Sedentary conditions and enhanced responses to GABA in the RVLM: role of the contralateral RVLM

Abstract

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.

Subregional differences in GABAA receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats

“…As expected from our previous work (Dombrowski & Mueller, ; Mischel & Mueller, ; Subramanian & Mueller, ), sedentary rats had significantly higher body weights but significantly lower right ventricle and adrenal gland weights compared to active rats. Soleus muscle and left ventricular weights were not different between groups (Table ).…”

“…Not only does our data reinforce the importance of examining structural, functional, and cellular neuroplasticity within subregions of the RVLM (Mischel et al, ), our new findings significantly increase our understanding of how inactivity may change neurotransmission through the RVLM. First, our results are evidence for novel mechanisms that may explain both enhanced sympathoexcitatory and enhanced sympathoinhibitory responses generated by excitation and inhibition of the RVLM in sedentary versus physically active rats (Dombrowski & Mueller, ;Mischel & Mueller, ; Subramanian & Mueller, ). Our observations also provide an anatomical basis for enhanced sympathoexcitatory responses during reflex changes in sympathetic outflow documented previously in sedentary animals (DiCarlo & Bishop, ; Negrao et al, ).…”

“…Perhaps prematurely, we attributed enhanced sympathoexcitation in sedentary animals to an increase in excitatory input (Mischel et al, ). Taking the results of the current study into account, it will now be important to consider the functional implications of differences in GABA receptors across the rostrocaudal extent of the RVLM, particularly since inactivity‐related enhancements in GABAergic transmission have only recently been proposed and demonstrated (Dombrowski & Mueller, ; Mueller & Mischel, ).…”

“…Several previous studies have indicated that there are functionally relevant changes in GABAergic transmission in the RVLM under a variety of physiological and pathophysiological conditions. For example, inhibitory responses to GABA microinjections in the RVLM are enhanced in rats fed a high salt diet (Adams, Madden, Sved, & Stocker, ) and inhibitory responses to unilateral microinjections of GABA into the RVLM are enhanced in sedentary versus physically active rats (Dombrowski & Mueller, ). Interestingly, in the later study, sedentary animals showed enhanced responses to GABA only after inhibition of the contralateral RVLM, presumably because under intact conditions the contralateral side was able to compensate for decreases in sympathetic nerve activity.…”

“…Our laboratory has provided functional evidence for alterations in GABAergic transmission in the RVLM of sedentary versus physically active rats (Dombrowski & Mueller, ; Mueller, ; Mueller & Mischel, ). For example, sedentary animals exhibit greater sympathoexcitatory responses to blockade of GABA A receptors in the RVLM (Mueller, ), enhanced sympathoinhibitory responses to GABA microinjections in the RVLM (Dombrowski & Mueller, ), and greater GABAergic modulation of pressor responses produced by direct activation of RVLM neurons with glutamate (Mueller & Mischel, ). Interestingly, these data suggest that sedentary conditions may upregulate GABA receptors, a proposition that is counterintuitive because sedentary conditions are associated with sympathetic overactivity (Mueller et al, ).…”