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The pathophysiology of airway diseases, such as asthma, is increasingly studied using transgenic mice and other mouse models of airway inflammation where allergen-induced changes in airway smooth muscle tone and mucous secretion is due, in part, to activation of preganglionic airway parasympathetic nerves. Ganglionic parasympathetic neurons located in the airways in several species, including humans, have anatomical and electrophysiological properties that limit transmission of preganglionic synaptic input. In this study, intracellular recordings were made from neurons in parasympathetic ganglia located on the trachea and bronchi of adult mice to determine electrophysiological properties associated with regulation of transmission of preganglionic input. Ganglionic neurons were characterized as having either tonic or phasic action potential accommodation patterns. Tonic neurons responded with repetitive action potentials sustained throughout a depolarizing current step, whereas phasic neurons generated one or a burst of action potential(s) and accommodated. A small subset displayed both patterns. Phasic neurons could be further differentiated as usually having either short- or long-duration afterhyperpolarizing potential following single and multiple action potentials. In most cells, stimulation of preganglionic nerves elicited one population of nicotinic fast excitatory postsynaptic potentials that were graded in amplitude, usually suprathreshold for action potential generation, and did not decrease in amplitude during higher frequency stimulation. Dye injection into the neurons revealed that dendrites were either absent or very short. These results provide evidence that in contrast to the characteristics of airway parasympathetic neurons reported in other species, including human, the electrophysiological and synaptic properties, and anatomical characteristics of mouse lower airway ganglionic neurons, are less associated with integration of presynaptic input. airway diseases; asthma doi: 10.1152/ajplung.00386.2009.

In the present study, we describe a subset of nerve fibers, characterized by their immunoreactivity for the calcium-binding protein calretinin, that are densely and selectively associated with cholinergic postganglionic neurons in the guinea pig tracheal ganglia. Retrograde neuronal tracing with cholera toxin B, combined with immunohistochemical analyses, showed that these nerve fibers do not originate from sensory neurons in the nodose, jugular, or dorsal root ganglia or from motor neurons in the nucleus ambiguus, dorsal motor nucleus of the vagus nerve, spinal cord, stellate ganglia, or superior cervical ganglia. Calretinin-immunoreactive nerve fibers disappeared from tracheal segments after 48 h in organotypic culture, indicating that the fibers were of extrinsic origin. However, calretinin-positive nerve fibers persisted in tracheal ganglia when tracheae were cocultured with the adjacent esophagus intact. Immunohistochemical analysis of the esophagus revealed a population of cholinergic neurons in the esophageal myenteric plexus that coexpressed calretinin. In functional studies, electrical stimulation of the esophagus in vitro evoked measurable contractions of the trachea. These contractions were not altered by prior organotypic culture of the trachea and esophagus to remove the extrinsic innervation to the airways but were significantly (P < 0.05) inhibited by the ganglionic blocker hexamethonium or by physical disruption of the tissue connecting the trachea and esophagus. These data suggest that a subset of esophageal neurons, characterized by the expression of calretinin and acetylcholine, provide a previously unrecognized excitatory input to tracheal cholinergic ganglia in guinea pigs. airway innervation; parasympathetic nervous system; gastroesophageal reflux disease doi:10.1152/ajplung.00166.2009.

By chordatympani denervation (CTD, parasympathectomy), the aquaporin 5 (AQP5), but not AQP1, protein level in the rat submandibular gland (SMG) was significantly decreased, dropping to 37% of that of the contralateral gland at 4 wk. The protein levels of AQP5 and AQP1 were not significantly affected by denervation of the cervical sympathetic trunk (sympathectomy). Administration of cevimeline hydrochloride, an M3 muscarinic receptor agonist (10 mg/kg for 7 days po), but not pilocarpine (0.3 mg/kg for 7 days po), recovered the AQP5 protein level reduced by CTD and increased the AQP1 protein level above the control one. The mRNA level of AQP5 was scarcely affected by CTD and cevimeline hydrochloride administration. Administration of chloroquine (50 mg/kg for 7 days po), a denaturant of lysosomes, increased the AQP5 protein level reduced by CTD. An extract obtained from the submandibular lysosomal fraction degraded the AQP5 protein in the total membrane fraction in vitro. These results suggest the possible regulation of the AQP5 protein level in the SMG by the parasympathetic nerves/M3 muscarinic receptor agonist and imply the involvement of lysosomal enzymes, but not a transcriptional mechanism, in this regulation. aquaporin-5; parasympathectomy; lysosomes; chloroquine

With aging, there is a decrease in parasympathetic nervous activity. Since the hepatic parasympathetic nerves (HPNs) are essential to the disposal of nutrients, through the hepatic insulin sensitizing substance (HISS), we tested the hypothesis that aging leads to a lowering of postprandial glucose disposal by a decrease of the HISS-dependent component of insulin action. Insulin sensitivity was quantified in fed or lasted, male and female Wistar rats (from 6 to 52 weeks), using a euglycemic clamp. The HISS-dependent component was quantified by administration of the muscarinic antagonist atropine. Total insulin action decreased gradually up to 52 weeks of age: The HISS-independent component of insulin action decreased until 9 weeks of age and remained unchanged thereafter; the HISS-dependent component decreased from 9 weeks of age throughout aging. The continuous decrease of HISS action, uncovered by blocking the HPN, is the key phenomenon for the gradual decrease of insulin sensitivity with aging. Key Words: Insulin resistance--Hepatic parasympathetic nerves--Hepatic insulin sensitizing substance--Type 2 diabetes mellitus.

Astrocytes play an important role in the coupling between neuronal activity and brain blood flow via their capacity to 'sense' neuronal activity and transmit that information to parenchymal arterioles. Here we show another role for astrocytes in neurovascular coupling: the ability to act as a signaling conduit for the vitally important process of upstream vasodilation (represented by pial arterioles) during both excessive (seizure) and physiological (sciatic nerve stimulation) increases in cerebral cortical neuronal activity. The predominance of an astrocytic rather than a vascular route was indicated by data showing that pial arteriolar-dilating responses to neuronal activation were completely blocked following selective disruption of the superficial glia limitans, whereas interference with interendothelial signaling was without effect. Results also revealed contributions from connexin 43, implying a role for gap junctions and/or hemichannels in the signaling process and that signaling from the glia limitans to pial arterioles may involve a diffusible mediator. bicuculline; connexin; gap junction; glia limitans; L-[alpha]-aminoadipic acid; sciatic nerve stimulation

cAMP plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication enoximone increases peripheral chemoreflex function in humans. In a single-blind, randomized, placebo-controlled crossover study of 15 men, we measured ventilatory, muscle sympathetic nerve activity, and hemodynamic responses to 5 min of isocapnic hypoxia, 5 min of hyperoxic hypercapnia, and 3 min of isometric handgrip exercise, separated by 1 wk, with enoximone and placebo administration. Enoximone increased cardiac output by 120 [+ or -] 3.7% from baseline (P < 0.001); it also increased the ventilatory response to acute hypoxia [13.6 [+ or -] 1 vs. 11.2 [+ or -] 0.7 1/min at 5 min of hypoxia, P = 0.03 vs. placebo (by ANOVA)]. Despite a larger minute ventilation and a smaller decrease in [O.sub.2] desaturation (83 [+ or -] 1 vs. 79 [+ or -] 2%, P = 0.003), the muscle sympathetic nerve response to hypoxia was similar between enoximone and placebo (123 [+ or -] 6 and 117 [+ or -] 6%, respectively, P = 0.28). In multivariate regression analyses, enoximone enhanced the ventilatory (P < 0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (P = 0.13). Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, inasmuch as central chemoreflex and isometric handgrip responses were not altered by enoximone. phosphodiesterase inhibitor; adenosine 3',5'-cyclic monophosphate

The parasympathetic (P) nervous system is thought to contribute significantly to focal atrial fibrillation (AF). Thus we hypothesized that P nerve fibers [and related muscarinic ([M.sub.2]) receptors] are preferentially located in the posterior left atrium (PLA) and that selective cholinergic blockade in the PLA can be successfully performed to alter vagal AF substrate. The PLA, pulmonary veins (PVs), and left atrial appendage (LAA) from six dogs were immunostained for sympathetic (S) nerves, P nerves, and M2 receptors. Epicardial electrophysiological mapping was performed in seven additional dogs. The PLA was the most richly innervated, with nerve bundles containing P and S fibers (0.9 [+ or -] 1, 3.2 [+ or -] 2.5, and 0.17 [+ or -] 0.3/[cm.sup.2] in the PV, PLA, and LAA, respectively, P < 0.001); nerve bundles were located in fibrofatty tissue as well as in surrounding myocardium. P fibers predominated over S fibers within bundles (P-to-S ratio = 4.4, 7.2, and 5.8 in PV, PLA, and LAA, respectively). [M.sub.2] distribution was also most pronounced in the PLA (17.8 [+ or -] 8.3, 14.3 [+ or -] 7.3, and 14.5 [+ or -] 8 [M.sub.2]-stained cells/[cm.sup.2] in the PLA, PV, and LAA, respectively, P = 0.012). Left cervical vagal stimulation (VS) caused significant effective refractory period shortening in all regions, with easily inducible AF. Topical application of 1% tropicamide to the PLA significantly attenuated VS-induced effective refractory period shortening in the PLA, PV, and LAA and decreased AF inducibility by 92% (P < 0.001). We conclude that 1) P fibers and [M.sub.2] receptors are preferentially located in the PLA, suggesting an important role for this region in creation of vagal AF substrate and 2) targeted P blockade in the PLA is feasible and results in attenuation of vagal responses in the entire left atrium and, consequently, a change in AF substrate. nervous system; autonomic; immunohistochemistry

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein--coupled inward rectifying [K.sup.+] channel GIRK1/4 and results in an acetylcholine-sensitive [K.sup.+] current, [I.sub.KACh]. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and [I.sub.KACh] activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN--SREBP-1) reversed the effect of lipid lowering on [I.sub.KACh] and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. [I.sub.KACh], attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis., Introduction The balance between the response of the heart to sympathetic and parasympathetic stimuli not only determines the rate and force of contraction but also plays a role in regulating [...]

Arterial blood pressure (BP) is regulated via the interaction of various local, humoral, and neural factors. In humans, the major neural pathway for acute BP regulation involves the baroreflexes. In response to baroreceptor activation/deactivation, as occurs during transient changes in BP, key determinants of BP, such as cardiac period/heart rate (via the sympathetic and parasympathetic nervous system) and vascular resistance (via the sympathetic nervous system), are modified to maintain BP homeostasis. In this review, the effects of aging on both the parasympathetic and sympathetic arms of the baroreflex are discussed. Aging is associated with decreased cardiovagal baroreftex sensitivity (i.e., blunted reflex changes in R-R interval in response to a change in BP). Mechanisms underlying this decrease may involve factors such as increased levels of oxidative stress, vascular stiffening, and decreased cardiac cholinergic responsiveness with age. Consequences of cardiovagal baroreflex impairment may include increased levels of BP variability, an impaired ability to respond to acute challenges to the maintenance of BP, and increased risk of sudden cardiac death. In contrast, baroreflex control of sympathetic outflow is not impaired with age. Collectively, changes in baroreftex function with age are associated with an impaired ability of the organism to buffer changes in BP. This is evidenced by the reduced potentiation of the pressor response to bolus infusion of a pressor drug after compared to before systemic ganglionic blockade in older compared with young adults. autonomic nervous system; blood pressure; baroreceptor doi:10.1152/ajpregu.00031.2007

The purpose of this study was to examine the effects of muscular power engagement, anaerobic participation, aerobic power level, and energy expenditure on postexercise parasympathetic reactivation. We compared the response of heart rate (HR) after repeated sprinting with that of exercise sessions of comparable net energy expenditure and anaerobic energy contribution. Fifteen moderately trained athletes performed 1) 18 maximal all-out 15-m sprints interspersed with 17 s of passive recovery (RS), 2) a moderate isocaloric continuous exercise session (MC) at a level of mean oxygen uptake similar to that of the RS trial, and 3) a high-intensity intermittent exercise session (HI) conducted at a level of anaerobic energy expenditure similar to that of the RS trial. Subjects were immediately seated after the exercise trials, and beat-to-beat HR was recorded for l0 min. Parasympathetic reactivation was evaluated through 1) immediate postexercise HR recovery, 2) the time course of the root mean square for the successive R-R interval difference between successive 30-s segments ([RMSSD.sub.30s]) and 3) HR variability vagal-related indexes calculated for the last 5-min stationary period of recovery. [RMSSD.sub.30s] increased during the 10-rain period after the MC trial, whereas [RMSSD.sub.30s] remained depressed after both the RS and HI trials. Parasympathetic reactivation indexes were similar for the RS and HI trials but lower than for the MC trial (P < 0.001). When data of the three exercise trials were considered together, only anaerobic contribution was related to HR trial-derived indexes. Parasympathetic reactivation is highly impaired after RS exercise and appears to be mainly related to anaerobic process participation. heart rate recovery; vagal-related indexes; autonomic activity; sprint interval training doi:10.1152/ajpheart.00062.2007

Heart rate variability and postexercise heart rate recovery are used to assess cardiac parasympathetic tone in human studies, but in some cases these indexes appear to yield discordant information. We utilized pyridostigmine, an acetylcholinesterase inhibitor that selectively augments the parasympathetic efferent signal, to further characterize parasympathetic regulation of rest and postexercise heart rate. We measured time- and frequency-domain indexes of resting heart rate variability and postexercise heart rate recovery in 10 sedentary adults and 10 aerobically tmmed athletes after a single oral dose of pyridostigmine (30 mg) and matching placebo in randomized, doubleblind, crossover trial. In sedentary adults, pyridostigmine decreased resting heart rate [from 66.7 (SD 12.6) to 58.1 beats/min (SD 7.6), P = 0.005 vs. placebo] and increased postexercise heart rate recovery at 1 mm [from 40.7 (SD 10.9) to 45.1 beats/min (SD 8.8), P = 0.02 vs. placebo]. In trained athletes, pyridostigmine did not change resting heart rate or postexercise heart rate recovery when compared with placebo. Time- and frequency-domain indexes of resting heart rate variability did not differ after pyridostigmine versus placebo in either cohort and were not significantly associated with postexercise heart rate recovery in either cohort. The divergent effects of pyridostigmine on resting and postexercise measures of cardiac parasympathetic function in sedentary subjects confirm that these measures characterize distinct aspects of cardiac parasympathetic regulation. The lesser effect of pyridostigmine on either measure of cardiac parasympathetic tone in the trained athletes indicates that the enhanced parasympathetic tone associated with exercise training is at least partially attributable to adaptations in the efferent parasympathetic pathway. heart rate variability; heart rate recovery; parasympathetic nervous system; exercise doi:10.1152/ajpheart.01339.2006

Airway hyperreactivity in antigen-challenged animals is mediated by eosinophil major basic protein (MBP) that blocks inhibitory [M.sub.2] muscarinic receptors on parasympathetic nerves, increasing acetylcholine release onto [M.sub.3] muscarinic receptors on airway smooth muscle. Acutely, anticholinergics block hyperreactivity in antigen-challenged animals and reverse asthma exacerbations in the human, but are less effective in chronic asthma. We tested whether atropine, given before antigen challenge, affected hyperreactivity, [M.sub.2] receptor function, eosinophil accumulation, and activation. Sensitized guinea pigs received atropine (1 mg/kg ip) 1 h before challenge and 6 h later. Twenty-four hours after challenge, animals were anesthetized, vagotomized, paralyzed, and ventilated. Airway reactivity to electrical stimulation of the vagi and to intravenous acetylcholine was not altered by atropine pretreatment in nonsensitized animals, indicating that atropine was no longer blocking postjunctional muscarinic receptors. Antigen challenge induced airway hyperreactivity to vagal stimulation that was significantly potentiated by atropine pretreatment. Bronchoconstriction induced by acetylcholine was not changed by antigen challenge or by atropine pretreatment. [M.sub.2] receptor function was lost in challenged animals but protected by atropine pretreatment. Eosinophils in bronchoalveolar lavage and within airway tissues were significantly increased by challenge but significantly reduced by atropine pretreatment. However, extracellular MBP in challenged airways was significantly increased by atropine pretreatment, which may account for reduced eosinophils. Depleting eosinophils with antibody to IL-5 before challenge prevented hyperreactivity and significantly reduced MBP in airways of atropine-pretreated animals. Thus atropine pretreatment potentiated airway hyperreactivity by increasing eosinophil activation and degranulation. These data suggest that anticholinergics enhance eosinophil interactions with airway nerves. anticholinergic; asthma; muscarinic receptors; parasympathetic nerves doi:10.1152/ajplung.00455.2006

Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy-N-methylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase C[beta]1, and protein kinase C-[alpha] and decreased levels of [[alpha].sub.2a]-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period. high-carbohydrate milk formula; parasympathetic nervous system; and sympathetic nervous system doi:10.1152/ajpendo.00672.2006

The present study investigated the effects of long-duration exercise on heart rate variability [as a marker of cardiac vagal tone (VT)]. Heart rate variability (time series analysis) was measured in mongrel dogs (n = 24) with healed myocardial infarctions during 1 h of submaximal exercise (treadmill running at 6.4 km/h at 10% grade). Long-duration exercise provoked a significant (ANOVA, all P < 0.01, means [+ or -] SD) increase in heart rate (1st min, 165.3 [+ or -] 15.6 vs. last min, 197.5 [- or +] 21.5 beats/min) and significant reductions in high frequency (0.24 to 1.04 Hz) power (VT: 1st min, 3.7 [+ or -] 1.5 vs. last min, 1.0 [+ or -] 0.9 ln [ms.sup.2]), R-R interval range (1st min, 107.9 [+ or -] 38.3 vs. last min, 28.8 [+ or -] 13.2 ms), and R-R interval SD (1st min, 24.3 [+ or -] 7.7 vs. last min 6.3 [+ or -] 1.7 ms). Because endurance exercise training can increase cardiac vagal regulation, the studies were repeated alter either a 10-wk exercise training (n = 9) or a 10-wk sedentary period (n = 7). After training was completed, long-duration exercise elicited smaller increases in heart rate (pretraining: 1st min, 156.0 [+ or -] 13.8 vs. last min, 189.6 [+ or -] 21.9 beats/min; and posttraining: 1st min, 149.8 [+ or -] 14.6 vs. last min, 172.7 [+ or -] 8.8 beats/min) and smaller reductions in heart rate variability (e.g., VT, pretraining: 1st min, 4.2 [+ or -] 1.7 vs. last min, 0.9 [+ or -] 1.1 ln [ms.sup.2]; and posttraining: 1st min, 4.8 [+ or -] 1.1 vs. last min, 2.0 [+ or -] 0.6 ln [ms.sup.2]). The response to long-duration exercise did not change in the sedentary animals. Thus the heart rate increase that accompanies long-duration exercise results, at least in part, from reductions in cardiac vagal regulation. Furthermore, exercise training attenuated these exercise-induced reductions in heart rate variability, suggesting maintenance of a higher cardiac vagal activity during exercise in the trained state. parasympathetic nervous system; exercise training; autonomic nervous system

Acupuncture is useful for functional bowel diseases, such as constipation and diarrhea. However, the mechanisms of beneficial effects of acupuncture on colonic function have scarcely ever been investigated. We tested the hypothesis that electroacupuncture (EA) at ST-36 stimulates colonic motility and transit via a parasympathetic pathway in conscious rats. Hook-shaped needles were inserted at bilateral ST-36 (lower limb) or BL-21 (back) and electrically stimulated at 10 Hz for 20 min. We also studied c-Fos expression in response to EA at ST-36 in Barrington's nucleus of the pons. EA at ST-36, but not BL-21, significantly increased the amplitude of motility at the distal colon. The calculated motility index of the distal colon increased to132 [+ or -] 9.9% of basal levels (n = 14, P < 0.05). In contrast, EA at ST-36 had no stimulatory effects in the proximal colon. EA at ST-36 significantly accelerated colonic transit [geometric center (GC) = 6.76 [+ or -] 0.42, n = 9, P < 0.001] compared with EA at BL-21 (GC = 5.23 [+ or -] 0.39, n = 7). The stimulatory effect of EA at ST-36 on colonic motility and transit was abolished by pretreatment with atropine. EA-induced acceleration of colonic transit was also abolished by extrinsic nerve denervation of the distal colon (GC = 4.69 [+ or -] 0.33, n = 6). The number of c-Fos-immunopositive cells at Barrington's nucleus significantly increased in response to EA at ST-36 to 8.1 [+ or -] 1.1 cells/section compared with that of controls (2.4 [+ or -] 0.5 cells/section, n = 3, P < 0.01). It is concluded that EA at ST-36 stimulates distal colonic motility and accelerates colonic transit via a sacral parasympathetic efferent pathway (pelvic nerve). Barrington's nucleus plays an important role in mediating EA-induced distal colonic motility in conscious rats. Barrington's nucleus; c-Fos; pelvic nerve

After periods of microgravity or bed rest, individuals often exhibit reduced [VO.sub.2 max], hypovolemia, cardiac and vascular effects, and autonomic dysfunction. Recently, alterations in expression of vascular and central nervous system NO synthase (NOS) have been observed in hindlimb-unloaded (HU) rats, a model used to simulate physiological effects of microgravity or bed rest. We examined the effects of 14 days of hindlimb unloading on hemodynamic responses to systemic NOS inhibition in conscious control and HU rats. Because differences in NO and autonomic regulation might occur after hindlimb unloading, we also evaluated potential differences in resting autonomic tone and effects of NOS inhibition after autonomic blockade. Administration of nitro-L-arginine methyl ester (L-NAME; 20 mg/kg iv) increased mean arterial pressure (MAP) to similar levels in control and HU rats. However, the change in MAP in response to L-NAME was less in HU rats, that had an elevated baseline MAP. In separate experiments, atropine (1 mg/kg iv) increased heart rate (HR) in control but not HU rats. Subsequent administration of the ganglionic blocker hexamethonium (30 mg/kg iv) decreased MAP and HR to a greater extent in HU rats. Administration of L-NAME after autonomic blockade increased MAP in both groups to a greater extent compared with intact conditions. However, the pressor response to L-NAME was still reduced in HU rats. These data suggest that hindlimb unloading in rats reduces peripheral NO as well as cardiac parasympathetic tone. Along with elevations in sympathetic tone, these effects likely contribute to alterations in vascular control and changes in autonomic reflex function following spaceflight or bed rest. cardiovascular deconditioning; simulated microgravity; parasympathetic nervous system; sympathetic nervous system; ganglionic blockade

Involvement of trigeminal spinal nucleus in parasympathetic reflex vasodilatation in cat lower lip. Am J Physiol Regulatory Integrative Comp Physiol 282: R492-R500, 2002.--We examined whether the trigeminal spinal nucleus (Vsp) forms part of the central mechanism by which electrical stimulation of the central cut end of the lingual nerve (LN) evokes parasympathetic reflex vasodilatation in the lower lip in artificially ventilated, cervically vagosympathectomized cats deeply anesthetized with [alpha]-chloralose and urethane. For this purpose, we made microinjections within the brain stem to produce nonselective, reversible local anesthesia (lidocaine) or soma-selective, irreversible neurotoxic damage (kainic acid). Local anesthesia of Vsp by microinjection of lidocaine (2%; 1 [mirco]l/site) reversibly and significantly reduced the ipsilateral-LN-evoked parasympathetic reflex vasodilatation. Unilateral microinjection of kainic acid (10 mM/site; 1 [micro]l) into Vsp ipsilateral to the stimulated LN led to an irreversible reduction in the reflex vasodilatation but had no effect on the vasodilatation elicited by stimulation of the contralateral LN. Such microinjection of kainic acid into Vsp had no effect on the vasodilatation evoked by electrical stimulation of the ipsilateral inferior salivatory nucleus. Electrical stimulation of Vsp elicited a blood flow increase in the lower lip in an intensity- and frequency-dependent manner, regardless of whether systemic arterial blood pressure rose or fell. Hexamethonium (1.0 mg/kg iv) significantly reduced the vasodilator responses elicited by electrical stimulation of the central cut end of LN or of Vsp, each to a similar degree. After hexamethonium, both vasodilator responses showed time-dependent recovery. These results strongly suggest that Vsp is an important bulbar relay for LN-evoked parasympathetic reflex vasodilatation in the cat lower lip. autonomic reflex; lidocaine; kainic acid; autonomic ganglion blocker

Research was conducted to examine the hypothesis that the blockade of hepatic nitric oxide synthase (NOS) causes insulin resistance. The rapid insulin sensitivity test was used to measure insulin sensitivity. Insulin resistance generated by denervation was not increased further by NOS blockade. Results indicate that blockade of NOS gives rise to peripheral insulin resistance secondary to blockade of the hepatic parasympathetic reflex release of hepatic insulin-sensitizing substance in response to insulin.

Hyperreactivity to histamine in antigen-challenged guinea pigs is believed to be due to M2 receptor dysfunction. This hypothesis is tested by examining the mechanism of bronchoconstriction in antigen-challenged animals. Results show that hyperreactivity to histamine is vagally mediated. It is also demonstrated that hyperreactivity is the result of the antagonistic action of eosinophil major basic protein on M2 muscarinic receptors. These results provide valuable insights that help explain the hyperreactivity of agents in patients with asthma.

The effects of saline versus atropine infusion of gastric emptying were investigated using a radiolabeled method that permits simultaneous measurement of the solid and liquid components of a meal in lean and obese male and female subjects. Results showed that obese subjects exhibit altered gastric cholinergic activity compared with lean subjects and that gender differences in gastric emptying may be due to differences in autonomic tone.

Electrical rhythmicity in gastrointestinal muscles and the enteric nervous system is discussed relative to its cellular/molecular basis and ionic species involved. The channels involved, when assignment of molecular entities to underlying ionic events has been achieved, might be targets for therapeutic agents. BLocking drugs can more easily be tested in expression systems than in native cells. Smooth muscle cells and interstitial cells of Cajal are involved in the body, which complicates study with different types of ionic conductance, and the relationship between the two is the focus here.

Thirty two thiobutabarbitol sodium-anesthetized male Sprague-Dawley rats were studied to determine the contribution of insular cortex in the modulation of baroreflex sensitivity. Baroreflex activity was found to be substantially reduced following bilateral lidocaine infusions into the insula, regardless of vagal stimulation. Negligible change was noted in plasma norepinephrine, indicating that attenuated parasympathetic output was essential to the modified baroreflex.

The beat to beat variation in the R-R interval of the electrocardiogram of conscious dogs was investigated under different conditions using sympathetic and parasympathetic blocking agents alone or in combination to determine the entropy measures of heart rate variability. Results reveal the the entropy of the variability in the heart rate of conscious dogs is brought about by the parasympathetic control of heart rate.

Research was conducted to investigate the effects of enantiomers of the beta2-agonists albuterol and formoterol on acetylcholine release from equine trachealis parasympathetic nerves. The trachea was prepared by dissecting the cartilages in the anterior aspect while tissues were collected from more than 15 horses. Results showed that metabolism of racemic beta2-agonists is stereoselective in humans, with negligible abosrption and preferential and rapid elimination of the R-enantiomer.

Research suggests that forebrain parasympathetic command neurons controlling cardiac autonomic balance are impaired by myocardial infarction. Experiments using male Wistar rats and retrograde transneuronal viral labeling techniques are described. Immune activation-mediated selective cerebral endothelial leakage is discussed in relation to local neuronal uptake.

Research indicates that hypertensive rats that have undergone dynamic exercise will only exhibit a reduction in cardiac sympathetic tonus and arterial pressure if the sinoartic nerve pathway is intact. The arterial baroreflex is required for the postexertional physiological response. Experiments using male spontaneously hypertensive rats are described.

Experiments were conducted to determine whether the changes in baroreflex control of heart rate in late pregnancy are caused by an aberration in the sympathetic or parasympathetic control of the heart. Results indicated that changes in baroreflex control of heart rate in pregnant rabbits are mediated by changes in both sympathetic and parasympathetic control of the heart. The pregnancy-induced decrease in baroreflex gain is due to a central defect in the regulation of sympathetic outflow.

The frequency-response characteristics of autonomic nervous system in concious rats were analyzed to determine the autonomic pathway from the central nervous system to the end organ. Results of the experiment indicated that the sympathetic transmission to the heart is slower as compared to the parasympathetic pathway. Furthermore, the transmission of neural signals from the central nervous system to the sympathetic nerve does not limit the frequency range of the sympathetic pathway.

The activation of prejunctional beta2-adrenoceptors on equine airway parasympathetic nerves aids ACh release, which demonstrates an excitatory role of beta2-adrenoceptors. ACh release is increased more by atropine than by Iso, indicating the predominance of prejunctional inhibitory muscarinic autoreceptors over excitatory beta2-adrenoceptors. Moreover, the inhibition of nitric oxide synthase by Ng-nitro-L-arginine does not appear to affect either the cholinergic contractile response or ACh release in both the absence and presence of Iso.

Whole cell path clamp methods facilitate the analysis of the inwardly rectifying K+ currents in secretory cells from normal adult sheep after unilateral parotid parasympathectomy and in the parotid glands of unweaned lambs. Functional parasympathetic innervation development promotes the inwardly rectifying current. Secretory cells from the parotid glands of unweaned lambs exhibit no inwardly rectifying current unlike those of the adult sheep that exhibit a prominent inwardly rectifying current.

Intravenous infusions of a conjugate of nerve growth factor and a transferrin receptor antibody (OX-26) prevent the loss of striatal choline acetyltransferase-immunoreactive neurons in the adult rat brain. The treatment mediates transfer of neurotrophin across the blood-brain barrier and explains the viability of cholinergic striatal neurons in a model of Huntington diseases. NGF exerts trophic effects over striatal and basal forebrain cholinergic neurons.

Experiments for measuring alterations in energy expenditure (EE) and respiratory quotient (RQ) of corticosterone (cort) dose-treated adrenalectomy (ADX) rats to characterize their corticosterone-resistant and corticosterone-sensitive metabolic properties reveal that cort doses eliminate the inhibition of food intake and body weight by ADX and reinstate ADX-induced decrease in motoric activity to sham levels in rats. EE suppression is seen in both light and dark conditions, but RQ suppression is seen only in dark conditions. Cort replacement partially revives EE to sham levels in light conditions.

Use of a canine model to examine whether intra-right vs intra-left pulmonary ATP induces sinus node automaticity inhibition and promotes neural afferent traffic through the left and right vagus nerves reveals that intra-right and intra-left pulmonary ATP has negative chronotropic impact on sinus mode automaticity and promotes neural traffic in the vagus nerves. Unilateral pulmonary ATP promotes ipsilateral vagal C-fiber function, while intra-RA ATP promotes bilateral vagal C-fiber functions. The time for intrapulmonary ATP peak effect on the systemic arterial blood pressure was higher than that for peak negative chronotropic impact, suggesting the interactions between ATP metabolites and nonpulmonary tissues.

Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) enhance choline acetyltransferase activity and development of cholinergic neurons from mesencephalic cranial motor nuclei in ventral mesencephalon cultures. CNTF and LIF are ineffective on cholinergic neurons from septal and striatal cultures, indicating their selective nature as pleiotropic cytokines.

Studies on anesthetized dogs reveal that efferent parasympathetic neurons modulate the right atrial pressure. These neurons are present in a region distinct from that of the neurons controlling heat rate. The wave pressure of the right atrium is considered an indicator of right atrial myocardial contractility.

Studies on rat dorsal vagal complex (DVC) reveal that circulating peptide YY (PYY) binds to areas in the pituitary and DVC regions with suitable receptors and incomplete blood-brain barrier. Regions with an intact blood-brain barrier prevent PYY binding. This hormone may be involved in modulating the digestive system by acting as neuromodulators.

Intracellular current-clamp and individual voltage-clamp techniques facilitated the analysis of the role of vasoactive intestinal contractor (VIC) during receptor-activated ionic conduction in neurons located in feline colonic parasympathetic ganglia. Experimental results demonstrated the potential of VIC to induce receptor-mediated channel and regulate the calcium channels stimulated by the omega-conotoxin-dependent voltages. These calcium channels are propagated through the endothelin(B) receptor subgroups of neurons.

An experimental model which allowed direct microapplication of nicotinic, muscarinic and beta-adrenergic agonists adjacent to spontaneously active in situ epicardial neurons was evolved to examine the alteration of functions produced by intrinsic cardiac neurons by these agonists. The results revealed that nicotinic and muscarinic receptors are possessed by intrinsic cardiac neurons, that a few intrinsic neurons have beta-adrenergic receptors and that cardiac control involves intrinsic cardiac neurons with nicotinic muscarinic and beta-adrenergic receptors.

A study was conducted to examine whether the vagal nerve innervating different organs are included in the etiology of immobilization (IMB) stress-induced hypocalcemia in rats. The results revealed that a reduction in the concentration of blood calcium level in rats was caused by IMB stress, and that IMB-induced hypocalcemia relied on the intact vagal innervation of the stomach and could be intervened by gastrin and histamine discharged by activation of the gastric vagus.

This study investigated by interview, the initial syncopal episode of 103 blood/injury-related vasovagal fainters in order to examine two competing hypotheses concerning their origins. Graham (Circulation, 23, 901-906, 1961) postulated that the faint resulted when sympathetic nervous system (SNS) activity ceased on termination of a threat, leaving parasympathetic nervous system (PNS) activation unopposed. Engel [Fainting (2nd edn), 1962; Annals of Internal Medicine, 89, 901-906, 1978] proposed that when in the face of threat with SNS activation, escape is blocked, the PNS becomes activated as the conservation-withdrawal reponse, leading to syncope. We found cases clearly conforming to each of these formulations as well as some with characteristics of both, and some who fainted in response to blood or injury but with no perception of threat. The Graham and Engel types did not differ in terms of fear or avoidance of blood, injury, or medically-related situations nor did they differ in the frequency with which their parents reported blood/injury-related syncopal episodes. It is proposed that both may be activated by a common psychological mechanism involving cessation of a defensive posture. In contrast, the non-threat fainters showed significantly less medically-related avoidance and had a greater percentage (94%) of parents with positive faint histories.

Inhibition of baroreflex vagal bradycardia by activation of the rostral ventrolateral medulla in rats. Am J Physiol Heart Circ Physiol 279: H1239-H1247, 2000.--In stressful conditions, baroreflex vagal bradycardia (BVB) is often suppressed while blood pressure is increased. To address the role of the rostral ventrolateral medulla (RVL), a principal source of sympathetic tone, in inhibition of BVB, we microinjected DL-homocysteic acid (DLH, 6 nmol) into the RVL of chloralose-urethan-anesthetized, sinoaortic-denervated rats to examine the effect on BVB. The BVB was provoked by electrical stimulation of the aortic depressor nerve ipsilateral to the injection sites. DLH microinjection was found to suppress BVB while increasing blood pressure. The inhibition of BVB was observed even during the early phase in which DLH transiently suppressed central inspiratory activity. The inhibition was not affected either by upper spinal cord transection or suprapontine decerebration. Similar results were obtained by microinjection of bicuculline methiodide (160 pmol), a GABA antagonist, into the RVL of carotid sinus nerve-preserved rats due to withdrawal of a tonic GABA-mediated, inhibitory influence including the input from arterial baroreceptors. In conclusion, activation of the RVL inhibits BVB at brain stem level independently of central inspiratory drive. aortic depressor nerve; DL-homocysteic acid; [Gamma]-aminobutyric acid; bicuculline; sympathetic-parasympathetic interaction

Inotropic, chronotropic, and dromotropic effects mediated via parasympathetic ganglia in the dog heart. Am J Physiol Heart Circ Physiol 279: H1201-H1207, 2000.--Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33~37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart. parasympathetic ganglionic cells; atrial contractility; sinus rate; atrioventricular conduction; trimethaphan

Central control of cardiac baroreflex responses during peripheral hyperosmolality. Am J Physiol Regulatory Integrative Comp Physiol 278: R1157-R1163, 2000.--Acute increases in peripheral osmolality evoke a pressor response and baroreflex-mediated bradycardia. These experiments were designed to determine if the fall in heart rate during peripheral sodium loading is 1) equivalent to bradycardia accompanying phenylephrine (PE) infusion, 2) mediated by the parasympathetic (PSNS) or sympathetic (SNS) nervous system, and 3) controlled by the median preoptic nucleus (MnPO). Male rats received an intravenous infusion of isotonic saline, hypertonic saline (2.5 M NaCl), or PE for 30 min. Blood pressure increased equivalently in the hypertonic NaCl and PE groups. However, heart rate fell more in animals infused with PE. Furthermore, pretreatment with methylatropine to block the PSNS had no effect on bradycardia, whereas blocking SNS influences on cardiac function significantly attenuated the fall in heart rate during peripheral hyperosmolality. Finally, kainic acid administration in the MnPO before testing increased bradycardia observed during hypertonic saline loading. Taken together, these data suggest that acute peripheral hyperosmolality acts at the MnPO to reduce cardiac SNS withdrawal during the pressor response that reduces the associated baroreflex bradycardia. baroreceptors; median preoptic nucleus; hypertonicity; sympathetic nervous system; parasympathetic nervous system

Yang, Cheryl C. H., Te-Chang Chao, Terry B. J. Kuo, Chang-Sheng Yin, and Hsing I. Chen. Preeclamptic pregnancy is associated with increased sympathetic and decreased parasympathetic control of HR. Am J Physiol Heart Circ Physiol 278: H1269-H1273, 2000.-- Previous work from our laboratory using heart rate variability (HRV) has demonstrated that women before menopause have a more dominant parasympathetic and less effective sympathetic regulations of heart rate compared with men. Because it is still not clear whether normal or preeclamptic pregnancy coincides with alternations in the autonomic functions, we evaluated the changes of HRV in 17 nonpregnant, 17 normotensive pregnant, and 11 preeclamptic women who were clinically diagnosed without history of diabetic neuropathy, cardiac arrhythmia, and other cardiovascular diseases. Frequency-domain analysis of short-term, stationary R-R intervals was performed to evaluate the total variance, low-frequency power (LF; 0.04-0.15 Hz), high-frequency power (HF; 0.15-0.40 Hz), ratio of LF to HF (LF/HF), and LF in normalized units (LF%). Natural logarithm transformation was applied to variance, LF, HF, and LF/HF for the adjustment of the skewness of distribution. We found that the normal pregnant group had a lower R-R value and HF but had a higher LF/HF and LF% compared with the nonpregnant group. The preeclamptic group had lower HF but higher LF/HF compared with either the normal pregnant or nonpregnant group. Our results suggest that normal pregnancy is associated with a facilitation of sympathetic regulation and an attenuation of parasympathetic influence of heart rate, and such alterations are enhanced in preeclamptic pregnancy. heart rate variability; power spectral analysis; parasympathetic activity; sympathovagal balance

Benthem, Lambertus, Thomas O. Mundinger, and Gerald J. Taborsky, Jr. Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system. Am J Physiol Endocrinol Metab 278: E603-E610, 2000.--We investigated the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting [[Beta].sub.2]-adrenergic mediation, which was confirmed by [Beta]-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and [Beta]-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. We conclude that 1) the insulin response, to showing food is mediated by the [[Beta].sub.2]-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the [[Beta].sub.2]-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone. cephalic phase of insulin release; feeding; pancreatic polypeptide

This article clarifies the claim that activation of 5-HT(sub)1A receptors helps in the treatment of obstructive respiratory airway diseases. Results suggest that in animals receptor activation raises the vagal tone of the airways leading to bronchoconstriction.

Research was conducted to examine the parasympathetic modulation of sinoatrial node pacemaker activity in rabbit heart. A compartmental model of the single rabbit sinoatrial node cell was extended to simulate cellular responses to bath applications of ACh and isoprenaline and the effects of neuronally released ACh. Results suggest that the model can be used over the full range of intensity and pattern of vagal input and can provided biophysically based explanations for various phenomena related to the autonomic control of cardiac pacemaking.