Patrick J. Mueller

Exercise training and sympathetic nervous system activity: evidence for physical activity dependent neural plasticity.

1 It has been generally accepted that regular physical activity is associated with beneficial effects on the cardiovascular system. In fact, the idea that exercise maintains cardiovascular health is evident by the direct links between a sedentary lifestyle and the risk of cardiovascular and other disease states. 2 Cardiovascular diseases, such as hypertension and heart failure, are often associated with sympathetic nervous system (SNS) overactivity. Conversely, exercise has been shown to reduce hypertension and decrease elevated SNS activity. In addition, there is evidence that exercise may reduce resting blood pressure and sympathetic outflow in normal individuals. 3 Although somewhat controversial in humans, evidence from animal studies also indicates that exercise training reduces baroreflex‐mediated and other forms of sympathoexcitation in normal individuals. Collectively, these data are consistent with the hypothesis that physical activity may decrease, and physical inactivity may increase, the incidence of cardiovascular disease via alterations in SNS activity. Despite the important clinical implications of this possibility, the mechanisms by which exercise alters control of SNS activity remain to be fully elucidated. 4 Recent evidence suggests that central nervous system (CNS) plasticity occurs under a variety of conditions, including varying levels of physical activity. The purpose of the present brief review is to provide evidence that changes within the CNS contribute importantly to altered regulation of the SNS observed following exercise training. The primary hypothesis is that physical activity versus inactivity produces plasticity within neural networks that regulate SNS activity. This hypothesis is supported by published and preliminary data that suggest that exercise training may reduce sympathoexcitation by reducing activation of neurons within cardiovascular regions of the brain. These mechanisms are likely to be important in disease states of sympathetic overactivity and in normal healthy individuals whose risk of cardiovascular disease is reduced by leading an active versus sedentary lifestyle.

Sympathetic vasoconstriction in active skeletal muscles during dynamic exercise

Studies utilizing systemic administration of alpha-adrenergic antagonists have failed to demonstrate sympathetic vasoconstriction in working muscles during dynamic exercise. The purpose of this study was to examine the existence of active sympathetic vasoconstriction in working skeletal muscles by using selective intra-arterial blockade. Six mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and with a catheter in one femoral artery. All dogs ran on a motorized treadmill at three intensities on separate days. After 2 min, the selective alpha 1-adrenergic antagonist prazosin (0.1 mg) was infused as a bolus into the femoral artery catheter. At mild, moderate, and heavy workloads, there were immediate increases in iliac conductance of 76 +/- 7, 54 +/- 11, and 22 +/- 6% (mean +/- SE), respectively. Systemic blood pressure and blood flow in the contralateral iliac artery were unaffected. These results demonstrate that there is sympathetic vasoconstriction in active skeletal muscles even at high exercise intensities.

Cardiovascular response to group I metabotropic glutamate receptor activation in NTS

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus tractus solitarius (NTS). Exogenous glutamate in the NTS activates neurons through ionotropic and metabotropic glutamate receptors (mGluRs). This study tested the hypothesis that group I mGluRs in the NTS produce depressor, bradycardic, and sympathoinhibitory responses. In urethan-anesthetized rats, unilateral 30-nl microinjections of the group I-selective mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The dose of drug that produced 50% of the maximal response (ED50) was 50-100 μM. The response to microinjection of equal concentrations of DHPG or the general mGluR agonist 1-aminocyclopentane-1 S,3 R-dicarboxylic acid (ACPD) produced similar cardiovascular effects. The cardiovascular response to injection of DHPG or ACPD was abolished by NTS blockade of mGluRs with α-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid did not attenuate the response to DHPG or ACPD injection. These data suggest that DHPG and ACPD activate mGluRs in the NTS and do not require ionotropic glutamate receptors to produce their cardiovascular response. In the NTS the group I mGluRs produce responses that are consistent with excitation of neurons involved in reducing sympathetic outflow, heart rate, and arterial pressure.Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus tractus solitarius (NTS). Exogenous glutamate in the NTS activates neurons through ionotropic and metabotropic glutamate receptors (mGluRs). This study tested the hypothesis that group I mGluRs in the NTS produce depressor, bradycardic, and sympathoinhibitory responses. In urethan-anesthetized rats, unilateral 30-nl microinjections of the group I-selective mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The dose of drug that produced 50% of the maximal response (ED50) was 50-100 microM. The response to microinjection of equal concentrations of DHPG or the general mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) produced similar cardiovascular effects. The cardiovascular response to injection of DHPG or ACPD was abolished by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid did not attenuate the response to DHPG or ACPD injection. These data suggest that DHPG and ACPD activate mGluRs in the NTS and do not require ionotropic glutamate receptors to produce their cardiovascular response. In the NTS the group I mGluRs produce responses that are consistent with excitation of neurons involved in reducing sympathetic outflow, heart rate, and arterial pressure.

Nitric oxide synthase activity and expression are decreased in the paraventricular nucleus of pregnant rats

Pregnancy is characterized by elevated heart rate and decreased total peripheral resistance and arterial blood pressure. Plasma volume is expanded and plasma osmolality is decreased, yet vasopressin secretion in pregnant animals, including humans, is no different than levels in the nonpregnant state. Although reflex compensatory sympathoexcitation is suppressed, baseline sympathetic nerve activity to the heart and vasculature is well maintained or slightly elevated in pregnancy. Clearly there are central nervous system (CNS) adaptations in systems for regulation of cardiovascular and body fluid homeostasis in pregnant animals. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important CNS sites for control of sympathetic nerve activity and vasopressin secretion. Nitric oxide (NO), an important neuromodulator in these hypothalamic nuclei, contributes to tonic inhibition of neurosecretory and pre-autonomic neurons. Alterations in NO within the PVN and SON could contribute to changes in regulation of vasopressin and sympathetic nerve activity in pregnancy. In the present study, nitric oxide synthase (NOS) activity (NADPH-diaphorase staining), neuronal NOS (nNOS) protein, and nNOS mRNA were assessed in nonpregnant estrus stage and near-term pregnant rats. nNOS mRNA, protein, and activity were greater in the PVN than in the SON. In the PVN only, pregnancy was associated with significant decreases in all three measurements for assessment of nNOS. Thus decreased NO production and relative disinhibition of the PVN may contribute to maintenance of baseline vasopressin secretion and baseline sympathetic nerve activity in the pregnant state.

EXPRESSION OF GROUP I METABOTROPIC GLUTAMATE RECEPTORS ON PHENOTYPICALLY DIFFERENT CELLS WITHIN THE NUCLEUS OF THE SOLITARY TRACT IN THE RAT

Group I metabotropic glutamate receptors (mGluRs) are G-coupled receptors that modulate synaptic activity. Previous studies have shown that Group I mGluRs are present in the nucleus of the solitary tract (NTS), in which many visceral afferents terminate. Microinjection of selective Group I mGluR agonists into the NTS results in a depressor response and decrease in sympathetic nerve activity. There is, however, little evidence detailing which phenotypes of neurons within the NTS express Group I mGluRs. In brainstem slices, we performed immunohistochemical localization of Group I mGluRs and either glutamic acid decarboxylase 67 kDa isoform (GAD67), neuronal nitric oxide synthase (nNOS) or tyrosine hydroxylase (TH). Fluoro-Gold (FG, 2%; 15 nl) was microinjected in the caudal ventrolateral medulla (CVLM) of the rat to retrogradely label NTS neurons that project to CVLM. Group I mGluRs were distributed throughout the rostral-caudal extent of the NTS and were found within most NTS subregions. The relative percentages of Group I mGluR expressing neurons colabeled with the different markers were FG (6.9+/-0.7) nNOS (5.6+/-0.9), TH (3.9+/-1.0), and GAD67 (3.1+/-1.4). The percentage of FG containing cells colabeled with Group I mGluR (13.6+/-2.0) was greater than the percent colabeled with GAD67 (3.1+/-0.5), nNOS (4.7+/-0.5), and TH (0.1+/-0.08). Cells triple labeled for FG, nNOS, and Group I mGluRs were identified in the NTS. Thus, these data provide an anatomical substrate by which Group I mGluRs could modulate activity of CVLM projecting neurons in the NTS.

Increased nitric oxide synthase activity and expression in the hypothalamus of hindlimb unloaded rats

Upon return from spaceflight or resumption of normal posture after bed rest, individuals often exhibit cardiovascular deconditioning. Although the mechanisms responsible for cardiovascular deconditioning have yet to be fully elucidated, alterations within the central nervous system have been postulated to be involved. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important brain regions in control of sympathetic outflow and body fluid homeostasis. Nitric oxide (NO) modulates the activity of PVN and SON neurons, and alterations in NO transmission within these brain regions may contribute to symptoms of cardiovascular deconditioning. The purpose of the present study was to examine nitric oxide synthase (NOS) activity and expression in the PVN and SON of control and hindlimb unloaded (HU) rats, an animal model of cardiovascular deconditioning. The number of neurons exhibiting NOS activity as assessed by NADPH-diaphorase staining was significantly greater in the PVN but not SON of HU rats. Western blot analysis revealed that neuronal NOS (nNOS) but not endothelial NOS (eNOS) protein expression was higher in the PVN of HU rats. In the SON, there was a strong trend for an increase in nNOS (p=0.052) and a significant increase in eNOS expression in HU rats. Our results suggest that increased nNOS in the PVN contributes to autonomic and humoral alterations following cardiovascular deconditioning. In contrast, the functional significance of increases in nNOS and eNOS protein in the SON may be related to alterations in vasopressin release observed previously in HU rats.

Tracheal tone and the role of ionotropic glutamate receptors in the nucleus ambiguus.

Excitatory amino acid (EAA) transmission in the rostral portion of the ventrolateral medulla (RVLM) appears to be required for reflex airway constriction. The purpose of the present study was to determine whether our prior observations of right sided dominance are also reflected at the level of the RVLM, particularly at the right nucleus ambiguus (NA). Microinjection of glutamate (109 nl, 100 mM) into the right NA of anesthetized dogs produced significant increases in tracheal smooth muscle tone as assessed by pressure changes in a saline filled cuff of the endotracheal tube (Delta15 +/- 2 mm Hg). Increasing inspired CO2 increased tracheal cuff pressure (Delta33 +/- 2 mm Hg) which was abolished by microinjections of the EAA antagonist kynurenic acid (109 nl, 100 mM) or the non-NMDA antagonist 6-nitro-7-sulfamobenzoquinoxaline-2,3-dione (NBQX, 109 nl, 10 mM) into the right NA. These results confirm that EAA receptors in the right NA are capable of modulating tracheal tone and suggest that non-NMDA receptors in the right NA are required for reflex airway constriction produced by systemic hypercapnia. Furthermore, the effects of right-sided NA microinjections in the present study, although not completely definitive, are consistent with previous studies that suggest dominant control of canine tracheal tone by the right vagus.