Adrenal Catecholamine Research Articles

Neural control of the circulation

The purpose of this brief review is to highlight key concepts about the neural control of the circulation that graduate and medical students should be expected to incorporate into their general knowledge of human physiology. The focus is largely on the sympathetic nerves, which have a dominant role in cardiovascular control due to their effects to increase cardiac rate and contractility, cause constriction of arteries and veins, cause release of adrenal catecholamines, and activate the renin-angiotensin-aldosterone system. These effects, as well as the control of sympathetic outflow by the vasomotor center in the medulla and the importance of sensory feedback in the form of peripheral reflexes, especially the baroreflexes, are discussed in the context of cardiovascular regulation.

Hyperoxia blunts counterregulation in humans and differential control of the sympathetic nervous system

Wehrwein and colleagues recently reported that the counterregulatory response to insulin-induced hypoglycaemia was reduced significantly during hyperoxia in normal human volunteers (Wehrwein et al. 2010). Specifically, they showed that the increased plasma concentrations of growth hormone, glucagon, adrenaline, cortisol and noradrenaline that occur under the conditions of hyperinsulinaemic hypoglycaemia were suppressed during hyperoxia. The study provides support for the hypothesis that oxygen tension can modulate glucose homeostasis. Studies in animals, such as those cited by Wehrwein et al. as well as those that demonstrate that hypoxia activates adrenomedullary sympathetic nerve activity and adrenal catecholamine release (Biesold et al. 1989), provide additional support. In the subsequent discussion of the potential mechanisms and limitations of their findings, the authors seem to hold the view that the sympathetic outflow operates in a uniform manner. They propose that the suppression of the release of glucagon, adrenaline and noradrenaline may be associated with the observations made by Seals et al. (1991) that hyperoxia suppresses muscle sympathetic activity and by others that muscle sympathetic nerve activity is elevated during hypoglycaemia in man (Fagius et al. 1986). They imply that hyperoxia may induce generalised sympathoinhibition and so suppress the counterregulatory responses. However, recent studies in rats suggest that hypersinsulinaemia per se activates muscle sympathetic activity selectively (Bardgett et al. 2010). Furthermore, we have recently shown that neuroglucoprivation activates a subpopulation of spinally projecting neurones in the rostral ventrolateral medulla (RVLM) (Verberne & Sartor, 2010). The properties of the neurones that were activated by depriving the brain of glucose were fundamentally different from those that are classically regarded as presympathetic vasomotor neurones (Guyenet, 2006). Presympathetic vasomotor neurones are profoundly inhibited by activation of the baroreceptors. In contrast, the neurones that were activated by neuroglucoprivation were baroinsensitive and lacked cardiac rhythm. Wehrwein and colleagues speculated that in experiments by others in which carotid chemoreceptors were denervated, carotid sinus baroreceptors may have also been impaired. While they dismissed these concerns, our studies confirm that RVLM neurones that control adrenomedullary adrenaline secretion are not under arterial baroreceptor control. Taken together, these observations add to an expanding body of evidence that supports the view that the sympathetic outflow to the periphery is differentially controlled (Morrison, 2001). Goldstein, in a recent review, also emphasised that viewing the ‘sympathoadrenal’ system as an integral whole is erroneous (Goldstein, 2010). In summary, Wehrwein and colleagues demonstrate that hyperoxia modulates the counterregulatory response to hypoglycaemia. The underlying mechanism remains unclear and merits further investigation in animal experiments. However, the interpretation of their findings would be enhanced by consideration of the modern view that the sympathetic nervous system operates differentially to orchestrate specific patterns of sympathetic activity that are associated with homeostatic reflexes.

Effects of tobacco smoke exposure during lactation on nutritional and hormonal profiles in mothers and offspring

Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4 × 1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (+50%), hypoinsulinemia (-40%), hypoleptinemia (-46%), as well as lower triglycerides (-53%) and very low-density lipoprotein cholesterol (-50%). Milk of S dams had higher lactose (+52%) and triglycerides (+78%). S pups presented higher body protein (+17%), lower total (-24%) and subcutaneous fat contents (-25%), hypoglycemia (-11%), hyperinsulinemia (+28%), hypocorticosteronemia (-40%), lower adrenal catecholamine content (-40%), hypertriglyceridemia (+34%), higher high-density lipoprotein cholesterol (+16%), and lower low-density lipoprotein cholesterol (-45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny.

Multiple Cerebral Infarction and Cardiomyopathy With Pheochromocytoma

A 44-year-old woman was admitted to our hospital with altered mental status and weakness in the left upper and lower limbs. A brain magnetic resonance imaging indicated multiple cerebral infarctions in the bilateral frontal and parietal lobes and in the left occipital lobe. Magnetic resonance angiography indicated overall arterial wall irregularity and stenosis. An electrocardiogram showed negative T waves, troponin I was elevated at 0.60 ng/mL, and an echocardiogram showed severe hypokinesis, leading to a diagnosis of ischemic heart disease; however, no stenosis was found at cardiac catheterization. No other etiology for the angiopathy could be found. Whole-body computed tomography demonstrated an adrenal tumor and urinary catecholamine levels were elevated. Following excision of the adrenal tumor, a diagnosis of pheochromocytoma was made. Postoperatively, the patient's arterial stenosis and cardiac abnormalities improved. It was hypothesized that the patient's cardiomyopathy and vasospasm were secondary to excessive catecholamine secretion from the pheochromocytoma.

Impaired neonatal survival of pro-opiomelanocortin null mutants

Intercrosses of heterozygous pro-opiomelanocortin (POMC) mice result in homozygous null progeny at lower frequencies than expected. Genotyping offspring at pre-, peri-, and postnatal stages revealed that over half of homozygous null mutants die in the early postnatal stages. To investigate the reasons for this early postnatal lethality, we analyzed in detail different parameters in the initial hours after birth. POMC null mutants born to heterozygous dams presented at birth with corticosterone levels no different from wildtype littermates, were euglycemic, and had normal liver glycogen stores. However, already 30min after birth corticosterone levels dropped by 80% and were undetectable thereafter, while corticosterone levels in wildtype animals increased during postnatal hours. Circulating adrenaline was almost below detection 1h after birth. Blood glucose levels fell sharply in all genotypes within 30min after birth; however, wildtype and heterozygous pups overcame hypoglycemia within an hour, while mutant pups stayed hypoglycemic. The depletion of liver glycogen stores in mutant pups was significantly less efficient compared to their littermates in the hours after birth. POMC null mutant mice born to POMC null mutant dams completely lack corticosterone and die of the expected respiratory dysfunction. In contrast, POMC null mutant mice born to heterozygous dams do not die of respiratory problems, but rather due to hypoglycemia. Our studies confirm an essential involvement of POMC peptides and of adrenal glucocorticoids and catecholamines on glucose homeostasis critical for early postnatal survival.

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Cytokine interactions with adrenal medullary chromaffin cells.

It is generally accepted that a bi-directional or reciprocal interaction occurs between the immune and neuroendocrine systems, and that this relationship is important for the appropriate physiological functioning of both systems. Similarly, an imbalance in this relationship may contribute to a number of pathologies, most notably those relating to stress. The aim of this article is to consider the interaction of cytokines with the adrenal medulla, a potentially important player in this relationship. The chromaffin cells of the adrenal medulla release catecholamines and a range of biologically active peptides in response to a wide variety of stress-related signals. A growing body of evidence indicates that this stress response is influenced by, and in turn has influence upon, immune signalling. This brief review will focus primarily on the best-described adrenal medullary active cytokines, namely interferon-α, interleukin-6, interleukin-1α/β and tumour necrosis factor-α. In each case, three key issues will be addressed: the physiologically relevant source of the cytokine; the intracellular signalling events arising from activation of its receptor and finally the cellular consequences of such activation in terms of modulation of gene expression and the secretory output of the chromaffin cells.

The Brain Renin-Angiotensin System Controls Divergent Efferent Mechanisms to Regulate Fluid and Energy Balance

The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release, and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. β-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure.

Inhibition of Ca2+ Channels and Adrenal Catecholamine Release by G Protein Coupled Receptors

Catecholamines and other transmitters released from adrenal chromaffin cells play central roles in the "fight-or-flight" response and exert profound effects on cardiovascular, endocrine, immune, and nervous system function. As such, precise regulation of chromaffin cell exocytosis is key to maintaining normal physiological function and appropriate responsiveness to acute stress. Chromaffin cells express a number of different G protein coupled receptors (GPCRs) that sense the local environment and orchestrate this precise control of transmitter release. The primary trigger for catecholamine release is Ca2+ entry through voltage-gated Ca2+ channels, so it makes sense that these channels are subject to complex regulation by GPCRs. In particular G protein βγ heterodimers (Gbc) bind to and inhibit Ca2+ channels. Here I review the mechanisms by which GPCRs inhibit Ca2+ channels in chromaffin cells and how this might be altered by cellular context. This is related to the potent autocrine inhibition of Ca2+ entry and transmitter release seen in chromaffin cells. Recent data that implicate an additional inhibitory target of Gβγ on the exocytotic machinery and how this might fine tune neuroendocrine secretion are also discussed.

Blockade by Nanomolar Resveratrol of Quantal Catecholamine Release in Chromaffin Cells

The cardiovascular protecting effects of resveratrol, an antioxidant polyphenol present in grapes and wine, have been attributed to its vasorelaxing effects and to its anti-inflammatory, antioxidant, and antiplatelet actions. Inhibition of adrenal catecholamine release has also been recently implicated in its cardioprotecting effects. Here, we have studied the effects of nanomolar concentrations of resveratrol on quantal single-vesicle catecholamine release in isolated bovine adrenal chromaffin cells. We have found that 30 to 300 nM concentrations of resveratrol blocked the acetylcholine (ACh) and high K(+)-evoked quantal catecholamine release, amperometrically measured with a carbon fiber microelectrode. At these concentrations, resveratrol did not affect the whole-cell inward currents through nicotinic receptors or voltage-dependent sodium and calcium channels, neither the ACh- or K(+)-elicited transients of cytosolic Ca(2+). Blockade by nanomolar resveratrol of secretion in ionomycin- or digitonin-treated cells suggests an intracellular site of action beyond Ca(2+)-dependent exocytotic steps. The fact that nanomolar resveratrol augmented cGMP is consistent with the view that resveratrol could be blocking the quantal secretion of catecholamine through a nitric oxide-linked mechanism. Because this effect occurs at nanomolar concentrations, our data are relevant in the context of the low circulating levels of resveratrol found in moderate consumers of red wines, which could afford cardioprotection by mitigating the catecholamine surge occurring during stress.

Functional Characterization of α9-Containing Cholinergic Nicotinic Receptors in the Rat Adrenal Medulla: Implication in Stress-Induced Functional Plasticity

An increase in circulating adrenal catecholamine levels constitutes one of the mechanisms whereby organisms cope with stress. Accordingly, stimulus-secretion coupling within the stressed adrenal medullary tissue undergoes persistent remodeling. In particular, cholinergic synaptic neurotransmission between splanchnic nerve terminals and chromaffin cells is upregulated in stressed rats. Since synaptic transmission is mainly supported by activation of postsynaptic neuronal acetylcholine nicotinic receptors (nAChRs), we focused our study on the role of alpha9-containing nAChRs, which have been recently described in chromaffin cells. Taking advantage of their specific blockade by the alpha-conotoxin RgIA (alpha-RgIA), we unveil novel functional roles for these receptors in the stimulus-secretion coupling of the medulla. First, we show that in rat acute adrenal slices, alpha9-containing nAChRs codistribute with synaptophysin and significantly contribute to EPSCs. Second, we show that these receptors are involved in the tonic inhibitory control exerted by cholinergic activity on gap junctional coupling between chromaffin cells, as evidenced by an increased Lucifer yellow diffusion within the medulla in alpha-RgIA-treated slices. Third, we unexpectedly found that alpha9-containing nAChRs dominantly (>70%) contribute to acetylcholine-induced current in cold-stressed rats, whereas alpha3 nAChRs are the main contributing channels in unstressed animals. Consistently, expression levels of alpha9 nAChR transcript and protein are overexpressed in cold-stressed rats. As a functional relevance, we propose that upregulation of alpha9-containing nAChR channels and ensuing dominant contribution in cholinergic signaling may be one of the mechanisms whereby adrenal medullary tissue appropriately adapts to increased splanchnic nerve electrical discharges occurring in stressful situations.

Hypothalamic Paraventricular Nucleus Lesion Involvement in the Sympathetic Control of Lipid Mobilization

The sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) is the principal initiator of lipolysis. Using pseudorabies virus, a transneuronal viral tract tracer, brain sites involved in the SNS outflow to WAT have been identified previously by us. One of these sites, the hypothalamic paraventricular nucleus (PVH) that shows predominantly unilateral sympathetic outflow from each half of the nucleus to ipsilaterally located WAT depots, was tested for laterality in lipid accumulation/mobilization in Siberian hamsters. First we tested whether unilateral PVH electrolytic lesions (PVHx) would increase lipid accumulation in WAT pads ipsilateral to the side of the PVHx. PVHx significantly increased body and WAT pad masses compared with sham PVHx; however, there was no laterality effect. In addition, bilateral PVHx increased body and WAT pad masses, as well as food intake, to a greater extent than did unilateral PVHx. We next tested for possible laterality effects on WAT lipid mobilization using food deprivation as the lipolytic stimulus in hamsters bearing unilateral or bilateral PVHx. Lipid mobilization was not prevented, as indicated indirectly by WAT mass and thus laterality of lipid mobilization could not be tested. We then tested whether removal of adrenal catecholamines via adrenal demedullation (ADMEDx) alone, or combined with bilateral PVHx, would block food deprivation-induced lipid mobilization, but neither did so. These results suggest that an intact PVH is not necessary for food deprivation-induced lipid mobilization and support the primacy of the SNS innervation of WAT, rather than adrenal medullary catecholamines, for lipid mobilization from WAT.

Nicotine exposure affects mother's and pup's nutritional, biochemical, and hormonal profiles during lactation in rats

We have shown that maternal nicotine exposure during lactation has long-lasting effects on body adiposity and hormonal status of rat offspring. Here, we studied the nutritional and hormonal profiles in this experimental model. Two days after birth, osmotic minipumps were implanted in lactating rats divided into two groups: NIC - continuous s.c. infusions of nicotine (6 mg/kg per day) for 14 days and C - saline. Dams and pups were killed at 15 and 21 days of lactation. Body weight and food intake were evaluated. Milk, blood, visceral fat, carcass, and adrenal gland were collected. All the significant data were P<0.05. At the end of nicotine exposure (15 days), dams presented higher milk production, hyperprolactinemia, and higher serum high-density lipoprotein cholesterol (HDL-C). Milk from NIC dams had higher lactose concentration and energy content. After nicotine withdrawal (21 days), dams showed lower food intake and hyperleptinemia. The 15-day-old NIC pups presented higher total body fat, higher HDL-C, serum leptin, serum corticosterone, and adrenal catecholamine content, but lower tyrosine hydroxylase protein levels. The 21-day-old NIC pups had higher body protein content and serum globulin. Thus, maternal nicotine exposure during lactation results in important changes in nutritional, biochemical, and hormonal parameters in dams and offspring. The pattern of these effects is clearly distinct when comparing the nicotine-exposed group to the withdrawal group, which could be important for the programming effects observed previously.

The effects of adrenalectomy and autonomic blockades on the exercise tachycardia in conscious rats

Heart rate (HR) during exercise is controlled by cardiac sympathetic (CSNA) and vagal (CVNA) efferent nerve activity and plasma catecholamines. To determine their relative contribution to the exercise tachycardia, we examined the effects of adrenalectomy (ADX) and autonomic blockades on the HR response during treadmill exercise for 32 min in 13 conscious rats. The baseline HR was not influenced by ADX, suggesting no significant role of adrenal catecholamines on the baseline HR. Since the baseline HR was increased 61 beats/min by atropine methyl nitrate (1.5 mg/kg) and decreased 26 beats/min by atenolol (3 mg/kg), CVNA determined the baseline HR more than CSNA. ADX did not affect the immediate increase in HR at 0–12 s from the exercise onset but reduced the subsequent increase in HR at 13–30 s. These increases in HR at the early period of exercise were more blunted by atenolol than atropine. On the other hand, the peak tachycardia response of 99 ± 8 beats/min at the end of exercise, which was the same between the intact and ADX conditions, was blunted to 73% by atenolol, to 77% by atropine, and to 35% by combined atenolol and atropine, respectively. In conclusion, it is likely that the tachycardia at the beginning of dynamic exercise is predominantly determined by the cardiac autonomic nerve activity, especially by a prompt increase in CSNA, and that the hormonal mechanism due to adrenal epinephrine contributes to a further increase in HR approximately in 13 s from the onset of exercise.

Programming of rat adrenal medulla by neonatal hyperleptinemia: adrenal morphology, catecholamine secretion, and leptin signaling pathway

Leptin serum concentration in early life is an important factor for adequate future development of the offspring. Previously, we demonstrated that hyperleptinemia on lactation programmed for hyperleptinemia, central leptin resistance with lower expression of the long form of leptin receptor at hypothalamus, and higher medullary catecholamine levels with cardiovascular consequences at adulthood. The central objective of this study was to determine the direct effect of leptin on adrenal medullary function of adult rats that were leptin treated during lactation. Adrenal morphology was also accessed. Recombinant murine leptin was injected in the pups during the first 10 days of life (group L, leptin-programmed) or at adulthood during 6 days (group LC). The controls of both experiments received saline (groups C and CC). Both treatments resulted in hyperleptinemia at 150 days old (+78% and 2-fold increase, respectively; P < 0.05). Programmed animals showed hypertrophy of adrenal and higher adrenal catecholamine content at 150 days old (3-fold increase, P < 0.05), and no changes were observed in the LC group. However, LC rats had lower adrenal content of tyrosine hydroxylase (-17%, P < 0.05). Leptin-programmed rats had a lower response to leptin in vitro stimulation (-22%, P < 0.05) and lower expression of key proteins of the leptin signaling pathway, leptin receptor and janus tyrosine kinase 2 in the medullas (-61% and -29%, respectively, P < 0.05). However, they presented higher expression of phosphorylated signal transducer and activator of transcription 3 (+2-fold, P < 0.05). Leptin treatment at adulthood did not affect these parameters. The higher catecholamine synthesis and secretion in the leptin-programmed rats observed in our previous study does not seem to be a consequence of the direct effect of leptin on the medullas. We suggest that the hyperleptinemia of the programmed animals increases adrenal medullary function through sympathetic nervous system activation. In conclusion, high leptin levels on lactation program the activity of the sympathoadrenal system at adulthood that may contribute to the development of adult chronic diseases such as hypertension.

GLUCOCORTICOID TREATMENT-EFFECT ON ADRENAL MEDULLARY CATECHOLAMINE PRODUCTION

Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal regulation of epinephrine synthesis during stress.

Adrenal Venous Sampling for Catecholamines: A Normal Value Study

Pheochromocytomas are rare, but potentially fatal, neoplasms. The diagnosis and localization of pheochromocytoma can be challenging, and recently there has been some debate regarding the role for adrenal venous sampling (AVS). The utility of AVS in this setting is hampered by a lack of normative value data for adrenal vein catecholamine concentrations and the reliability of lateralization ratios. We sought to address these concerns by analyzing AVS catecholamine concentrations from patients who did not have pheochromocytoma. Eighteen patients underwent successful AVS for evaluation of cortisol-producing adrenal masses. All had normal 24-h urinary excretion of fractionated catecholamines and metanephrines. There was a wide range of catecholamine concentrations in both the right (epinephrine 389-118326 pg/ml; norepinephrine 156-11193 pg/ml) and left (epinephrine 113-9327 pg/ml; norepinephrine 229-2216 pg/ml) adrenal veins. The right adrenal vein-to-left adrenal vein epinephrine gradient was as high as 83:1 (median 2.1:1; P < 0.02). Although less striking, similar findings were also seen for norepinephrine. This report provides a reference range for adrenal vein catecholamine concentrations in nonpheochromocytoma patients and illustrates the wide variation in epinephrine and norepinephrine concentrations. Epinephrine and norepinephrine concentrations are statistically significantly higher in the right vs. the left adrenal vein; in the case of epinephrine, up to an 83-fold difference was found between the right and left adrenal veins. These data highlight why AVS should not be used in the investigation of adrenal pheochromocytoma.

Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice

Current research employed electrical records from superior vagus and sympathetic nerve branch that supply fat retroperitoneal tissue (RS nerve) to investigate whether very moderate swim training in obese-programmed mice would change sympathetic and parasympathetic autonomic nervous system activities. Neonatal mice were treated with monosodium L: -glutamate (MSG), during their first 5days of life, to induce obesity. Mice started training on weaning, comprising free swimming 3days/week, 15min/day for 10weeks. After 12h fasting, the nerve electrical signals of the 90-day-old mice were processed to obtain firing rates. Blood samples were collected to measure glucose and insulin levels. Adrenal catecholamine content was measured. MSG treatment caused obesity. Hyperglycemia and hyperinsulinemia in MSG-obese mice, without any change in food intake, were obtained. Vagus firing rates were higher in obese mice than those in lean ones. A decrease in RS nerve activity and lower adrenal catecholamine stores have been observed. Swimming normalized blood glucose and insulin levels and MSG-obesity onset was attenuated by exercise. Vagus activity from obese mice decreased, whereas RS nerve activity and adrenal catecholamine levels increased in trained ones. Results suggest that autonomic activity imbalance and metabolic dysfunctions observed in MSG-obese mice were inhibited by precocious and moderate exercise training.

Centrally evoked increase in adrenal sympathetic outflow elicits immediate secretion of adrenaline in anaesthetized rats

To examine whether feedforward control by central command activates preganglionic adrenal sympathetic nerve activity (AdSNA) and releases catecholamines from the adrenal medulla, we investigated the effects of electrical stimulation of the hypothalamic locomotor region on preganglionic AdSNA and secretion rate of adrenal catecholamines in anaesthetized rats. Pre- or postganglionic AdSNA was verified by temporary sympathetic ganglionic blockade with trimethaphan. Adrenal venous blood was collected every 30 s to determine adrenal catecholamine output and blood flow. Hypothalamic stimulation for 30 s (50 Hz, 100-200 microA) induced rapid activation of preganglionic AdSNA by 83-181% depending on current intensity, which was followed by an immediate increase of 123-233% in adrenal adrenaline output. Hypothalamic stimulation also increased postganglionic AdSNA by 42-113% and renal sympathetic nerve activity by 94-171%. Hypothalamic stimulation induced preferential secretion of adrenal adrenaline compared with noradrenaline, because the ratio of adrenaline to noradrenaline increased greatly during hypothalamic stimulation. As soon as the hypothalamic stimulation was terminated, preganglionic AdSNA returned to the prestimulation level in a few seconds, and the elevated catecholamine output decayed within 30-60 s. Adrenal blood flow and vascular resistance were not affected or slightly decreased by hypothalamic stimulation. Thus, it is likely that feedforward control of catecholamine secretion from the adrenal medulla plays a role in conducting rapid hormonal control of the cardiovascular system at the beginning of exercise.

Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation

Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.5 x 10(-5) M/kg/day) led to a significant fourfold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation. Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the AHF group, and the AHF+PP36 group two days after AHF induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group. In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the AHF group and the AHF+PP36 group. There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands' catecholamine content between the AHF group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the AHF group's animals. These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.