To determine whether CCK influences sympathetic vasomotor function, we examined the effect of systemic CCK administration on mean arterial blood pressure (MAP), heart rate (HR), lumbar sympathetic nerve discharge (LSND), splanchnic sympathetic nerve discharge (SSND), and the discharge of presympathetic neurons of the rostral ventrolateral medulla (RVLM) in ␣-chloralose-anesthetized rats. CCK (1-8 g/kg iv) reduced MAP, HR, and SSND and transiently increased LSND. Vagotomy abolished the effects of CCK on MAP and SSND as did the CCK-A receptor antagonist devazepide (0.5 mg/kg iv). The bradycardic effect of CCK was unaltered by vagotomy but abolished by devazepide. CCK increased superior mesenteric arterial conductance but did not alter iliac conductance. CCK inhibited a subpopulation (ϳ49%) of RVLM presympathetic neurons whereas ϳ28% of neurons tested were activated by CCK. The effects of CCK on RVLM neuronal discharge were blocked by devazepide. RVLM neurons inhibited by exogenous CCK acting via CCK-A receptors on vagal afferents may control sympathetic vasomotor outflow to the gastrointestinal tract vasculature. blood pressure; splanchnic sympathetic nerve; lumbar sympathetic nerve; rat CHOLECYSTOKININ (CCK) is a gastrointestinal hormone with actions including gastrointestinal vasodilatation (18), reduced gut motility, gastric acid secretion, and pancreatic secretion (3, 28). In the central nervous system, it is one of the most abundant neuropeptides, probably playing a major role in satiety as well as anxiety-related behavior (6, 38). Of the two types of CCK receptors, the A-type (CCK-A receptor) is predominantly found in the periphery, although it is also present in discrete brain regions and has a higher affinity for the sulfated octapeptide form of CCK. In the brain, the B-type receptor (CCK-B receptor) predominates and has a high affinity for both the sulfated and nonsulfated forms of CCK (13).Peripherally, CCK has been implicated in postprandial intestinal hyperemia because systemic administration of the peptide produces intestinal vasodilatation (18). In contrast, its effects on the vascular resistance of forelimb, skin, or muscle have been found to be negligible (10), suggesting that the actions of CCK may target specific vascular beds.CCK receptors are located on vagal afferents (11, 35) and in the nucleus of solitary tract (NTS) (7, 35), a major site of termination of vagal afferents. Although peptides generally do not permeate the blood-brain barrier, CCK may potentially act on neurons of the area postrema, a circumventricular organ with neuronal cell bodies lying outside the blood brain barrier but with projections to several areas within the brain (6). There are also regions within the NTS and the dorsal nucleus of vagus nerve that have altered blood-brain barrier properties potentially facilitating the access of peptides such as CCK (6). Thus CCK may act either directly on the central nervous system to influence sympathetic vasomotor function and/or peripherally via vagal afferent fibers, conveying ...

Verberne AJ, Sartor DM. Rostroventrolateral medullary neurons modulate glucose homeostasis in the rat. Am J Physiol Endocrinol Metab 299: E802-E807, 2010. First published August 31, 2010; doi:10.1152/ajpendo.00466.2010.-Several lines of evidence support the view that the premotor sympathetic input to the adrenal gland arises from the rostroventrolateral medulla (RVLM). The aim of this study was to determine whether RVLM neurons play a role in glucose homeostasis. We identified RVLM neurons that control epinephrine secretion by searching for medullospinal neurons that responded to neuroglucoprivation induced by systemic 2-deoxyglucose (2-DG) administration. We tested the effect of disinhibition of the RVLM on arterial blood pressure and plasma glucose concentration. RVLM medullospinal barosensitive neurons (n ϭ 17) were either unaffected or slightly inhibited by 2-DG. In contrast, we found a group (n ϭ 6) of spinally projecting neurons that were excited by 2-DG administration. These neurons were not barosensitive and had spinal conduction velocities in the unmyelinated range (Ͻ1 m/s). These neurons may mediate epinephrine secretion and participate in the counterregulatory responses to neuroglucoprivation. To test the hypothesis that activation of the RVLM leads to adrenomedullary activation and subsequent hyperglycemia, we applied the GABAA antagonist bicuculline to the RVLM and measured blood pressure, heart rate, and blood glucose in rats with intact adrenals or after bilateral adrenalectomy. Disinhibition of the RVLM resulted in hypertension, tachycardia, and hyperglycemia (4.9 Ϯ 0.3 to 14.7 Ϯ 0.9 mM, n ϭ 5, P Ͻ 0.05). Adrenalectomy significantly reduced the hyperglycemic response but did not alter the cardiovascular responses. These data suggest that the RVLM is a key component of the neurocircuitry that is recruited in the counterregulatory response to hypoglycemia. glucose homeostasis; counterregulation; sympathetic nervous system; adrenal glands EPINEPHRINE IS A GLUCOSE-COUNTERREGULATORY HORMONE that is of major importance in countering hypoglycemia in individuals with type 1 and advanced type 2 diabetes (7). Epinephrine is synthesized by chromaffin cells in the adrenal medulla and its secretion is controlled by a distinct group of sympathetic preganglionic neurons (21).It has long been assumed that epinephrine is an important modulator of cardiovascular function, but it probably contributes minimally to blood pressure regulation (38). Indeed, it is likely that its primary role is as a metabolic hormone which serves to mobilise glucose by activation of liver glycogenolysis and gluconeogenesis (13).In contrast to the sympathetic preganglionic neurons that control vasomotor tone, the sympathetic preganglionic neurons that control epinephrine secretion are not particularly responsive to baroreceptor stimulation. Instead, they are strongly activated by neuroglucoprivation induced by administration of the glucoprivic agent 2-deoxyglucose (2-DG) (21), a glucose analog that does not undergo glycolysis. Insulin-i...

Systemic administration of the gastrointestinal hormone cholecystokinin (CCK) selectively inhibits splanchnic sympathetic vasomotor discharge and differentially affects presympathetic vasomotor neurons of the rostroventrolateral medulla (RVLM). Stimulation of the sympathoexcitatory region of the periaqueductal grey (PAG) produces profound mesenteric vasoconstriction. In this study, our aim was to identify phenotypically different populations of RVLM presympathetic vasomotor neurons using juxtacellular neuronal labelling and immunohistochemical detection of the adrenergic neuronal marker phenylethanolamine-N-methyl transferase (PNMT) and to determine whether the PAG provides functional excitatory input to these neurons. Fifty-eight percent (36/62) of RVLM presympathetic neurons were inhibited by systemic administration of CCK. These cells had conduction velocities (3.6 +/- 0.2 m/sec) in the non-C-fiber range consistent with neurons possessing lightly myelinated spinal axons. Of these, 79% (22/28) were excited by PAG stimulation, and 59% (10/17) were not immunoreactive for PNMT. Conversely, 42% (26/62) of RVLM presympathetic neurons were either unaffected or activated by CCK administration and had slower conduction velocities (1.4 +/- 0.3 m/sec) than cells inhibited by CCK. Fifty percent (11/22) of these cells were driven by PAG stimulation, and most (11/14 or 79%) were PNMT-positive. These results suggest that cardiovascular responses elicited by PAG stimulation occur via activation of non-C1 and C1 RVLM presympathetic neurons. RVLM neurons inhibited by CCK were more likely to be driven by PAG stimulation and may be a subset of neurons responsible for driving gastrointestinal sympathetic vasomotor tone. CCK-induced inhibition of a subpopulation of RVLM presympathetic neurons may be implicated in postprandial hyperemia and postprandial hypotension.

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Circulating ghrelin reduces blood pressure, but the mechanism for this action is unknown. This study investigated whether ghrelin has direct vasodilator effects mediated through the growth hormone secretagogue receptor 1a (GHSR1a) and whether ghrelin reduces sympathetic nerve activity. Mice expressing enhanced green fluorescent protein under control of the promoter for growth hormone secretagogue receptor (GHSR) and RT-PCR were used to locate sites of receptor expression. Effects of ghrelin and the nonpeptide GHSR1a agonist capromorelin on rat arteries and on transmission in sympathetic ganglia were measured in vitro. In addition, rat blood pressure and sympathetic nerve activity responses to ghrelin were determined in vivo. In reporter mice, expression of GHSR was revealed at sites where it has been previously demonstrated (hypothalamic neurons, renal tubules, sympathetic preganglionic neurons) but not in any artery studied, including mesenteric, cerebral, and coronary arteries. In rat, RT-PCR detected GHSR1a mRNA expression in spinal cord and kidney but not in the aorta or in mesenteric arteries. Moreover, the aorta and mesenteric arteries from rats were not dilated by ghrelin or capromorelin at concentrations >100 times their EC(50) determined in cells transfected with human or rat GHSR1a. These agonists did not affect transmission from preganglionic sympathetic neurons that express GHSR1a. Intravenous application of ghrelin lowered blood pressure and decreased splanchnic nerve activity. It is concluded that the blood pressure reduction to ghrelin occurs concomitantly with a decrease in sympathetic nerve activity and is not caused by direct actions on blood vessels or by inhibition of transmission in sympathetic ganglia.

Presympathetic vasomotor adrenergic (C1) and nonadrenergic (non-C1) neurons in the rostral ventrolateral medulla (RVLM) provide the main excitatory drive to cardiovascular sympathetic preganglionic neurons in the spinal cord. C1 and non-C1 neurons contain cocaine- and amphetamine-regulated transcript (CART), suggesting that CART may be a common marker for RVLM presympathetic neurons. To test this hypothesis, we first used double-immunofluorescence staining for CART and tyrosine hydroxylase (TH) to quantify CART-immunoreactive (-IR) catecholamine and noncatecholamine neurons in the C1 region. Next, we quantified the proportion of CART-IR RVLM neurons that expressed Fos in response to a hypotensive stimulus, using peroxidase immunohistochemistry for Fos and dual immunofluorescence for CART and TH. Finally, we fluorescently detected CART immunoreactivity in electrophysiologically identified, juxtacellularly labeled RVLM presympathetic neurons. In the RVLM, 97% of TH-IR neurons were CART-IR, and 74% of CART-IR neurons were TH-IR. Nitroprusside infusion significantly increased the number of Fos-IR RVLM neurons compared with saline controls. In nitroprusside-treated rats, virtually all Fos/TH neurons in the RVLM were immunoreactive for CART (98% +/- 1.3%, SD; n = 7), whereas 29% +/- 8.3% of CART-positive, TH-negative neurons showed Fos immunoreactivity. Six fast (2.8-5.8 m/second, noncatecholamine)-, two intermediate (2.1 and 2.2 m/second)-, and five slow (<1 m/second, catecholamine)-conducting RVLM presympathetic vasomotor neurons were juxtacellularly labeled. After fluorescent detection of CART and biotinamide, all 13 neurons were found to be CART-IR. These results suggest that, in rat RVLM, all catecholamine and noncatecholamine presympathetic vasomotor neurons contain CART.

Mechanisms underlying the depressor and sympathoinhibitory responses evoked from the caudal medullary raphe (MR) region were investigated in pentobarbital sodium-anesthetized, paralyzed rats. Intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 200 μA) of the MR elicited a mixed sympathetic response that consisted of a long-latency sympathoexcitatory (SE) peak (onset = 146 ± 7 ms) superimposed on an inhibitory phase (onset = 59 ± 10 ms). Chemical stimulation of the MR (glutamate; Glu) most frequently elicited depressor responses accompanied by inhibition of sympathetic nerve discharge. Occasionally, these responses were preceded by transient pressor and SE responses. We examined the influence of intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 25–200 μA) and Glu stimulation of the MR on the discharge of rostral ventrolateral medulla (RVLM) premotor SE neurons. Peristimulus-time histograms of RVLM unit discharge featured a prominent inhibitory phase in response to MR stimulation (onset = 20 ± 2 ms; duration = 42 ± 4 ms; n = 12 units). Glu stimulation of the MR reduced blood pressure (−37 ± 2 mmHg, n = 19) and inhibited the discharge of RVLM SE neurons (15 of 19 neurons). Depressor and sympathoinhibitory responses elicited by chemical and electrical stimulation of the MR region are mediated by inhibition of RVLM premotor SE neurons and withdrawal of sympathetic vasomotor discharge.