Influences of gender on sympathetic nerve responses to static exercise.

We compared reflex responses to static handgrip at 30% maximal voluntary contraction (MVC) in 26 untrained men (mean age 35 +/- 3 yr) and 23 untrained women (mean age 39 +/- 4 yr). Women demonstrated attenuated increases in blood pressure and muscle sympathetic nerve activity (MSNA; by microneurography) compared with men. This difference was also observed during a period of posthandgrip circulatory arrest. 31P-nuclear magnetic resonance (NMR) spectroscopy studies demonstrated attenuations in the production of diprotonated phosphate and the development of cellular acidosis in women compared with men. Subjects also performed ischemic handgrip to fatigue. During this paradigm, MSNA responses were similar in the two groups, suggesting that freely perfused conditions are necessary for the full expression of the gender effect. Finally, we examined MSNA responses to adductor pollicus exercise in 7 men (26 +/- 1 yr) and 6 women (25 +/- 2 yr). MVC values and times to fatigue were similar in the two groups (MVC: men, 4.3 +/- 0.4 kg; women, 4.0 +/- 0.3 kg; not significant. Time to fatigue: men, 209 +/- 16 s; women, 287 +/- 50 s; not significant). At periods of end exercise and postexercise circulatory arrest, MSNA responses were attenuated in the women compared with the men. We conclude that, during nonischemic static exercise, sympathetic neural outflow is less in women compared with men. This response is due to an attenuated metaboreflex in women. Finally, on the basis of the adductor pollicus experiments, this effect appears independent of muscle mass, workload, and the level of training.

A new form of long QT syndrome associated with syndactyly.

OBJECTIVES: The purpose of this study was to characterize a possible association between long QT syndrome and syndactyly. BACKGROUND: Long QT syndrome causes syncope and sudden death from ventricular arrhythmias. Syndactyly is a developmental disorder that causes webbing of the hands and feet. Both disorders can be inherited as isolated, autosomal dominant traits, but an association between them has not been established. METHODS: We identified three children with long QT syndrome, atrioventricular (AV) block and simple syndactyly. Phenotypic and laboratory data were obtained from families, attending physicians and medical records. RESULTS: All patients had bilateral cutaneous syndactyly and were diagnosed with long QT syndrome within the 1st 2 years of life. Structural heart disease, particularly a patent ductus arteriosus, was present in all three patients. Analysis of electrocardiograms showed marked prolongation of the QT intervals with rate-corrected QT intervals of 633, 628 and 680 ms, respectively. Transient AV block was also noted. Two of the three children died suddenly despite treatment with beta-adrenergic blocking agents and permanent pacing. CONCLUSIONS: We postulate that these children have a new form of long QT syndrome associated with syndactyly and a high risk of sudden death. The association of syndactyly with long QT syndrome may provide insight into the mechanisms underlying both disorders. Patients with syndactyly should be evaluated for the presence of long QT syndrome, and if it is found, aggressive treatment may be warranted.

Sympathetic and blood pressure responses to voluntary apnea are augmented by hypoxemia.

Oscillations of arterial pressure during sleep are the hemodynamic hallmark of the sleep apnea syndrome. The mechanism of these transient pressure elevations is incompletely understood. To investigate the role of the arterial chemoreflex in the neurocirculatory responses to apnea, we measured mean arterial pressure (MAP; Finapres) and muscle sympathetic nerve activity (MSNA; peroneal microneurography) during voluntary end-expiratory apnea during exposure to room air, 10.5% O2 in N2 (hypoxemia), and 100% O2 (hyperoxia) in 11 healthy men. While the men breathed spontaneously, MSNA (in bursts/min) rose during hypoxemia and decreased during hyperoxia and MAP remained unchanged. During room air exposure, apnea led to a rise of 94 +/- 54% in MSNA total amplitude and a rise of 6.5 +/- 2.1 mmHg in MAP. MSNA and MAP increased by 616 +/- 158% and 10.8 +/- 2.4 mmHg, respectively, during hypoxemic apnea of equal duration (time-matched responses) and by 98 +/- 41% and 4.9 +/- 2.0 mmHg, respectively, during hyperoxic apnea (P < 0.05 for hypoxemic vs. hyperoxic apnea for both). Thus, in awake healthy humans, activation of the arterial chemoreflex by hypoxemia appears to contribute importantly to the sympathetic and blood pressure responses to apnea.

Role of diprotonated phosphate in evoking muscle reflex responses in cats and humans.

Lactic acid and H+ evoke muscle reflexes that raise sympathetic nerve activity. Whether these substances are direct afferent stimulants or markers for the acidification of other substances is unknown. Diprotonated phosphate (H2PO4-), a possible mediator of fatigue, increases as the cell acidifies and phosphate is produced. Its role in evoking muscle reflexes is unknown. We used 31P-nuclear magnetic resonance to measure forearm muscle H+ and H2PO4- and microneurography to measure muscle sympathetic nerve activity (MSNA, peroneal nerve) during a handgrip protocol designed to dissociate H+ from H2PO4-. Ischemic handgrip (50% maximal voluntary contraction x 2 min) was followed by a 1-min rest period during which the muscle was freely perfused. This was followed by a second bout of ischemic handgrip and a 5-min recovery. In seven of eight subjects, MSNA correlated with H2PO4-, whereas it correlated with pH in only one subject. To determine whether muscle reflex responses are evoked by H+, lactic acid, monoprotonated phosphate (HPO4(2-), or H2PO4-, we injected H+, lactate, H2PO4- [all 50 mM in 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffered to pH 6], and HPO4(2-) (50 mM, pH 7.5 in 10 mM HEPES) into the arterial supply of the triceps surae of the cat (n = 9) as we measured mean arterial blood pressure (MAP). H2PO4- increased MAP more than HPO4(2-), H+, or lactate (27.1 +/- 3.7 vs. 5.0 +/- 1.3, 4.6 +/- 3.1, and 7.7 +/- 3.2 rise in mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Glycogen depletion-induced lactate reductions attenuate reflex responses in exercising humans.

Post leg exercise circulatory arrest (PLE-CA) raises blood pressure (BP) and reduces peak forearm vascular conductance (C). This reflex is evoked by activation of muscle afferents that are often sensitive to lactic acid. We tested the hypothesis that lactic acid reductions induced by muscle glycogen depletion would attenuate the lower-limb metaboreceptor-mediated pressor and forearm vasoconstrictor responses. Eleven subjects had C measured (plethysmography) during post leg exercise circulatory arrest (PLE-CA) (supine bicycle exercise for 9 min, 10 s at 75% VO2max before and after undergoing a glycogen-depletion paradigm (24-h fast followed by 10 min of supine leg exercise at 75% VO2max). In six subjects with lower lactate values, C during PLE-CA was higher after glycogen depletion (0.39 +/- 0.05 vs. 0.21 +/- 0.01 ml.min-1.100 ml-1 x mmHg-1; P < 0.01) and BP was lower (113 +/- 6 vs. 128 +/- 6 mmHg, P < 0.01). In five subjects without attenuated lactate responses, C and BP during PLE-CA were not different. Muscle biopsies (n = 5) demonstrated that the paradigm lowered muscle glycogen concentrations. Thus glycogen depletion-induced reductions in muscle lactate are associated with reduced muscle metaboreceptor-mediated responses.

Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure.

BACKGROUND: Resting sympathetic nervous system activity is increased in heart failure. Whether sympathetic nervous system responses during exercise are increased is controversial. Furthermore, the role of muscle metaboreceptors and central command in regulating sympathetic outflow has been largely unexplored. METHODS AND RESULTS: Muscle sympathetic nerve activity (MSNA, peroneal nerve) was measured in nine heart failure subjects and eight age-matched control subjects during static exercise (30% maximal voluntary contraction) for 2 minutes and during a period of posthandgrip regional circulatory arrest. This maneuver isolates the metaboreceptor contribution to sympathetic nervous system responses. MSNA responses were similar during static exercise in the two groups. During posthandgrip regional circulatory arrest we observed a marked attenuation in MSNA responses in the heart failure subjects (15% increase in heart failure versus 57% increase in control subjects). A cold pressor test demonstrated a normal MSNA response to a potent nonspecific stimulus in the heart failure subjects (heart failure subjects, 141% increase; control subjects, 215% increase; NS). Nuclear magnetic resonance spectroscopy studies in five separate heart failure subjects and five control subjects suggested that the attenuated metaboreceptor response in heart failure was not due to reduced H+ production. CONCLUSIONS: Skeletal muscle metaboreceptor responses are impaired in heart failure. Because MSNA responses during static exercise are similar in the two groups, mechanisms aside from metaboreceptor stimulation must be important in increasing sympathetic nervous system activity.

Dichloroacetate reduces sympathetic nerve responses to static exercise.

Lactic acid is thought to be a stimulant of muscle metaboreceptors. The goal of the present study was to determine if inhibition of lactic acid production by dichloroacetate (DCA) would attenuate muscle sympathetic nerve activity (MSNA) during static forearm exercise. DCA increases pyruvate dehydrogenase levels. Thus, for a given amount of pyruvate produced, less lactic acid is formed. Seven subjects performed static forearm exercise at 20% maximal voluntary contraction until fatigue followed by posthandgrip circulatory arrest (PHG-CA) (trial.1). Subjects then received DCA (35 mg/kg) and repeated the exercise protocol (trial 2). We observed an attenuated rise in forearm venous lactate and MSNA. The trial 2 MSNA value during PHG-CA was 51 +/- 11% less than the value during trial 1 (P less than 0.01). In seven control subjects, two bouts of static forearm exercise were performed with an intervening saline infusion. This intervention had no effect on lactate or MSNA responses to exercise. We conclude that DCA attenuates lactate responses to static exercise, and this is associated with a blunted MSNA response.