A, 19 ± 3 µm). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KC1 were also not different between groups; however, constriction decayed with distance (P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ~25-30% in mdx mice compared with C57BL/10 mice (P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice. [ABSTRACT FROM AUTHOR] more...

Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in α-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced α-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of α-adrenergic agonists [phenylephrine (PE; α1) or clonidine (CL; α2)]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of α-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase. [ABSTRACT FROM AUTHOR] more...

Our laboratory has previously reported a decline in sympathetic nervous system restraint of skeletal muscle blood flow during prolonged mild-intensity exercise. This decline may be explained by a decrease in α1- and α2-adrenergic receptor responsiveness over time. Thus the purpose of the present study was to investigate the effect of exercise duration on α1- and α2-adrenergic receptor responsiveness during prolonged constant-load exercise. Mongrel dogs (n = 6) were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. On separate days, flow-adjusted doses of selective α1 - (phenylephrine) α2-adrenergic-receptor (clonidine) agonists, and tyramine (to evoke endogenous norepinephrine release) were infused following 5, 30 and 50 mm of mild-intensity treadmill exercise (3 miles/h), with hindlimb blood flow (HBF) and mean arterial pressure (MAP) monitored continuously. Vascular conductance (VC) was calculated as HBF/MAP. While the dogs ran on the treadmill at 3 miles/h, infusion of phenylephrine resulted in similar decreases in VC after 5 [73% (SD 10)], 30 [76% (SD 9)], and 50 [73% (SD 10)] min of exercise. Infusion of the α2-agonist clonidine also produced similar decreases in VC after 5 [58% (SD 10)], 30 [58% (SD 11)], and 50 [53% (SD 12)] min of exercise. Infusion of tyramine resulted in similar decreases in VC after 5 [55% (SD 15)], 30 [51% (SD 10)], and 50 [50% (SD 7)] min of exercise. These results demonstrate that α1- and α2-adrenergic receptor responsiveness to infusion of selective α1- and α2-adrenergic-receptor agonists and endogenous norepinephrine release (tyramine) does not decline during prolonged mild-intensity exercise. Thus a decrease in α-adrenergic receptor responsiveness over time does not appear to be responsible for the decrease in sympathetic restraint of muscle blood flow during prolonged exercise. [ABSTRACT FROM AUTHOR] more...

Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This "functional sympatholysis" may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P < 0.05). Similarly, in obese individuals, LBNP evoked a comparable decrease in FVC (−10.9 ± 5.7%) in the resting forearm, with the reduction in FVC (15%MVC: −9.7 ± 3.3%; 30%MVC: −0.3 ± 4.0%) also blunted during exercise in an intensity‐dependent manner (P < 0.05). The magnitude of sympatholysis was similar between groups (P > 0.05) and was intensity‐dependent (P < 0.05). Our findings suggest that functional sympatholysis is not impaired in young obese individuals without overt cardiovascular diseases. [ABSTRACT FROM AUTHOR] more...

Increasing the relaxation phase of the contraction–relaxation cycle will increase active skeletal muscle blood flow (Q˙m). However, it remains unknown if this increase in Q˙m alters the vasoconstriction responses in active skeletal muscle. This investigation determined if decreasing mechanical impedance would impact vasoconstriction of the active skeletal muscle. Eight healthy men performed rhythmic handgrip exercise under three different conditions; "low" duty cycle at 20% maximal voluntary contraction (MVC), "low" duty cycle at 15% MVC, and "high" duty cycle at 20% MVC. Relaxation time between low and high duty cycles were 2.4 sec versus 1.5 sec, respectively. During steady‐state exercise lower body negative pressure (LBNP) was used to evoke vasoconstriction. Finger photoplethysmography and Doppler ultrasound derived diameters and velocities were used to measure blood pressure, forearm blood flow (FBF: mL min−1) and forearm vascular conductance (FVC: mL min−1 mmHg) throughout testing. The low duty cycle increased FBF and FVC versus the high duty cycle under steady‐state conditions at 20% MVC (P < 0.01). The high duty cycle had the greatest attenuation in %ΔFVC (−1.9 ± 3.8%). The low duty cycle at 20% (−13.3 ± 1.4%) and 15% MVC (−13.1 ± 2.5%) had significantly greater vasoconstriction than the high duty cycle (both: P < 0.01) but were not different from one another (P = 0.99). When matched for work rate and metabolic rate (V˙O2), the high duty cycle had greater functional sympatholysis than the low duty cycle. However, despite a lower V˙O2, there was no difference in functional sympatholysis between the low duty cycle conditions. This may suggest that increases in Q˙m play a role in functional sympatholysis when mechanical compression is minimized. Increasing the relaxation phase of the contraction–relaxation cycle increases forearm blood flow, but leads to increased vasoconstriction during lower body negative pressure relative to less relaxation. We show that duty cycle can impact bulk blood flow delivery during lower body negative pressure. These findings may have important implications for populations that are flow limited. [ABSTRACT FROM AUTHOR] more...