Activation of the Rostral Ventrolateral Medulla Reveals Specialized Control of Sympathetic Nerves Involved in Regulation of Blood Glucose and Blood Pressure

Abstract

BACKGROUND The sympathetic nervous system mediates the “fight-or-flight” response, including stimulation of the adrenal glands to secrete epinephrine. Epinephrine increases heart rate and contractility and increases blood glucose. Sympathetic nerve activity to functionally distinct targets is regulated differentially by the rostral ventrolateral medulla (RVLM). Therefore, it is important to recognize the numerous roles of the RVLM in control of both blood pressure and blood glucose. Anatomical evidence suggests that innervation of the adrenal gland is from ipsilateral spinal sympathetic neurons and, in turn by RVLM neurons primarily from the ipsilateral side; however, the functional implications of lateralized innervation are lacking. Functional evidence also suggests that withdrawal of tonic GABAergic inhibition in the RVLM during decreases in blood pressure is an important regulatory mechanism in the excitation of sympathetic vasoconstrictor nerves (e.g., splanchnic SNA). We were interested in whether similar neurotransmitter mechanisms mediate hypotension-induced increases in adrenal SNA (AdSNA). Thus, the goals of the present study were to 1) compare effects of contralateral vs. ipsilateral RVLM activation on sSNA and AdSNA, 2) determine the role of RVLM GABAA receptors in hypotension-induced increases in sSNA and AdSNA and 3) investigate functional outcomes in a physiologically relevant model of altered glucose regulation. We hypothesized that activation of the RVLM produces differential increases in sSNA versus AdSNA, given the unique functional role of AdSNA in glucose regulation. METHODS We measured AdSNA and sSNA in male Sprague-Dawley rats during ipsilateral or contralateral glutamatergic activation of the RVLM. We produced decreases in blood pressure (sodium nitroprusside, i.v.) before and after bilateral GABAA receptor blockade (bicuculline, 5mM 90nL). In related experiments, blood glucose was also recorded before and after 2-deoxyglucose (2-DG, i.v.). Lastly, adrenal glands from active (12 wk running wheels) and sedentary animals were analyzed to measure adrenal medulla size. RESULTS Our results indicated that glutamate (100 mM, 30nL) injected into the left RVLM produced increases in ipsilateral AdSNA that were more than twice that of increases following right RVLM (contralateral) injections (p<0.05; n=6). In contrast, sSNA responses were equivalent to glutamate injections on either side of the RVLM. In response to hypotension, both sSNA and AdSNA increased; however, increases in sSNA but not AdSNA were eliminated by bicuculline (p<0.05; n=4). In preliminary experiments, sedentary animals demonstrated potentially greater increases in glucose in response to 2-DG stimulation (p=0.21, n=4) and possibly smaller adrenal medulla size (p=0.142, n=3). CONCLUSION The results confirm previous anatomical findings that the RVLM has predominantly ipsilateral innervation of adrenal nerves. Baroreflex-mediated increases in sSNA but not AdSNA are mediated by GABAA receptors in the RVLM. A deeper understanding of neural control of adrenal function provides insight into comorbidities between cardiovascular and metabolic disease pathologies.