A sedentary lifestyle is a major risk factor for cardiovascular disease, and both conditions are associated with overactivity of the sympathetic nervous system. Ongoing discharge of sympathetic nerves is regulated by the rostral ventrolateral medulla (RVLM), which in turn is modulated by the primary excitatory and inhibitory neurotransmitters glutamate and γ-amino-butyric acid (GABA), respectively. We reported previously that sedentary conditions enhance GABAergic modulation of sympathoexcitation in the RVLM, despite overall increased sympathoexcitation. Thus the purpose of this study was to test the hypothesis that sedentary conditions increase responsiveness to GABA in RVLM. Male Sprague-Dawley rats performed either chronic wheeling running or remained sedentary for 12-15 wk. Animals were instrumented to perform RVLM microinjections under Inactin anesthesia while mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (SSNA) were recorded. Unilateral microinjections of GABA (30 nl, 0.3-600 mM) into the RVLM produced dose-dependent decreases in MAP and SSNA; however, no group differences were observed. Inhibition of the contralateral RVLM (muscimol, 2 mM, 90 nl) caused decreases in MAP and SSNA that were not different between groups but enhanced decreases in SSNA to GABA in sedentary rats only. In sinoaortic denervated rats, GABA microinjections before or after inhibition of the contralateral RVLM caused decreases in MAP and SSNA that were not different between groups. Our results suggest that the contralateral RVLM plays an important role in buffering responses to inhibition of the ipsilateral RVLM under sedentary but not physically active conditions. Based on these studies and others, sedentary conditions appear to enhance both sympathoinhibitory and sympathoexcitatory mechanisms in the RVLM. Enhanced sympathoinhibition may act to reduce already elevated sympathetic nervous system activity following sedentary conditions.

Mg-deficient guinea pigs developed significantly increased hearing loss during 4 weeks of noise exposure [95 dB(A)] as compared to animals fed a Mg-rich diet. The hearing loss was negatively correlated to the Mg content of the perilymph (r = -0.86). Besides this auditory effect, there was a decrease of intracellular Mg and an increase of collagen in the myocardium, both of which were correlated to the hearing loss and caused by Mg deficiency and noise stress.

The muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. During submaximal exercise muscle metaboreflex activation (MMA) elicits a pressor response virtually solely by increasing cardiac output (CO) while baroreceptor unloading increases mean arterial pressure (MAP) primarily through peripheral vasoconstriction. The interaction between the two reflexes when activated simultaneously has not been well established. We activated the muscle metaboreflex in chronically instrumented canines during dynamic exercise (via graded reductions in hindlimb blood flow; HLBF) followed by simultaneous baroreceptor unloading (via bilateral carotid occlusion; BCO). We hypothesized that simultaneous activation of both reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that coactivation of muscle metaboreflex and arterial baroreflex resulted in additive interaction although the mechanisms for the pressor response were different. MMA increased MAP via increases in CO, heart rate (HR), and ventricular contractility whereas baroreflex unloading during MMA caused further increases in MAP via a large decrease in nonischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature), indicating substantial peripheral vasoconstriction. Moreover, there was significant vasoconstriction within the ischemic muscle itself during coactivation of the two reflexes but the remaining vasculature vasoconstricted to a greater extent, thereby redirecting blood flow to the ischemic muscle. We conclude that baroreceptor unloading during MMA induces preferential peripheral vasoconstriction to improve blood flow to the ischemic active skeletal muscle.

More people die as a result of physical inactivity than any other preventable risk factor including smoking, high cholesterol, and obesity. Cardiovascular disease, the number one cause of death in the United States, tops the list of inactivity-related diseases. Nevertheless, the vast majority of Americans continue to make lifestyle choices that are creating a rapidly growing burden of epidemic size and impact on the United States healthcare system. It is imperative that we improve our understanding of the mechanisms by which physical inactivity increases the incidence of cardiovascular disease and how exercise can prevent or rescue the inactivity phenotype. The current review summarizes research on changes in the brain that contribute to inactivity-related cardiovascular disease. Specifically, we focus on changes in the rostral ventrolateral medulla (RVLM), a critical brain region for basal and reflex control of sympathetic activity. The RVLM is implicated in elevated sympathetic outflow associated with several cardiovascular diseases including hypertension and heart failure. We hypothesize that changes in the RVLM contribute to chronic cardiovascular disease related to physical inactivity. Data obtained from our translational rodent models of chronic, voluntary exercise and inactivity suggest that functional, anatomical, and molecular neuroplasticity enhances glutamatergic neurotransmission in the RVLM of sedentary animals. Collectively, the evidence presented here suggests that changes in the RVLM resulting from sedentary conditions are deleterious and contribute to cardiovascular diseases that have an increased prevalence in sedentary individuals. The mechanisms by which these changes occur over time and their impact are important areas for future study.

During both static and dynamic exercise hypertensive subjects can experience robust increases in arterial pressure to such an extent that heavy exercise is often not recommended in these patients due to the dangerously high levels of blood pressure sometimes observed. Currently, the mechanisms mediating this cardiovascular dysfunction during exercise in hypertension are not fully understood. The major reflexes thought to mediate the cardiovascular responses to exercise in normotensive healthy subjects are central command, arterial baroreflex and responses to stimulation of skeletal muscle mechano-sensitive and metabo-sensitive afferents. This review will summarize our current understanding of the roles of these reflexes and their interactions in mediating the altered cardiovascular responses to exercise observed in hypertension. We conclude that much work is needed to fully understand the mechanisms mediating excessive pressor response to exercise often seen in hypertensive patients.

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When oxygen delivery to active skeletal muscle is limited, afferent signals from the muscle elicit reflex increases in cardiac output (CO) and mean arterial pressure (MAP) in order to increase perfusion to the ischemic muscle ‐ termed the muscle metaboreflex (MMR). Previous studies have shown that in normal subjects, CO is increased predominantly through increases in heart rate (HR) while maintaining stroke volume (SV) essentially constant. However, increases in HR alone have limited ability to raise CO because as HR increases, SV falls due to decreased filling time. Increases in ventricular contractility can limit the falls in SV, however with sustained increases in CO, blood is translocated from the venous to the arterial circulation and ventricular filling pressure falls which limits the ability to maintain elevated CO. To sustain increases in CO, central blood volume mobilization must also occur to maintain ventricular filling pressure. We previously showed that MMR activation does increase central venous pressure (Sheriff, Augustyniak and O'Leary, Am. J. Physiol., 1998), but whether this translates into increases in left ventricular end‐diastolic pressure (LVEDP) is unknown. MMR was activated via reductions in hindlimb blood flow during mild treadmill exercise in chronically instrumented canines before and after induction of heart failure (HF, rapid ventricular pacing, 220–240 bpm, ~30 days). In normal animals, MMR activation induced a rise in LVEDP from 14.4 ± 1.8 to 18.2 ± 1.8 mmHg (p<0.05) despite substantial increases in HR (Δ 26 ± 4 bpm), CO (Δ 1.45 ± 0.16 l/min) and MAP (Δ 42.3 ± 2.6 mmHg). After induction of HF, MMA activation increased LVEDP from 28.6 ± 2.5 to 38.7 ± 2.6 mmHg (p<0.05) which was a significantly larger rise than observed in normal animals. In HF, the attenuated rise in CO (Δ 0.20 ± 0.08 l/min) with MMR activation likely contributes to the exaggerated increase in LVEDP. We conclude that MMR activation elicits significant blood volume mobilization which increases cardiac filling pressure which thereby likely helps sustain SV despite shortened filling time. In HF, the limited ability to raise CO is not due to reduced filling pressures.Support or Funding InformationNIH RO1 Grants HL055473 and HL126706This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A sedentary lifestyle is a major risk factor for cardiovascular disease (CVD). CVD is often associated with enhanced activation of the sympathetic nervous system. The sympathetic nervous system is under tonic and phasic control by the rostral ventrolateral medulla (RVLM). In sedentary rats, there is enhanced sympathoexcitation in response to glutamatergic activation of the RVLM. Since the activity of RVLM is tonically restrained by γ‐amino‐butyric acid (GABA), we hypothesized that sedentary conditions may also lead to decreased responsiveness to GABA in RVLM when compared to physically active conditions. In Inactin anesthetized, sedentary (SED) or physically active (EX) rats, mean arterial pressure (MAP), heart rate (HR) and splanchnic sympathetic nerve activity (sSNA) were recorded during unilateral microinjection of GABA (30 nl, 0.3–600 mM) into the RVLM. Following GABA injections, the contralateral RVLM was inhibited with 90 nl of 2mM Muscimol and the GABA injections were repeated. There were no significant differences between SED or EX conditions for MAP, HR and sSNA responses to GABA both before and after contralateral blockade of the RVLM. Based on our results the enhanced sympathoexcitation seen in our sedentary model is not due to reduced responsiveness to GABA and may be due to enhanced responsiveness to excitatory neurotransmission. (Supported by R01‐HL096787; R01‐HL096787‐S1)