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Sympathetic nerve discharge (SND) responses to hyperthermia are attenuated in aged rats without heart failure (HF) and in young HF ([Y.sub.HF]) rats, demonstrating that individually aging and HF alter SND regulation. However, the combined effects of aging and HF on SND regulation to heat stress are unknown, despite the high prevalence of HF in aged individuals. We hypothesized that SND responses to heating would be additive when aging and HF are combined, demonstrated by marked reductions in SND and mean arterial pressure (MAP) responses to heating in aged HF ([A.sub.HF]) compared with aged sham HF ([A.sub.SHAM]) rats, and in [A.sub.HF] compared with [Y.sub.HF] rats. Renal and splenic SND responses to hyperthermia (colonic temperature increased to 41.5[degrees]C) were determined in anesthetized [Y.sub.HF], young sham ([Y.sub.SHAM]), [A.sub.HF], and [A.sub.SHAM] Fischer rats. HF was induced by myocardial infarction and documented using echocardiographic, invasive, and postmortem measures. The severity of HF was similar in [Y.sub.HF] and [A.sub.HF] rats. SND responses to heating were attenuated in [Y.sub.HF] compared with [Y.sub.SHAM] rats, demonstrating an effect of HF on SND regulation in young rats. In contrast, [A.sub.HF] and [A.sub.SHAM] rats demonstrated similar SND responses to heating, suggesting a prominent influence of age on SND regulation in [A.sub.HF] rats. Splenic SND and MAP responses to heating were similar in [Y.sub.HF], [A.sub.HF], and [A.sub.SHAM] rats, indicating that the imposition of HF in young rats changes the regulatory status of these variables to one consistent with aged rats. These data suggest that the effect of HF on SND regulation to hyperthermia is age dependent. sympathetic nerve discharge; sympathetic nervous system; acute heat stress doi: 10.1152/ajpregu.00434.2010.

The midbrain periaqueductal gray (PAG) mediates the physiological responses to a wide range of stressors. It consists of four longitudinal columns that have different anatomical connections and functional properties. Previous anatomical and behavioral studies have led to the hypothesis that the dorsolateral PAG, but not the adjacent lateral and dorsomedial subregions, is a key center that integrates the behavioral response to acute psychological threatening stimuli. In this study, we tested whether, consistent with this hypothesis, activation of neurons in the dorsolateral PAG evokes a pattern of cardiovascular and respiratory responses that is distinct from that evoked from surrounding regions. Arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) were recorded simultaneously in urethane-anesthetized rats. Microinjections of very small amounts of D,L-homocysteic acid (750 pmol in 15 nl) were made in sites throughout the dorsomedial, dorsolateral, and lateral PAG subregions. Increases in RSNA of similar magnitude accompanied by small to moderate increases in arterial pressure and heart rate were evoked from all three PAG subregions. In contrast, large increases in both PNA burst rate (respiratory rate) and overall respiratory activity were evoked only from a highly circumscribed region that corresponded closely to the dorsolateral PAG subregion at an intermediate to caudal level. Within this region, the evoked increases in RSNA and respiratory activity were highly correlated (r = 0.914, P < 0.001), suggesting the possibility that a common population of 'command neurons' within the dorsolateral PAG may generate both sympathetic and respiratory responses from this region. phrenic nerve activity; renal sympathetic nerve activity; dorsomedial periaqueductal gray; lateral periaqueductal gray; psychological stress doi: 10.1152/ajpregu.00249.2010.

Walter B. Cannon's research on the sympathetic nervous system and neurochemical transmission was pioneering. Wisdom has endowed our body with a powerful autonomic neural regulation of the circulation that provides optimal perfusion of every organ in accordance to its metabolic needs. Exquisite sensors tuned to an optimal internal environment trigger central and peripheral sympathetic and parasympathetic motor neurons and allow desirable and beneficial adjustments to physiologic needs as well as to acute cardiovascular stresses. This short review, presented as The Walter B. Cannon Memorial Award Lecture for 2009, addresses the mechanisms that disrupt sensory signaling and result in a chronic maladjustment of the autonomic neural output that in many cardiovascular diseases results in excessive increases in the risks of dying. The hopes for any reduction of those risks resides in an understanding of the molecular determinants of neuronal signaling. sensory transduction; baroreceptors; chemoreceptors; ion channels doi: 10.1152/ajpregu.00130.2010.

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24-47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 [+ or -] 2 mg/dl (mean [+ or -] SE), and 2 drinks to 72 [+ or -] 4 (RW) and 80 [+ or -] 2 mg/dl (EtOH). RW quadrupled plasma resveratrol (P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 [+ or -] 1.2; and EtOH, +5.7 [+ or -] 1.2 [min.sup.-1]; p < 0.001), decreased total HRV by 28-33% (P < 0.05) and high-frequency spectral power by 32-42% (vagal HR modulation), and increased low-frequency power by 2834% and the ratio of low frequency to high frequency by 98-119% (sympathetic HR modulation) (all, P [less than or equal to] 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect. sympathetic nervous system; parasympathetic nervous system; spectral analysis doi: 10.1152/ajpheart.00700.2009.

Since humans are under ceaseless orthostatic stress, the mechanisms to maintain arterial pressure (AP) against gravitational fluid shift are important. As one mechanism, it was reported that upright tilt reset baroreflex control of renal sympathetic nerve activity (SNA) to a higher SNA in anesthetized rabbits. In the present study, we tested the hypothesis that upright tilt causes a parallel resetting of baroreflex control of renal and cardiac SNAs in anesthetized rabbits. In anesthetized rabbits (n = 8, vagotomized and aortic denervated) with 0[degrees] supine and 60[degrees] upright tilt postures, renal and cardiac SNAs were simultaneously recorded while isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg. Upright tilt shifted the reverse-sigmoidal curve of the CSP-SNA relationship to higher SNA similarly in renal and cardiac SNAs. Although upright tilt increased the maximal gain, the response range and the minimum value of SNA, the curves were almost superimposable in these SNAs regardless of postures. Scatter plotting of cardiac SNA over renal SNA during the stepwise changes in CSP was close to the line of identity in 0[degrees] supine and 60[degrees] upright tilt postures. In addition, upright tilt also shifted the reverse-sigmoidal curve of the CSP-heart rate relationship to a higher heart rate, with increases in the maximal gain and the response range. In conclusion, upright posture caused a resetting of arterial baroreflex control of SNA similarly in renal and cardiac SNAs in anesthetized rabbits. blood pressure; orthostasis; sympathetic nervous system doi: 10.1152/ajpheart.00340.2009.

Ramchandra R, Watson AM, Hood SG, May CN. Response of cardiac sympathetic nerve activity to intravenous irbesartan in heart failure. Am J Physiol Regul Integr Comp Physiol 298: R1056-R1060, 2010. First published February 10, 2010; doi: 10.1152/ajpregu.00767.2009.--To determine the effect of irbesartan treatment on resting levels and arterial baroreflex control of cardiac sympathetic nerve activity (CSNA) in heart failure (HF), we studied conscious normal sheep and sheep with HF induced by rapid ventricular pacing for 8-10 wk (n = 7 per group). In HF, there is a large increase in CSNA that is detrimental to outcome. The causes of this increase in CSNA and the effect of angiotensin receptor blockers on CSNA in HF are unclear. CSNA, arterial blood pressure, heart rate (HR), and arterial baroreflex curves were recorded during a resting period and after 90 min of irbesartan infusion (12 mg*[kg.sup.-1]*[h.sup.-1] iv). This dose of irbesartan abolished the pressor response to intravenous ANG II infusion but caused only a slight decrease in the pressor response to centrally administered ANG II. In HF, there was a large increase in CSNA (from 44 [+ or -] 3 to 87 [+ or -] 3 bursts/100 heartbeats). Irbesartan reduced arterial pressure in the normal and HF groups, but the usual baroreflex-mediated increases in CSNA and HR were prevented. This resulted from a significant leftward shift in the CSNA and HR baroreflex curves in both groups. Irbesartan also decreased the sensitivity of the arterial baroreflex control of CSNA. Shortterm treatment with an angiotensin receptor blocker, at a dose that abolished the response to circulating, but not central, ANG II, prevented the reflex increase in CSNA in response to the drug-induced fall in arterial pressure. angiotensin receptor blockade; baroreflex doi: 10.1152/ajpregu.00767.2009.

Am J Physiol Regul Integr Comp Physiol 298: R89-R95, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00449.2009.--The role played by the sympathetic drive in the development of [N.sup.G]-nitro-L-arginine methyl ester (L-NAME)-induced hypertension is not firmly established. Therefore, the present study was undertaken in conscious rats in which hypertension was induced by treatment with L-NAME over the course of either 2 or 14 days. Mean arterial pressure (MAP) was measured via a catheter placed in the femoral artery, drugs were administered via a cannula placed in the femoral vein, and renal sympathetic nerve activity (RSNA) was monitored using an implanted electrode. Despite the remarkable increase in arterial pressure, heart rate did not change after treatment with L-NAME. RSNA was similar in L-NAME-induced hypertensive rats treated over the course of 2 or 14 days, as well as in normotensive rats. It was also demonstrated that L-NAME-induced hypertensive rats displayed a resetting of the baroreflex control of RSNA to hypertensive levels, with decreased sensitivity over the course of 2 or 14 days. Furthermore, the sympathetic-vagal balance examined in the time and frequency domain and the renal and plasma norepinephrine content did not differ between groups. In conclusion, the evaluation of the sympathetic drive in conscious rats demonstrated that the arterial hypertension induced by L-NAME treatment over the course of 2 and 14 days does not show sympathetic overactivity. baroreflex; nitric oxide; sympathetic activity.

Am J Physiol Regul Integr Comp Physiol 298: R9-R14, 2010. First published October 14, 2009; doi: 10.1152/ajpregu.00554.2009.--Recent studies report that the menstrual cycle alters sympathetic neural responses to orthostatic stress in young, eumenorrheic women. The purpose of the present study was to determine whether oral contraceptives (OC) influence sympathetic neural activation during an orthostatic challenge. Based on evidence that sympathetic baroreflex sensitivity (BRS) is increased during the 'low hormone' (LH) phase (i.e., placebo pills) in women taking OC, we hypothesized an augmented muscle sympathetic nerve activity (MSNA) response to orthostatic stress during the LH phase. MSNA, mean arterial pressure (MAP), and heart rate (HR) were recorded during progressive lower body negative pressure (LBNP; -5, -10, -15, -20, -30, -40 mmHg; 3 min/stage) in 12 healthy women taking OC (age 22 [+ or -] 1 years). Sympathetic BRS was assessed by examining relations between spontaneous fluctuations of diastolic arterial pressure and MSNA. Subjects were examined twice: once during LH phase and once ~3 wk after LH during the 'high hormone' phase (randomized order). Resting MSNA (10 [+ or -] 2 vs. 13 [+ or ] 2 bursts/rain), MAP (85 [+ or -] 3 vs. 84 [+ or -] 3 mmHg), and HR (62 [+ or -] 2 vs. 65 [+ or -] 3 beats/min) were not different between phases. MSNA and HR increased during progressive LBNP (P < 0.001), and these increases were similar between phases. Progressive LBNP did not change MAP during either phase. Sympathetic BRS increased during progressive LBNP, but these responses were not different between LH and high hormone phases. In conclusion, our results demonstrate that OCs do not alter cardiovascular and sympathetic neural responses to an orthostatic challenge in young, healthy women. muscle sympathetic nerve activity; arterial blood pressure; lower body negative pressure; baroreflex; menstrual cycle

Am J Physiol Heart Circ Physiol 298: H229-H234, 2010. First published November 13, 2009; doi: 10.1152/ajpheart.00880.2009.--The effects of aerobic exercise training (ET) on muscle sympathetic nerve activity (MSNA) and renal vascular responses to mental stress (MS) have not been determined in humans. We hypothesized that aerobic ET would reduce MSNA and renal vasoconstriction during MS. MSNA, mean arterial pressure (MAP), heart rate, renal blood flow velocity (RBFV), and peak oxygen uptake ([Vo.sub.2peak]) were recorded in 23 healthy adults. Fourteen subjects participated in 8 wk of aerobic ET, while nine subjects served as sedentary controls (Con). ET significantly increased [Vo.sub.2peak] ([DELTA]18 [+ or -] 1%; P < 0.001) and decreased RBFV at rest (60 [+ or -] 4 to 48 [+ or -] 3 cm/s; P < 0.01), whereas Con did not alter [Vo.sub.2peak] or RBFV. ET did not alter resting MSNA (11 [+ or -] 1 to 9 [+ or -] 1 bursts/min) orMAP (84 [+ or -] 2 to 83 [+ or -] 2 mmHg), and these findings were similar in the Con group. MS elicited similar increases in MSNA (~[DELTA]2 bursts/min; P < 0.05), MAP (-A15 mmHg; P < 0.001), and heart rate (~[DELTA]20 beats/min; P < 0.001) before and after ET, and the responses were not different between ET and Con. Likewise, MS elicited similar decreases in RBFV and renal vascular conductance before and after ET, and the responses were not different between ET and Con. Perceived stress levels during MS were similar before and after the 8-wk study in both ET and Con. In conclusion, ET does not alter MSNA and renal vascular responses to MS in healthy humans. autonomic control; blood pressure; mental arithmetic; muscle sympathetic nerve activity; renal vascular conductance

Sepsis and septic shock are the chief cause of death in intensive care units, with mortality rates between 30 and 70%. In a large animal model of septic shock, we have demonstrated hypotension, increased cardiac output, and tachycardia, together with renal vasodilatation and renal failure. The changes in cardiac sympathetic nerve activity (CSNA) that may contribute to the tachycardia have not been investigated, and the changes in renal SNA (RSNA) that may mediate the changes in renal blood flow and function are unclear. We therefore recorded CSNA and RSNA during septic shock in conscious sheep. Septic shock was induced by administration of Escherichia coli, which caused a delayed hypotension and an immediate, biphasic increase in heart rate (HR) associated with similar changes in CSNA. After E. coli, RSNA decreased for over 3 h, followed by a sustained increase (180%), whereas renal blood flow progressively increased and remained elevated. There was an initial diuresis, followed by oliguria and decreased creatinine clearance. There were differential changes in the range of the arterial baroreflex curves; it was depressed for HR, increased for CSNA, and unchanged for RSNA. Our findings, recording CSNA for the first time in septic shock, suggest that the increase in SNA to the heart is not driven solely by unloading of baroreceptors and that the increase has an important role to increase HR and cardiac output. There was little correlation between the changes in RSNA and renal blood flow, suggesting that the renal vasodilatation was mediated mainly by other mechanisms. acute renal failure; renal blood flow doi: 10.1152/ajpregu.00437.2009.

Sympathetic nerve activity (SNA) consists of discharges that vary in amplitude and frequency, reflecting the level of recruitment of nerve fibers and the rhythmic generation and entrainment of activity by the central nervous system. It is unknown whether selective changes in these amplitude and frequency components account for organ-specific changes in SNA in response to alterations in blood volume or for the impaired SNA responses to volume changes in heart failure (HF). To address these questions, we measured cardiac SNA (CSNA) and renal SNA (RSNA) simultaneously in conscious, normal sheep and sheep in HF induced by rapid ventricular pacing. Volume expansion decreased CSNA (-62 [+ or -] 10%, P < 0.05) and RSNA (-59 [+ or -] 10%, P < 0.05) equally (n = 6). CSNA decreased as a result of a reduction in burst frequency, whereas RSNA fell because of falls in burst frequency and amplitude. Hemorrhage increased CSNA (+74 [+ or -] 9%, P < 0.05) more than RSNA (+21 [+ or -] 5%, P < 0.09), in both cases because of increased burst frequency, whereas burst amplitude decreased. In HF, burst frequency of CSNA (from 26 [+ or -] 3 to 75 [+ or -] 3 bursts/min) increased more than that of RSNA (from 63 [+ or -] 4 to 79 [+ or -] 4 bursts/min). In HF, volume expansion caused no change in CSNA and an attenuated decrease in RSNA, due entirely to decreased burst amplitude. Hemorrhage did not significantly increase SNA in either nerve in HF. These findings support the concept that the number of sympathetic fibers recruited and their firing frequency are controlled independently. Furthermore, afferent stimuli, such as changes in blood volume, cause organ-specific responses in each of these components, which are also selectively altered in HF. differential control of sympathetic nerve activity; burst amplitude; burst frequency; burst incidence; hemorrhage

The purpose of the study was to determine the interactive effect of aging and forearm muscle heating on renal vascular conductance and muscle sympathetic nerve activity (MSNA) during ischemic isometric handgrip. A tubelined, water-perfused sleeve was used to heat the forearm in 12 young (27 [+ or -] 1 yr) and 9 older (63 [+ or -] 1 yr) subjects. Ischemic isometric handgrip was performed before and after heating. Muscle temperature (intramuscular thermistor) was 34.3 [+ or -] 0.2 and 38.7 [+ or -] 0.1[degrees]C during normothermia and heating, respectively. At rest, heating had no effect on renal blood velocity (Doppler ultrasound) or renal vascular conductance in either group (young, n = 12; older, n = 8). Heating compared with normothermia caused a significantly greater increase in renal vasoconstriction during exercise and postexercise muscle ischemia (PEMI) in both groups. However, the increase in renal vasoconstriction during heating was greater in the older compared with the young subjects (18 [+ or -] 3 vs. 8 [+ or -] 3%). During handgrip, heating elicited greater increases in MSNA responses in the older group (young, n = 12; older, n = 6), whereas no statistical difference was observed between groups during PEMI. In summary, aging augments renal vascular responses to ischemic isometric handgrip during heating of the exercising muscle. The greater renal vasoconstriction was associated with augmented MSNA in the older subjects. kidney; sympathetic; hyperthermia

We have recently shown that polycystic ovary syndrome (PCOS) is associated with high muscle sympathetic nerve activity (MSNA). Animal studies support the concept that low-frequency electroacupuncture (EA) and physical exercise, via stimulation of ergoreceptors and somatic afferents in the muscles, may modulate the activity of the sympathetic nervous system. The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS. In a randomized controlled trial, 20 women with PCOS were randomly allocated to one of three groups: low-frequency EA (n = 9), physical exercise (n = 5), or untreated control (n = 6) during 16 wk. Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment. Biometric, hemodynamic, endocrine, and metabolic parameters were measured. Low-frequency EA (P = 0.036) and physical exercise (P = 0.030) decreased MSNA burst frequency compared with the untreated control group. The low-frequency EA group reduced sagittal diameter (P = 0.001), while the physical exercise group reduced body weight (P = 0.004) and body mass index (P = 0.004) compared with the untreated control group. Sagittal diameter was related to MSNA burst frequency (Rs = 0.58, P < 0.005) in the EA group. No correlation was found for body mass index and MSNA in the exercise group. There were no differences between the groups in hemodynamic, endocrine, and metabolic variables. For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS. Thus, treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS. polycystic ovary syndrome; sympathetic nerve activity: testosterone; insulin resistance; metabolic syndrome; cardiovascular disease

Acute alcohol intoxication results in impaired hemodynamic counterregulation to blood loss and is associated with an attenuated hemorrhage-induced release of catecholamines and AVP. We speculated that restoration of the neuroendocrine response to hemorrhage would improve mean arterial blood pressure (MABP) recovery during acute alcohol intoxication. Previously, we demonstrated that intracerebroventricular (ICV) choline, a precursor of acetylcholine, transiently increases sympathetic nervous system (SNS) outflow but is not capable of improving neuroendocrine and hemodynamic compensation to hemorrhage in alcohol-treated rats. We hypothesized that prolongation of the observed effect via ICV neostigmine, an acetylcholinesterase inhibitor, would enhance SNS outflow, restore the neuroendocrine response, and in turn improve hemodynamic responses to hemorrhage during acute alcohol intoxication. ICV neostigmine (1 [micro]g) increased MABP, catecholamines, and AVP within 5 min and reversed hypotension due to 40% hemorrhage and intragastric alcohol (30% wt/vol, 2.5 g/kg) administration in chronically catheterized male Sprague-Dawley rats (225-250 g body wt). Acute alcohol intoxication before 50% hemorrhage decreased basal MABP, accentuated hypotension midhemorrhage, suppressed the hemorrhage-induced release of norepinephrine and AVP, and prevented restoration of MABP to basal levels after fluid resuscitation with lactated Ringer solution. ICV neostigmine (0.5 [micro]g) produced a sustained increase in MABP beginning at 30 min of hemorrhage that persisted throughout fluid resuscitation in control and alcohol-treated animals. ICV neostigmine enhanced epinephrine responses and restored the hemorrhage-induced release of norepinephrine and AVP in alcohol-treated rats. These results demonstrate that inhibition of acetylcbolinesterase in the central nervous system enhances SNS outflow, restores the neuroendocrine response to severe blood loss, and thereby improves hemodynamic counterregulation during acute alcohol intoxication. This study provides evidence for a central (and not peripheral) role of alcohol in impairing hemodynamic stability during hemorrhagic shock. ethanol; mean arterial blood pressure; sympathetic nervous system

The importance of dietary salt in the development of hypertension has long been a source of controversy. Recent studies suggest a combination of high-salt and ANG II infusion may increase sympathetic drive; however, the effect of a change in dietary salt alone is unclear. Using telemetry, we recorded renal sympathetic nerve activity (RSNA), arterial pressure (MAP), and heart rate (HR) in seven New Zealand white rabbits before and during a 6-day period of increased salt intake (normal NaCl 0.5 g x [kg.sup.-1] x [day.sup.-1], high NaCl 2.5 g x [kg.sup.-1] x [day.sup.-1]) and a second group of seven rabbits with normal salt intake throughout. The responses to stressful stimuli encountered in the laboratory were recorded and compared with rest in control and high-salt groups. Resting MAP, HR, and RSNA were not significantly altered with high salt intake [88 [+ or -] 5 vs. 91 [+ or -] 6 mmHg; 251 [+ or -] 8 vs. 244 [+ or -] 9 beats per minute (bpm); 9.7 [+ or -] and 1.2 vs. 10.8 [+ or -] 1.7 normalized units (nu)] despite significant reductions in plasma renin activity ( 1.88 [+ or -] 0.18 vs. 1.27 [+ or -] 0.15 nmol ANG I x [1.sup.-1] x [h.sup.-1]; P < 0.05) and ANG II (7.5 [+ or -] 1.2 vs. 4.3 [+ or -] 0.8 pmol/1). Increasing levels of stressful stimuli (resting in home cage, containment in box, handling, and nasopharyngeal activation) in animals on a normal salt diet caused graded increases in MAP (89 [+ or -] 2 mmHg, 95 [+ or -] 2 mmHg, 107 [+ or -] 4 mmHg, and 122 [+ or -] 5 mmHg, respectively) and RSNA (9.7 [+ or -] 0.9 nu; 11.8 [+ or -] 2.7 nu; 31.4 [+ or -] 3.7 nu; 100 nu) but not HR (245 [+ or -] 8 bpm; 234 [+ or -] 8 bpm; 262 [+ or -] 9 bpm; 36 [+ or -] 5 bpm). High dietary salt did not significantly alter the responses to stress. We conclude that a 6-day period of high salt intake does not alter the level of RSNA, with non-neural mechanisms primarily responsible for the observed renin-angiotensin system suppression. blood pressure; dietary salt; renin-angiotensin system

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which in turn decreases ERSNA via activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. We now examined whether the ERSNA-induced increases in ARNA are modulated by dietary sodium and the role of endothelin (ET). The ARNA response to reflex increases in ERSNA was enhanced in high (HNa)- vs. low-sodium (LNa) diet rats, 7,560 [+ or -] 1,470 vs. 900 [+ or -] 390% * s. The norepinephrine (NE) concentration required to increase [PGE.sub.2] and substance P release from isolated renal pelvises was 10 pM in HNa and 6,250 pM in LNa diet rats. In HNa diet pelvises 10 pM NE increased [PGE.sub.2] release from 67 [+ or -] 6 to 150 [+ or -] 13 pg/min and substance P release from 6.7 [+ or -] 0.8 to 12.3 [+ or -] 1.8 pg/min. In LNa diet pelvises 6,250 pM NE increased [PGE.sub.2] release from 64 [+ or -] 5 to 129 [+ or -] 22 pg/min and substance P release from 4.5 [+ or -] 0.4 to 6.6 [+ or -] 0.7 pg/min. In the renal pelvic wall, ETB-R are present on unmyelinated Schwann cells close to the afferent nerves and ETA-R on smooth muscle cells. ETA-receptor (R) protein expression in the renal pelvic wall is increased in LNa diet. In HNa diet, renal pelvic administration of the ETB-R antagonist BQ788 reduced ERSNA-induced increases in ARNA and NE-induced release of [PGE.sub.2] and substance P. In LNa diet, the ETA-R antagonist BQ123 enhanced ERSNA-induced increases in ARNA and NE-induced release of substance P without altering [PGE.sub.2] release. In conclusion, activation of ETB-R and ETA-R contributes to the enhanced and suppressed interaction between ERSNA and ARNA in conditions of HNa and LNa diet, respectively, suggesting a role for ET in the renal control of ERSNA that is dependent on dietary sodium. sensory nerves; substance P; [PGE.sub.2]; endothelin A receptors; endothefin B receptors; renal pelvis; norepinephrine

The role of nociceptin and its spinal cord neural pathways in etectroacupuncture (EA)-related inhibition of visceral excitatory reflexes is not clear. Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand for a G proteincoupled receptor, called the N/OFQ peptide (NOP) receptor, which has been found to be distributed in the spinal cord. The present study investigated the importance of this system in visceral-cardiovascular reflex modulation during EA. Cardiovascular pressor reflex responses were induced by gastric distension in Sprague-Dawley rats anesthetized by ketamine and xylazine. An intrathecal injection of nociceptin (10 nM) at T1-2 attenuated the pressor responses by 35%, similar to the influence of EA at P 5-6 (42% decrease). An intrathecal injection of the NOP antagonist, [N-[Phe.sup.1]] [nociceptin.sub.1-13] N[H.sub.2], partially reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not alter the EA-like inhibitory effect of nociceptin on the pressor reflex, whereas a combination of nociceptin receptor antagonist with naloxone completely abolished the EA response. An intrathecal injection of nociceptin attenuated the pressor responses to the electrical stimulation of the rostral ventrolateral medulla by 46%, suggesting that nociceptin can regulate sympathetic outflow. Furthermore, a bilateral microinjection of NOP antagonist into either the dorsal horn or the intermediolateral column at T1 partially reversed the EA inhibitory effect. These results suggest that nociceptin in the spinal cord mediates part of the EA-related modulation of visceral reflex responses. nociceptin/orphanin FQ peptide receptors; pressor response; dorsal horn; intermediolateral column; acupuncture

Smoking increases cardiovascular risk in young women and eliminates the protective effect of the premenopausal state. Increased sympathetic nervous system (SNS) activity is associated with increased cardiovascular risk. One potential mechanism by which smoking increases risk is through chronic SNS activation. It has been reported that premenopausal women have high SNS activity during the midluteal (ML) phase, which falls to low levels during the early follicular (EF) phase. We tested the hypothesis that smoking disrupts this fall in SNS activity during the EF phase. We measured blood pressure and muscle sympathetic nerve activity (MSNA) using microneurography in 11 premenopausal female smokers and 11 age-matched nonsmoking controls at two separate times during the ovarian cycle: ML phase (8-10 days after the luteinizing hormone surge) and EF phase (days 1-4 of the menstrual cycle). The change in MSNA from the EF phase to the ML phase was significantly different between the smoking and nonsmoking groups (P = 0.036). Whereas there was a significant decrease in MSNA from the ML phase to the EF phase among nonsmoking controls (22.7 [+ or -] 3.3 vs. 17.9 [+ or -] 2.8 bursts/min, P = 0.012), MSNA remained elevated during the EF phase in smokers (22.5 [+ or -] 3 .8 vs. 26.8 [+ or -] 4.0 bursts/min, P = 0.28). Surprisingly, mean arterial pressure (MAP) was significantly lower during the ML phase than in the EF phase in both nonsmokers (P = 0.0080) and smokers (P = 0.0094). We conclude that smoking disrupts the ovarian pattern of SNS activity by preventing the normal fall in MSNA during the EF phase of the ovarian cycle. Such chronic alterations may contribute to the pathogenesis of cardiovascular risk in young smoking females. cigarette smoking; muscle sympathetic nerve activity; menstrual cycle; premenopausal women

Granulocyte colony-stimulating factor (G-CSF) has been used for the repair of infarcted myocardium, but concerns have been raised regarding its proarrhythmic potential. We analyzed the influence of G-CSF treatment on sympathetic nerve remodeling and the expression of nestin in a rat model of experimental myocardial infarction (MI). Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to receive either saline (MI/C) or G-CSF (MI/G) for 5 days. At 56 days after infarction, MI/G rats had a significantly higher left ventricular ejection fraction accompanied by a significant decrease in the left ventricular end-diastolic dimension than the MI/C group. Myocardial norepinephrine levels revealed a significant elevation in MUG rats in the border zone compared with MI/C rats. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the changes of myocardial norepinephrine. At 5 days after infarction, MI/G rats had increased numbers of tissue-infiltrated [CD34.sup.+] cells, although a similar increase in circulating neutrophil counts between sham-operated rats treated with G-CSF and MI/G rats was observed. Compared with MI/C rats, MI/G rats showed an increase of nestin and nerve growth factor expression, as assessed by protein expression and mRNA levels. The arrhythmia scores during programmed stimulation were significantly higher in MI/G rats than in MI/C rats, suggesting proarrhythmic potential. These findings suggest that, although G-CSF administration after infarction improved myocardial function, it resulted in the activation of nestin and nerve growth factor expression and increased sympathetic reinnervation, which may increase the arrhythmogenic response to programmed electrical stimulation. sympathetic nervous system; remodeling

The aim of the present study was to investigate how loading of cardiopulmonary baroreceptors induced by water immersion (WI) modifies baroreflex control of renal sympathetic nerve activity (RSNA) in conscious dogs. Nine dogs were chronically instrumented for measuring carotid sinus nerve activity (CSNA), RSNA, carotid arterial (Pca), and central venous (Pcv) pressures. The stimulus-response relationships of Pca-CSNA and Pca-RSNA were determined simultaneously in the same dog by changing Pca using rapid intravenous infusions vasoactive drugs during pre-WI and WI. WI increased central venous pressure significantly (P < 0.05) by 10.4 mmHg. WI shifted the Pca-RSNA curve acutely leftward compared with the pre-WI period, which was associated with significant (P < 0.05) decreases in the saturation pressure by 39.0 mmHg and operating range by 43.1 mmHg. WI relocated the operating pressure to near the saturation pressure, where the gain was low. The Pca-CSNA curve obtained during WI was identical to that obtained during pre-WI period. These results suggest that the shift in baroreflex control of RSNA could be attributed to the inhibitory influence of the cardiopulmonary mechanoreceptor loading and not by the resetting of carotid baroreceptors per se. cardiopulmonary baroreceptors; baroreflex; renal sympathetic nerve activity; water immersion

Human studies suggest that cardiovascular neural sympathetic control is predominantly modulated by the right cerebral hemisphere. It is unknown whether post-ganglionic sympathetic activity [muscle sympathetic nerve activity (MSNA)] shows any functional asymmetry. Eight right-handed volunteers (3 women and 5 men, 32 [+ or -] 2 yr of age) underwent ECG, beat-by-beat blood pressure, respiratory activity, and simultaneous right and left MSNA recordings during spontaneous and controlled breathing (CB, 15 breaths/rain, 0.25 Hz). Dynamic carotid baroreceptor stimulation was obtained by 0.1-Hz sinusoidal suction, from 0 to -50 mmHg, randomly applied to the right, left, and combined right and left sides of the neck during CB. Laterality was assessed by changes in the MSNA burst rate (in bursts/min, and bursts/100 beats), strength [amplitude (A) and area (AA)], and the oscillatory component at 0.1 Hz during baroreceptor stimulation. Amplitude parameters were normalized by CB burst mean amplitude and area of the same side. At rest, the right and left MSNA burst rate and total MSNA activity were similar. Conversely, the right MSNA normalized burst AN (1.36 [+ or -] 0.18) and [AA.sub.N] (1.31 [+ or -] 0.16) were larger than the left MSNA [A.sub.N] (1.04 [+ or -] 0.09) and [AA.sub.N] (1.02 [+ or -] 0.08). Unilateral and bilateral carotid baroreflex stimulation abolished the right prevalence of [A.sub.N] and [AA.sub.N]. In conclusion, the right lateralization of sympathetic activity to the vessels is indicated by normalized burst strength parameters of bilateral MSNA recordings at rest during spontaneous breathing. Carotid baroreceptor stimulation disrupted such expression of MSNA lateralization possibly by disturbing the synchronizing action of right cerebral hemisphere. sympathetic control of circulation; muscle sympathetic nerve activity recording; burst amplitude; area; laterality

Previous studies from our laboratory have demonstrated that altering muscle temperature of the exercising forearm can elicit changes in muscle sympathetic nerve activity (MSNA) during ischemic isometric handgrip. The purpose of the current study was to determine the interactive effect of muscle temperature and blood flow on MSNA responses during dynamic handgrip (DHG). Eight subjects performed two bouts of graded DHG to fatigue followed by 2 min of postexercise muscle ischemia (PEMI). Local heating of the forearm increased muscle temperature from 33.6 [+ or -] 0.3 to 38.3 [+ or -] 0.5[degrees]C (P < 0.05). Mean arterial pressure and heart rate increased in a linear fashion during graded DHG (P < 0.05) but were not affected by muscle temperature. MSNA (burst frequency and total activity) at fatigue and PEMI were elevated in all conditions (P < 0.05). However, MSNA responses were not different between temperature conditions. To ascertain the effect of blood flow, eight additional subjects completed two trials of ischemic DHG under control or warm conditions followed by 2 min of PEMI. MSNA, expressed as burst frequency and total activity, was significantly greater in warm compared with the control trial ([DELTA]14 [+ or -] 3 and [DELTA]9 [+ or -] 2 bursts/30 s, and [DELTA]1,234 [+ or -] 260 and [DELTA]751 [+ or -] 199 units/30 s, respectively). This finding supports the concept that muscle heating sensitizes skeletal muscle afferents during muscle contractions and augments MSNA in humans. However, on the basis of these findings, we conclude that muscle blood flow modulates the effect of muscle temperature on MSNA during exercise. metaboreflex; mechanoreflex; perfusion; ischemia; muscle thermoreflex

Control of exercising muscle blood flow is a balance between local vasodilatory factors and the increase in global sympathetic vasoconstrictor outflow. Hypoxia has been shown to potentiate the muscle sympathetic nerve response to exercise, potentially limiting the increase in muscle blood flow. Accordingly, we investigated sympathetic restraint to exercising muscle during whole body exercise in hypoxia. Six dogs chronically instrumented with ascending aortic and hindlimb flow probes and a terminal aortic catheter were studied at rest and mild [2.5 miles/h (mph), 5% grade] and moderate (4.0 mph, 10% grade) exercise while breathing room air or hypoxia ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] ~45 mmHg) in the intact control condition and following systemic [alpha]-adrenergic blockade (phentolamine). Hypoxia caused an increase in cardiac output (CO), hindlimb flow ([Flow.sub.L]), and blood pressure (BP), while total ([Cond.sub.T]) and hindlimb conductance ([Cond.sub.L]) were unchanged at rest and mild exercise but increased with moderate exercise. During both mild and moderate exercise, [alpha]-blockade in normoxia resulted in significant vasodilation as evidenced by increases in CO (10%), [Flow.sub.L] (17%), [Cond.sub.T] (33%), [Cond.sub.L] (43%), and a decrease in BP (-18%), with the increase in [Cond.sub.L] greater than the increase in [Cond.sub.T] during mild exercise. Compared with the normoxic response, [alpha]-blockade in hypoxia during exercise resulted in a significantly greater increase in [Cond.sub.T] (59%) and [Cond.sub.L] (74%) and a correspondingly greater decrease in BP (-34%) from baseline. These findings indicate that there is considerable hypoxia-induced sympathetic restraint of muscle blood flow during both mild and moderate exercise, which helps to maintain arterial blood pressure in hypoxia. sympathetic nervous system; [alpha]-adrenergic receptor; dog; blood flow regulation

Both static and dynamic exercise are known to increase cardiac pump function as well as arterial blood pressure. Feedforward control by central command and feedback control by the exercise pressor reflex are thought to be the neural mechanisms causing these effects during exercise. It remains unknown as to how each mechanism activates cardiac sympathetic nerve activity (CSNA) during exercise, especially at its onset. Thus we examined the response of CSNA to stimulation of the mesencephalic locomotor region (MLR, i.e., central command) and to static muscle contraction of the triceps surae muscles or stretch of the calcaneal tendon in decerebrate cats. We found that MLR stimulation immediately increased CSNA, which was followed by a gradual increase in heart rate, mean arterial pressure, and ventral root activity in a stimulus intensity-dependent manner. The latency of the increase in CSNA from the onset of MLR stimulation ranged from 67 to 387 ms. Both static contraction and tendon stretch also rapidly increased CSNA. Their latency from the development of tension in response to ventral root stimulation ranged from 78 to 670 ms. These findings suggest that both central command and the muscle mechanoreflex play a role in controlling cardiac sympathetic outflow at the onset of exercise. mechanoreflex; renal sympathetic nerve activity; group III and IV afferents

The role of nucleus of solitary tract (NTS) [A.sub.2a] adenosine receptors in baroreflex mechanisms is controversial. Stimulation of these receptors releases glutamate within the NTS and elicits baroreflex-like decreases in mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas inhibition of these receptors attenuates HR baroreflex responses. In contrast, stimulation of NTS [A.sub.2a] adenosine receptors increases preganglionic adrenal sympathetic nerve activity (pre-ASNA), and the depressor and sympathoinhibitory responses are not markedly affected by sinoaortic denervation and blockade of NTS glutamatergic transmission. To elucidate the role of NTS [A.sub.2a] adenosine receptors in baroreflex function, we compared full baroreflex stimulus-response curves for HR, RSNA, and pre-ASNA (intravenous nitroprusside/phenylephrine) before and after bilateral NTS microinjections of selective adenosine [A.sub.2a] receptor agonist (CGS-21680; 2.0, 20 pmol/50 nl), selective [A.sub.2a] receptor antagonist (ZM-241385; 40 pmol/100 nl), and nonselective [A.sub.1] + [A.sub.2a] receptor antagonist (8-SPT; 1 nmol/100 nl) in urethane/[alpha]-chloralose anesthetized rats. Activation of [A.sub.2a] receptors decreased the range, upper plateau, and gain of baroreflex-response curves for RSNA, whereas these parameters all increased for pre-ASNA, consistent with direct effects of the agonist on regional sympathetic activity. However, no resetting of baroreflex-response curves along the MAP axis occurred despite the marked decreases in baseline MAP. The antagonists had no marked effects on baseline variables or baroreflex-response functions. We conclude that the activation of NTS [A.sub.2a] adenosine receptors differentially alters baroreflex control of HR, RSNA, and pre-ASNA mostly via non-baroreflex mechanism(s), and these receptors have virtually no tonic action on baroreflex control of these sympathetic outputs. [A.sub.2a] adenosine receptor agonist; [A.sub.2a] adenosine receptor antagonist; baroreflex function; renal nerve; adrenal nerve

Despite the longstanding appreciation of communication between the nervous and the immune systems, the nature and significance of these interactions to immunity remain enigmatic. Here, we show that 6-hydroxydopamine-mediated ablation of the mouse peripheral sympathetic nervous system increases primary CD[8.sup.+] T cell responses to viral and cellular antigens presented by direct priming or cross-priming. The sympathetic nervous system also suppresses antiviral CD[4.sup.+] T cell responses, but this is not required for suppressing CD[8.sup.+] T cell responses. Adoptive transfer experiments indicate that enhanced CD[8.sup.+] responses do not result from permanent alterations in CD[8.sup.+] T cell function in sympathectomized mice. Rather, additional findings suggest that the sympathetic nervous system tempers the capacity of antigen-presenting cells to activate naive CD[8.sup.+] T cells. We also show that antiviral CD[8.sup.+] T cell responses are enhanced by administration of a [[beta].sub.2] (but not [[beta].sub.1] or [alpha]) adrenergic antagonist. These findings demonstrate a critical role for the sympathetic nervous system in limiting CD[8.sup.+] T cell responses and indicate that CD[8.sup.+] T cell responses may be altered in patients using [beta]-blockers, one of the most widely prescribed classes of drugs. antigen presentation | vaccine | cross-priming | direct-priming | dendritic cell

Slow local skin heating (LH) causes vasodilator responses, some of which are dependent on sympathetic nerve function. It is not known, however, how the rate of LH affects either the sympathetic or the nonadrenergic components of the responses to LH and whether the adrenergic effects of LH depend on tonic sympathetic activity or whether LH stimulates transmitter release. In part 1, cutaneous vascular conductance (CVC) responses to slow and fast LH (+0.1[degrees] and +2[degrees]C/min) from 34[degrees] to 40[degrees]C were compared both at control sites and at sites pretreated with bretylium tosylate (BT; blocks transmitter release from adrenergic terminals). We confirmed, as previously found, the axon reflex (AR) response to slow LH to be blocked by BT (P < 0.05). Pretreatment with BT reduced the AR only with fast LH. BT inhibited the peak vasodilation achieved with both rates of LH (P < 0.05). Longer-term LH was associated with a slow fall in CVC, the classical 'die away' phenomenon, at untreated sites (P < 0.05) but not at BT-pretreated sites. Thus the LH-stimulated AR is only partially dependent on intact sympathetic function, and the 'die away' phenomenon is dependent on such function. In part 2, we tested whether the conditions in part 1 (whole body and local skin temperatures of 34[degrees]C) completely suppressed sympathetic nerve activity. The infusion of BT by microdialysis did not change the CVC (P > 0.05), suggesting the absence of tonic activity in those conditions and therefore that the adrenergic components of the responses in part 1 are via the stimulation of the transmitter release by LH. bretylium; norepinephrine release; local control of blood flow; axon reflex; human

Sympathetic neural responses to mental stress are well documented but controversial, whereas sympathetic neural responses to emotional stress are unknown. The purpose of this study was to investigate neural and cardiovascular responses to emotional stress evoked by negative pictures and reexamine the relationship between muscle sympathetic nerve activity (MSNA) and perceived stress. Mean arterial pressure (MAP), heart rate (HR), MSNA, and perceived stress levels were recorded in 18 men during three randomized trials: 1) neutral pictures, 2) negative pictures, and 3) mental stress. MAP and HR increased during mental stress ([DELTA]14 [+ or -] 2 mmHg and [DELTA]15 [+ or -] 2 beats/min, P < 0.001) but did not change during viewing of negative or neutral pictures. MSNA did not change during viewing of neutral ([DELTA]1 [+ or -] 1 burst/min, n = 16) or negative ([DELTA]0 [+ or -] 1 burst/min, n = 16) pictures or during mental stress/[DELTA]1 [+ or -] 2 burst/min, n = 13). Perceived stress levels were higher during mental stress (3 [+ or -] 0 arbitrary units) than during viewing negative pictures (2 [+ or -] 0 arbitrary units, P < 0.001). Perceived stress levels were not correlated to changes in MSNA during negative pictures (r = 0.10, P = 0.84) or mental stress (r = 0.36, P = 0.23). In conclusion, our results demonstrate robust increases in MAP and HR during mental stress, but not during emotional stress evoked by negative pictures. Although the influence of mental stress on MSNA remains unresolved, our findings challenge the concept that perceived stress levels modulate MSNA during mental stress. muscle sympathetic nerve activity: negative pictures: blood pressure; mental arithmetic

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which decreases ERSNA to prevent sodium retention. High-sodium diet enhances ARNA, suggesting an important role for ARNA in suppressing ERSNA during excess sodium intake. Mean arterial pressure (MAP) is elevated in afferent renal denervated by dorsal rhizotomy (DRX) rats ted high-sodium diet. We examined whether the increased MAP in DRX is due to impaired arterial baroreflex function. In DRX and sham DRX rats fed high-sodium diet, arterial baroreflex function was determined in conscious rats by intravenous nitroprusside and phenylephrine or calculation of transfer function gain from arterial pressure to ERSNA (spontaneous baroreflex sensitivity). Increasing MAP did not suppress ERSNA to the same extent in DRX as in sham DRX, -60 [+ or -] 4 vs. -77 [+ or -] 6%. Maximum gain, -4.22 [+ or -] 0.45 vs. -6.04 [+ or -] 0.90% [DELTA]ERSNA/mmHg, and the maximum value of instantaneous gain, -4.19 [+ or -] 0.45 vs. -6.04 [+ or -] 0.81% AERSNA/mmHg, were less in DRX than in sham DRX. Likewise, transfer function gain was lower in DRX than in sham DRX, 3.9 [+ or -] 0.2 vs. 6.1 [+ or -] 0.5 NU/mmHg. Air jet stress produced greater increases in ERSNA in DRX than in sham DRX, 35,000 [+ or -] 4,900 vs. 20,900 [+ or -] 3,410%'s (area under the curve). Likewise, the ERSNA responses to thermal cutaneous stimulation were greater in DRX than in sham DRX. These studies suggest impaired arterial baroreflex suppression of ERSNA in DRX ted high-sodium diet. There were no differences in arterial baroreflex function in DRX and sham DRX ted normal-sodium diet. Impaired arterial baroreflex function contributes to increased ERSNA, which would eventually lead to sodium retention and increased MAP in DRX rats fed high-sodium diet. dorsal rhizotomy; high-sodium diet; renorenal reflexes: spontaneous baroreflex sensitivity; reflex renal nerve stimulation

Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity. hypertension; sympathetic nervous system; neuropeptides; phosphoinositol-3 kinase; melanocortin receptors

It is well known that environmental stimulation is important for the proper development of sensory function. The vestibular system senses gravitational acceleration and then alters cardiovascular and motor functions through reflex path-ways. The development of vestibular-mediated cardiovascular and motor functions may depend on the gravitational environment present at birth and during subsequent growth. To examine this hypothesis, arterial pressure (AP) and renal sympathetic nerve activity (RSNA) were monitored during horizontal linear acceleration and performance in a motor coordination task in rats born and reared in 1-G or 2-G environments. Linear acceleration of [+ or -] 1 G increased AP and RSNA. These responses were attenuated in rats with a vestibular lesion, suggesting that the vestibular system mediated AP and RSNA responses. These responses were also attenuated in rats born in a 2-G environment. AP and RSNA responses were partially restored in these rats when the hypergravity load was removed, and the rats were maintained in a 1-G environment for 1 wk. The AP response to compressed air, which is mediated independently of the vestibular system, did not change in the 2-G environment. Motor coordination was also impaired in the 2-G environment and remained impaired even after 1 wk of unloading. These results indicate that hypergravity impaired both the vestibulo-cardiovascular reflex and motor coordination. The vestibulo-cardiovascular reflex was only impaired temporarily and partially recovered following 1 wk of unloading. In contrast, motor coordination did not return to normal in response to unloading. vestibular system; renal sympathetic nerve activity; arterial pressure; rotarod; linear acceleration

This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 [+ or -] 0.4 normalized units (NU)/mmHg] than for renal (7.6 [+ or -] 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 [+ or -] 1 and 96 [+ or -] 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 [+ or -] 0.2 NU/mmHg) than for renal (2.3 [+ or -] 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 [+ or -] 2 and 28 [+ or -] 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 [+ or -] 0.06; n = 204 [+ or -] 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way. arterial pressure; baroreceptor reflex; sympathetic nervous system; transfer function

Sympathetic vasoconstriction of cerebral vessels has been proposed to be a protective mechanism for the brain, limiting cerebral perfusion and microcirculatory pressure during transient increases in arterial pressure. To furnish direct neural evidence for this proposition, we aimed to develop a method for recording cerebral sympathetic nerve activity (SNA) from the superior cervical ganglion (SCG). We hypothesized that SNA recorded from the SCG increases during imposed hypertension, but not during hypotension. Lambs (n = 11) were anesthetized ([alpha]chloralose, 20 mg*[kg.sup.-1]*[h.sup.-1]) and ventilated. SNA was measured using 25-[micro]m tungsten microelectrodes inserted into the SCG. Arterial blood pressure (AP) was pharmacologically raised (adrenaline, phenylephrine, or ANG II, 1-50 [micro]g/kg iv), mechanically raised (intravascular balloon in the thoracic aorta), or lowered (sodium nitroprusside, 1-50 [micro]g/kg iv). In response to adrenaline (n = 10), mean AP increased 135 [+ or -] 10% from baseline (mean [+ or -] SE), and the RMS value of SNA (Square Root of the Mean of the Squares, [SNA.sub.RMS]) increased 255 [+ or -] 120%. In response to mechanically induced hypertension, mean AP increased 43 [+ or -] 3%, and [SNA.sub.RMS] increased 53 [+ or -] 13%. Generally, (9 of 10 animals), [SNA.sub.RMS] did not increase, as AP was lowered with sodium nitroprusside. Using a new model for direct recording of cerebral SNA from the SCG, we have demonstrated that SNA increases in response to large induced rises, but not falls, in AP. These findings furnish direct support for the proposed protective role for sympathetic nerves in the cerebral circulation. cerebral circulation; hypertension; sympathetic nervous system; adrenaline; lamb

It is generally accepted that cardiac sympathetic tone dominates the control of heart rate (HR) in mice. However, we have recently challenged this notion given that HR in the mouse is responsive to ambient temperature (Ta) and that the housing Ta is typically 2123[degrees]C, well below the thermoneutral zone ([approximately equal to]30[degrees]C) of this species. To specifically test the hypothesis that cardiac sympathetic tone is the primary mediator of HR control in the mouse, we first examined the metabolic and cardiovascular responses to rapid changes in Ta to demonstrate the sensitivity of the mouse cardiovascular system to Ta. We then determined HR in 1) mice deficient in cardiac sympathetic tone ('B-less' mice), 2) mice deficient in cardiac vagal tone [muscarinic M2 receptor ([M.sub.2][R.sup.-/-]) mice], and 3) littermate controls. At a [T.sub.a] of 30[degrees]C, the HR of [beta]-less mice was identical to that of wild-type mice (351 [+ or -] 11 and 363 [+ or -] 10 beats/min, respectively). However, the HR of [M.sub.2][R.sup.-/-] mice was significantly greater (416 [+ or -] 7 beats/min), demonstrating that vagal tone predominates over HR control at this Ta. When these mice were calorically restricted to 70% of normal intake, HR fell equally in wild-type, B-less, and [M.sub.2] [R.sup.-/-] mice (AHR = 73 [+ or -] 9, 76 [+ or -] 3, and 73 [+ or -] 7 beats/min, respectively), suggesting that the fall in intrinsic HR governs bradycardia of calorically restricted mice. Only when the [T.sub.a] was relatively cool, at 23[degrees]C, did [beta]-less mice exhibit a HR (442 [+ or -] 14 beats/rain) that was different from that of littermate controls (604 [+ or -] 10 beats/min) and [M.sub.2] [R.sup.-/-] mice (602 [+ or -] 5 beats/min). These experiments conclusively demonstrate that in the absence of cold stress, regulation of vagal tone and modulation of intrinsic rate are important determinants of HR control in the mouse. telemetry; intrinsic heart rate; cold stress; caloric restriction; sympathetic nervous system

The cardiac sympathetic nervous system is one putative key factor involved in the intrauterine programming of adult cardiovascular disease. We therefore analyzed cardiac autonomic system activity in small for gestational age (SGA) neonates. Heart rate variability (HRV) from 24-h ECG recordings were analyzed for time-domain and frequencydomain parameters in 27 SGA neonates [median 261 (240-283) days of gestation] compared with 27 appropriate for gestational age (AGA) neonates [median 270 (239-293) days of gestation]. In addition, salivary [alpha]-amylase levels were analyzed during resting conditions and in response to a pain-induced stress event in 18 SGA [median 266 (240-292) days of gestation[ and 34 AGA [median 271 (240-294) days of gestation] neonates. Overall HRV was not significantly different in SGA neonates compared with AGA neonates (SD of all valid NN intervals: P = 0.14; triangular index: P = 0.29), and the sympathovagal balance [low frequency (LF)/high frequency (HF)] was similar (P = 0.62). Parameters mostly influenced by sympathetic activity did not reveal significant differences: (SD of the average of valid NN intervals: P = 0.27; average of the hourly means of SDs of all NN intervals: P = 0.66, LF: P = 0.83) as well as vagal tone-influenced parameters were unaltered (average of the hourly square root of the mean of the sum of the squares of differences between adjacent NN intervals: P = 0.59; proportion of pairs of adjacent NN intervals differing by >50 ms: P = 0.93; HF: P = 0.82). Median resting levels for [alpha]-amylase were not significantly different in SGA neonates (P = 0.13), and a neonatal stress stimulus revealed similar stress response patterns (P = 0.29). HRV and salivary [alpha]-amylase levels as indicators of cardiac autonomic activity were not altered in SGA neonates compared with AGA neonates. Thus, it appears that the intrauterine activation of the sympathetic system in SGA fetuses does not directly persist into postnatal life, and neonatal sympathovagal balance appears to be preserved. intrauterine programming; cardiovascular; amylase; heart rate variability; sympathovagal balance

Suppressed parasympathetic nervous system (PSNS) function has been found in a variety of cardiovascular diseases, such as hypertension, heart failure, and diabetes. However, whether impaired PSNS function plays a significant role in ventricular dysfunction remains to be investigated. Cardiac regulation by the PSNS is primarily mediated by the [M.sub.2] muscarinic acetylcholine receptor ([M.sub.2]-AChR). In this study, we tested the hypothesis that lack of [M.sub.2]-AChR-mediated PSNS function may adversely impact cardiac ventricular function. Using [M.sub.2]-AChR knockout (KO) and wild-type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in [M.sub.2]-AChR KO and WT mice. A bolus injection of isoproterenol (Iso) induced a greater increase in heart rate in [M.sub.2]-AChR KO mice than in WT mice. However, the responses of change in pressure over time (dP/dt) to Iso were similar in the two groups. After chronic infusion with Iso for 1 wk, the baseline values of left ventricular function were increased to similar extents in [M.sub.2]-AChR KO and WT mice. However, the [M.sub.2]-AChR KO mice exhibited impaired ventricular function, indicated as attenuated dP/dt and increased end-diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine. Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in [M.sub.2]-AChR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that [M.sub.2]-AChR may mediate an inhibitory regulation on MMP function. The overall results from this study suggest that [M.sub.2]-AChR-mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses. muscarinic; cardiac; contractility; matrix metalloproteinase; isoproterenol

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24-47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 [+ or -] 2 and 39 [+ or -] 2 mg/dl, respectively, and two drinks to 72 [+ or -] 4 and 83 [+ or -] 3 mg/dl, respectively. Wine quadrupled plasma resveratrol (P < 0.001) and increased catechin (P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 [+ or -] 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 [+ or -] 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 [+ or -] 0.3 l/min) and wine (+1.2 [+ or -] 0.3 l/min) (P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9-10 bursts/min (P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks (P < 0.001). No beverage augmented, and the second wine dose attenuated (P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols. microneurography; sympathetic nervous system; blood pressure; cardiovascular diseases; risk factors

Short-term blood pressure (BP) variability is limited by the arterial baroreflex. Methods for measuring the spontaneous baroreflex sensitivity (BRS) aim to quantify the gain of the transfer function between BP and pulse interval (PI) or the slope of the linear relationship between parallel BP and PI changes. These frequency-domain (spectral) and time-domain (sequence) techniques were tested in conscious mice equipped with telemetric devices. The autonomic relevance of these indexes was evaluated using pharmacological blockades. The significant changes of the spectral bandwidths resulting from the autonomic blockades were used to identify the low-frequency (LF) and high-frequency (HF) zones of interest. The LF gain was 1.45 [+ or -] 0.14 ms/mmHg, with a PI delay of 0.5 s. For the HF gain, the average values were 2.0 [+ or -] 0.19 ms/mmHg, with a null phase. LF and HF bands were markedly affected by atropine. On the same 51.2-s segments used for cross-spectral analysis, an average number of 26.4 [+ or -] 2.2 slopes were detected, and the average slope in resting mice was 4.4 [+ or -] 0.5 ms/mmHg. Atropine significantly reduced the slopes of the sequence method. BRS measurements obtained using the sequence technique were highly correlated to the spectral estimates. This study demonstrates the applicability of the recent methods used to estimate spontaneous BRS in mice. There was a vagal predominance in the baroreflex control of heart rate in conscious mice in the present conditions. baroreceptors; heart rate; sympathetic; vagus nerve

Heart rate (HR) power spectral indexes are limited as measures of the cardiac autonomic nervous systems (CANS) in that they neither offer an effective marker of the [beta]-sympathetic nervous system (SNS) due to its overlap with the parasympathetic nervous system (PNS) in the low-frequency (LF) band nor afford specific measures of the CANS due to input contributions to HR [e.g., arterial blood pressure (ABP) and instantaneous lung volume (ILV)]. We derived new PNS and SNS indexes by multisignal analysis of cardiorespiratory variability. The basic idea was to identify the autonomically mediated transfer functions relating fluctuations in ILV to HR (ILV [right arrow] HR) and fluctuations in ABP to HR (ABP [right arrow] HR) so as to eliminate the input contributions to HR and then separate each estimated transfer function in the time domain into PNS and SNS indexes using physiological knowledge. We evaluated these indexes with respect to selective pharmacological autonomic nervous blockade in 14 humans. Our results showed that the PNS index derived from the ABP [right arrow] HR transfer function was correctly decreased after vagal and double (vagal + [beta]-sympathetic) blockade (P < 0.01) and did not change after [beta]-sympathetic blockade, whereas the SNS index derived from the same transfer function was correctly reduced after [beta]-sympathetic blockade in the standing posture and double blockade (P < 0.05) and remained the same after vagal blockade. However; this SNS index did not significantly decrease after [beta]-sympathetic blockade in the supine posture. Overall, these predictions were better than those provided by the traditional high-frequency (HF) power, LF-to-HF ratio, and normalized LF power of HR variability. heart rate variability; modeling; power spectral analysis; system identification; transfer function

Inhibition of neuronal nitric oxide synthase (nNOS) in cardiac postganglionic sympathetic neurons leads to enhanced cardiac sympathetic responsiveness in normal animals, as well as in animal models of cardiovascular diseases. We used isolated atria from mice with selective genetic disruption of nNOS ([nNOS.sup.-/-]) and their wild-type littermates (WT) to investigate whether sympathetic heart rate (HR) responses were dependent on nNOS. Immunohistochemistry was initially used to determine the presence of nNOS in sympathetic [tyrosine hydroxylase (TH) immunoreactive] nerve terminals in the mouse sinoatrial node (SAN). After this, the effects of postganglionic sympathetic nerve stimulation (1-10 Hz) and bath-applied norepinephrine (NE; [10.sup.-8]-[10.sup.-4] mol/1) on HR were examined in atria from [nNOS.sup.-/-] and WT mice. In the SAN region of WT mice, TH and nNOS immunoreactivity was virtually never colocalized in nerve fibers, [nNOS.sup.-/-] atria showed significantly reduced HR responses to sympathetic nerve activation and NE (P < 0.05). Similarly, the positive chronotropic response to the adenylate cyclase activator forskolin ([10.sup.-7]-[10.sup.-5] mol/l) was attenuated in [nNOS.sup.-/-] atria (P < 0.05). Constitutive NOS inhibition with L-nitroarginine (0.1 mmol/l) did not affect the sympathetic HR responses in [nNOS.sup.-/-] and WT atria. The paucity of nNOS in the sympathetic innervation of the mouse SAN, in addition to the attenuated HR responses to neuronal and applied NE, indicates that presynaptic sympathetic neuronal NO does not modulate neuronal NE release and SAN pacemaking in this species. It appears that genetic deletion of nNOS results in the inhibition of adrenergic-adenylate cyclase signaling within SAN myocytes. neuronal nitric oxide synthase; autonomic nervous system; sinoatrial node

Congestive heart failure (CHF) induces abnormal regulation of peripheral blood flow during exercise. Previous studies have suggested that a reflex from contracting muscle is disordered in this disease. However, there has been very little investigation of the muscle reflex regulating sympathetic outflows in CHF. Myocardial infarction (MI) was induced by the coronary artery ligation in rats. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. We examined renal and lumbar sympathetic nerve activities (RSNA and LSNA, respectively) during 1-min repetitive (1- to 4-s stimulation to relaxation) contraction or stretch of the triceps surae muscles. During these interventions, the RSNA and LSNA responded synchronously as tension was developed. The RSNA and LSNA responses to contraction were significantly greater in MI rats (n = 13) with FS 40% (RSNA: +49 [+ or -] 7 vs. + 19 [+ or -] 4 a.u., P < 0.01; LSNA: +28 [+ or -] 7 vs. +8 [+ or -] 2 a.u., P < 0.01) at the same tension development. Stretch also increased the RSNA and LSNA to a larger degree in MI (n = 13) than in control animals (n = 13) (RSNA: +36 [+ or -] 6 vs. +19 [+ or -] 3 a.u., P < 0.05; LSNA: +24 [+ or -] 3vs. +9 [+ or -] 2 a.u., P < 0.01). The data demonstrate that CHF exaggerates sympathetic nerve responses to muscle contraction as well as stretch. We suggest that muscle afferent-mediated sympathetic outflows contribute to the abnormal regulation of peripheral blood flow seen during exercise in CHF. exercise; myocardial infarction; sympathetic nervous system

We previously developed a mathematical analysis technique for estimating the static gain values of the arterial total peripheral resistance (TPR) baroreflex ([G.sub.A]) and the cardiopulmonary TPR baroreflex ([G.sub.C]) from small, spontaneous beat-to-beat fluctuations in arterial blood pressure, cardiac output, and stroke volume. Here, we extended the mathematical analysis so as to also estimate the entire arterial TPR baroreflex impulse response [[h.sub.A](t)] as well as the lumped arterial compliance (AC). The extended technique may therefore provide a linear dynamic characterization of TPR baroreflex systems during normal physiological conditions from potentially noninvasive measurements. We theoretically evaluated the technique with respect to realistic spontaneous hemodynamic variability generated by a cardiovascular simulator with known system properties. Our results showed that the technique reliably estimated [h.sub.A](t) [error = 30.2 [+ or -] 2.6% for the square root of energy ([E.sub.A]), 19.7 [+ or -] 1.6% for absolute peak amplitude ([P.sub.A]), 37.3 [+ or -] 2.5% for [G.sub.A], and 33.1 [+ or -] 4.9% for the overall time constant] and AC (error = 17.6 [+ or -] 4.2%) under various simulator parameter values and reliably tracked changes in [G.sub.C]. We also experimentally evaluated the technique with respect to spontaneous hemodynamic variability measured from seven conscious dogs before and after chronic arterial baroreceptor denervation. Our results showed that the technique correctly predicted the abolishment of [h.sub.A](t) [[E.sub.A] = 1.0 [+ or -] 0.2 to 0.3 [+ or -] 0.1, [P.sub.A] = 0.3 [+ or -] 0.1 to 0.1 [+ or -] 0.0 [s.sup.-1], and [G.sub.A] = -2.1 [+ or -] 0.6 to 0.3 [+ or -] 0.2 (P < 0.05)] and the enhancement of [G.sub.C] [-0.7 [+ or -] 0.44 to - 1.8 [+ or -] 0.2 (P < 0.05)] following the chronic intervention. Moreover, the technique yielded estimates whose values were consistent with those reported with more invasive and/or experimentally difficult methods. autonomic nervous system; hemodynamics; modeling; system identification; transfer function

The contribution of the organum vasculosum laminae terminalis (OVLT) in mediating central hyperosmolality-induced increases of sympathetic nerve activity (SNA) and arterial blood pressure (ABP) was assessed in anesthetized rats. Solutions of graded NaCl concentration (150, 375, and 750 mM) were injected (150 [micro]l) into the forebrain vascular supply via an internal carotid artery (ICA). Time-control experiments (n = 6) established that ICA NaCl injections produced short-latency, transient increases of renal SNA (RSNA) and mean ABP (MAP) (P < 0.05-0.001). Responses were graded, highly reproducible, and unaltered by systemic blockade of vasopressin V1 receptors (n = 4). In subsequent studies, stimulus-triggered averaging of RSNA was used to accurately locate the OVLT. Involvement of OVLT in responses to ICA NaCl was assessed by recording RSNA and MAP responses before and 15 min after electrolytic lesion of the OVLT (n = 6). Before lesion, NaCl injections increased RSNA and MAP (P < 0.05-0.001), similar to time control experiments. After lesion, RSNA responses were significantly reduced (P < 0.05-0.001), but MAP responses were unaltered. To exclude a role for fibers of passage, the inhibitory GABA-A receptor agonist muscimol was microinjected into the OVLT (50 pmol in 50 nl) (n = 6). Before muscimol, hypertonic NaCl increased RSNA, lumbar SNA (LSNA), and MAP (P < 0.05-0.001). After muscimol, both RSNA and LSNA were significantly reduced in response to 375 and 750 mM NaCl (P < 0.05). MAP responses were again unaffected. Injections of vehicle (saline) into OVLT (n = 6) and muscimol lateral to OVLT (n = 5) each failed to alter responses to ICA NaCl. We conclude that OVLT neurons contribute to sympathyo-excitation by central hyperosmolality. sympathetic nerve discharge; body fluid homeostasis; blood pressure; osmolality

Neurons within the dorsomedial hypothalamus (DMH) play a critical role in subserving the cardiovascular and neuroendocrine response to psychological stress. An increase in respiratory activity is also a characteristic feature of the physiological response to psychological stress, but there have been few studies of the role of DMH neurons in regulating respiratory activity. In this study we determined the effects of activation of DMH neurons on respiratory activity (assessed by measuring phrenic nerve activity, PNA) and the relationship between evoked changes in respiratory activity and changes in sympathetic vasomotor activity in spontaneously breathing urethane-anesthetized rats. Microinjections of bicuculline (4-40 pmol in 20 nl) into the DMH evoked dose-dependent increases in PNA burst frequency and amplitude. These were accompanied by dose-dependent decreases in mean tracheal CO2 levels, indicative of hyperventilation. In control experiments, microinjections of bicuculline into sites adjacent to the DMH evoked much smaller or no changes in PNA. In experiments where renal sympathetic nerve activity (RSNA) was also measured, cycle-triggered averaging revealed that RSNA under resting conditions was partly correlated with the PNA, but in response to DMH disinhibition there was no consistent change in the amplitude of the respiratory-related variations in RSNA. The results indicate that DMH neurons can exert a powerful stimulatory effect on respiratory activity, causing hyperventilation. This is not associated with an increase in the degree of coupling between PNA and RSNA, indicating that the DMH-evoked increase in RSNA is not a consequence of increased central respiratory drive. arterial pressure; renal sympathetic nerve activity; heart rate; psychological stress

The purpose of this study was to determine if plasma osmolality alters baroreflex control of sympathetic activity when controlling for a change in intravascular volume; we hypothesized that baroreflex control of sympathetic activity would be greater during a hyperosmotic stimulus compared with an isoosmotic stimulus when intravascular volume expansion was matched. Seven healthy subjects (25 [+ or -] 2 yr) completed two intravenous infusions: a hypertonic saline infusion (HSI; 3% NaCl) and, on a separate occasion, an isotonic saline infusion (ISO; 0.9% NaCl), both at a rate of 0.15 ml x [kg.sup.-1] x [min.sup.-1]. To isolate the effect of osmolality, comparisons between HSI and ISO conditions were retrospectively matched based on hematocrit; therefore, baroreflex control of sympathetic outflow was determined at 20 min of a HSI and 40 min of an ISO. Muscle sympathetic outflow (MSNA) was directly measured using the technique of peroneal microneurography; osmolality and blood pressure (Finometer) were assessed. The baroreflex control of sympathetic outflow was estimated by calculating the slope of the relationship between MSNA and diastolic blood pressure during controlled breathing. Plasma osmolality was greater during the HSI compared with the ISO (HSI: 292 [+ or -] 0.9 mosmol/kg and ISO: 289 [+ or -] 0.8 mosmol/kg, P < 0.05). Hematocrits were matched (HSI: 39.1 [+ or -] 1% and ISO: 39.1 [+ or -] 1%, P > 0.40); thus, we were successful in isolating osmolality. The baroreflex control of sympathetic outflow was greater during the HSI compared with the ISO (HSI: -8.3 [+ or -] 1.2 arbitrary units x [beat.sup.1] x mm[Hg.sup.-1] vs. ISO: -4.0 [+ or -] 0.8 arbitrary units x [beat.sup.-1] x mm[Hg.sup.-1], P = 0.01). In conclusion, when controlling for intravascular volume, increased plasma osmolality enhances baroreflex control of sympathetic activity in humans. baroreceptor; muscle sympathetic nerve activity; intravascular volume

We sought to investigate arterial baroreflex (ABR) control of muscle sympathetic nerve activity (MSNA) in the transition from rest to steady-state dynamic exercise. This was accomplished by assessing the relationship between spontaneous variations in diastolic blood pressure (DBP) and MSNA at rest and during the time course of reaching steady-state arm cycling at 50% peak oxygen uptake ([Vo.sub.2peak]). Specifically, DBP-MSNA relations were examined in eight subjects (25 [+ or -] 1 yr) at the start of unloaded arm cycling and then during the initial and a later period of arm cycling once the 50% [Vo.sub.2peak] work rate was achieved. Heart rate and arterial blood pressure were progressively increased throughout exercise. Although resting MSNA [16 [+ or -] 2 burst/min; 181 [+ or -] 36 arbitrary units (au) total activity] was unchanged during unloaded cycling, MSNA burst frequency and total activity were significantly elevated during the initial (27 [+ or -] 4 burst/min; 367 [+ or -] 76 au; P < 0.05) and later (36 [+ or -] 7 burst/min; 444 [+ or -] 91 au; P < 0.05) periods of exercise. The relationships between DBP and burst incidence, burst strength, and total MSNA were progressively shifted rightward from unloaded to the initial to the later period of 50% [Vo.sub.2peak] arm cycling without any changes in the slopes of the linear regressions (i.e., ABR sensitivity). Thus a continuous and dynamic resetting of the ABR control of MSNA occurred during the transition from rest to steady-state dynamic exercise. These findings indicate that the ABR control of MSNA was well maintained throughout dynamic exercise in humans, progressively being reset to operate around the exercise-induced elevations in blood pressure and MSNA without any changes in reflex sensitivity. arterial blood pressure; sympathetic nervous system; arm cycling; exercise onset

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasodilators and exert positive chronotropic and inotropic effects on the heart. Receptors for CGRP and AM are calcitonin receptor-like receptor (CLR)/receptor-activity-modifying protein (RAMP) 1 and CLR/ RAMP2 heterodimers, respectively. The present study was designed to delineate distinct cardiovascular effects of CGRP and AM. Thus a V5-tagged rat CLR was expressed in transgenic mice in the vascular musculature, a recognized target of CGRP. Interestingly, basal arterial pressure and heart rate were indistinguishable in transgenic mice and in control littermates. Moreover, intravenous injection of 2 nmol/kg CGRP, unlike 2 nmol/kg AM, decreased arterial pressure equally by 18 [+ or -] 5 mmHg in transgenic and control animals. But the concomitant increase in heart rate evoked by CGRP was 3.7 times higher in transgenic mice than in control animals. The effects of CGRP in transgenic and control mice, different from a decrease in arterial pressure in response to 20 nmol/kg AM, were suppressed by 2 [micro]mol/kg of the CGRP antagonist CGRP(8-37). Propranolol, in contrast to hexamethonium, blocked the CGRP-evoked increase in heart rate in both transgenic and control animals. This was consistent with the immunohistochemical localization of the V5-tagged CLR in the superior cervical ganglion of transgenic mice. In conclusion, hypotension evoked by CGRP in transgenic and control mice was comparable and CGRP was more potent than AM. Unexpectedly, the CLR/RAMP CGRP receptor overexpressed in postganglionic sympathetic neurons of transgehic mice enhanced the positive chronotropic action of systemic CGRP. calcitonin gene-related peptide; sympathetic nervous system; baroreceptor reflex