Autonomic control of the heart is altered in Sprague-Dawley rats with spontaneous hydronephrosis

The renal medulla plays an important role in cardiovascular regulation, through interactions with the autonomic nervous system. Hydronephrosis is characterized by substantial loss of renal medullary tissue. However, whether alterations in autonomic control of the heart are observed in this condition is unknown. Thus we assessed resting hemodynamics and baroreflex sensitivity (BRS) for control of heart rate in urethane/chloralose-anesthetized Sprague-Dawley rats with normal or hydronephrotic kidneys. While resting arterial pressure was similar, heart rate was higher in rats with hydronephrosis (290 ± 12 normal vs. 344 ± 11 mild/moderate vs. 355 ± 13 beats/min severe; P < 0.05). The evoked BRS to increases, but not decreases, in pressure was lower in hydronephrotic rats (1.06 ± 0.06 normal vs. 0.72 ± 0.10 mild/moderate vs. 0.63 ± 0.07 ms/mmHg severe; P < 0.05). Spectral analysis methods confirmed reduced parasympathetic function in hydronephrosis, with no differences in measures of indirect sympathetic activity among conditions. As a secondary aim, we investigated whether autonomic dysfunction in hydronephrosis is associated with activation of the renin-angiotensin system (RAS). There were no differences in circulating angiotensin peptides among conditions, suggesting that the impaired autonomic function in hydronephrosis is independent of peripheral RAS activation. A possible site for angiotensin II-mediated BRS impairment is the solitary tract nucleus (NTS). In normal and mild/moderate hydronephrotic rats, NTS administration of the angiotensin II type 1 receptor antagonist candesartan significantly improved the BRS, suggesting that angiotensin II provides tonic suppression to the baroreflex. In contrast, angiotensin II blockade produced no significant effect in severe hydronephrosis, indicating that at least within the NTS baroreflex suppression in these animals is independent of angiotensin II.     

Cyclosporine attenuates the autonomic modulation of reflex chronotropic responses in conscious rats

Cyclosporine A (CyA), an immunosuppressant drug, has been shown to attenuate the baroreflex control of heart rate (HR). This study investigated whether or not the CyA-induced baroreflex dysfunction is due to alterations in the autonomic (sympathetic and parasympathetic) control of the heart. We evaluated the effect of muscarinic or beta-adrenergic blockade by atropine and propranolol, respectively, on reflex HR responses in conscious rats treated with CyA (20 mg x kg(-1) x day(-1) dissolved in sesame oil) for 11-13 days or the vehicle. Baroreflex curves relating changes in HR to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (NP), respectively, were constructed and the slopes of the curves were taken as a measure of baroreflex sensitivity (BRS(PE) and BRS(NP)). Intravenous administration of PE and NP produced dose-related increases and decreases in BP, respectively, that were associated with reciprocal changes in HR. CyA caused significant (P < 0.05) reductions in reflex HR responses as indicated by the smaller BRS(PE) (-0.97 +/- 0.07 versus -1.47 +/- 0.10 beats x min(-1) x mmHg(-1) (1 mmHg = 133.322 Pa)) and BRS(NP) (-2.49 +/- 0.29 versus -5.23 +/- 0.42 beats x min(-1) x mmHg(-1)) in CyA-treated versus control rats. Vagal withdrawal evoked by muscarinic blockade elicited significantly lesser attenuation of BRS(PE) in CyA compared with control rats (40.2 +/- 8.0 versus 57.7 +/- 4.4%) and abolished the BRS(PE) difference between the two groups, suggesting that CyA reduces vagal activity. CyA also appears to impair cardiac sympathetic control because blockade of beta-adrenergic receptors by propranolol was less effective in reducing reflex tachycardic responses in CyA compared with control rats (41.6 +/- 4.2 versus 59.5 +/- 4.5%). These findings confirm earlier reports that CyA attenuates the baroreceptor control of HR. More importantly, the study provides the first pharmacological evidence that CyA attenuates reflex chronotropic responses via impairment of the autonomic modulation of the baroreceptor neural pathways.     

Thyroid status influences baroreflex function and autonomic contributions to arterial pressure and heart rate

The effect of thyroid status on arterial baroreflex function and autonomic contributions to resting blood pressure and heart rate (HR) were evaluated in conscious rats. Rats were rendered hyperthyroid (Hyper) or hypothyroid (Hypo) with triiodothyronine and propylthiouracil treatments, respectively. Euthyroid (Eut), Hyper, and Hypo rats were chronically instrumented to measure mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Baroreflex function was evaluated with the use of a logistic function that relates LSNA or HR to MAP during infusion of phenylephrine and sodium nitroprusside. Contributions of the autonomic nervous system to resting MAP and HR were assessed by blocking autonomic outflow with trimethaphan. In Hypo rats, the arterial baroreflex curve for both LSNA and HR was shifted downward. Hypo animals exhibited blunted sympathoexcitatory and tachycardic responses to decreases in MAP. Furthermore, the data suggest that in Hypo rats, the sympathetic influence on HR was predominant and the autonomic contribution to resting MAP was greater than in Eut rats. In Hyper rats, arterial baroreflex function generally was similar to that in Eut rats. The autonomic contribution to resting MAP was not different between Hyper and Eut rats, but predominant parasympathetic influence on HR was exhibited in Hyper rats. The results demonstrate baroreflex control of LSNA and HR is attenuated in Hypo but not Hyper rats. Thyroid status alters the balance of sympathetic to parasympathetic tone in the heart, and the Hypo state increases the autonomic contributions to resting blood pressure.     

Impaired cardiac and sympathetic autonomic control in rats differing in acetylcholine receptor sensitivity

Acetylcholine receptors (AChR) are important in premotor and efferent control of autonomic function; however, the extent to which cardiovascular function is affected by genetic variations in AChR sensitivity is unknown. We assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) in rats bred for resistance (FRL) or sensitivity (FSL) to cholinergic agents compared with Sprague-Dawley rats (SD), confirmed by using hypothermic responses evoked by the muscarinic agonist oxotremorine (0.2 mg/kg i.p.) (n > or = 9 rats/group). Arterial pressure, ECG, and splanchnic sympathetic (SNA) and phrenic (PNA) nerve activities were acquired under anesthesia (urethane 1.3 g/kg i.p.). HRV was assessed in time and frequency domains from short-term R-R interval data, and spontaneous heart rate BRS was obtained by using a sequence method at rest and after administration of atropine methylnitrate (mATR, 2 mg/kg i.v.). Heart rate and SNA baroreflex gains were assessed by using conventional pharmacological methods. FRL and FSL were normotensive but displayed elevated heart rates, reduced HRV and HF power, and spontaneous BRS compared with SD. mATR had no effect on these parameters in FRL or FSL, indicating reduced cardiovagal tone. FSL exhibited reduced PNA frequency, longer baroreflex latency, and reduced baroreflex gain of heart rate and SNA compared with FRL and SD, indicating in FSL dual impairment of cardiac and circulatory baroreflexes. These findings show that AChR resistance results in reduced cardiac muscarinic receptor function leading to cardiovagal insufficiency. In contrast, AChR sensitivity results in autonomic and respiratory abnormalities arising from alterations in central muscarinic and or other neurotransmitter receptors.     

Gender difference in baroreflex-mediated bradycardia in young rats: role of cardiac sympathetic and parasympathetic components.

In a previous clinical study we have demonstrated a significantly lower baroreflex-mediated bradycardic response in young women compared with men. The present study determined whether sexual dimorphism in baroreflex sensitivity in young rats also covers the reflex tachycardic response. The study was then extended to test the hypothesis that an attenuated cardiac cholinergic component of the baroreflex heart rate response in females may account for the gender difference. Baroreflex sensitivity (BRS) was expressed as the regression coefficient of the reciprocal relationship between evoked changes in blood pressure and heart rate. BRS measured in conscious rats with phenylephrine (BRS(PE)) and nitroprusside (BRS(NP)) represented the reflex bradycardic and tachycardic responses, respectively. Female rats exhibited significantly lower BRS(PE) compared with male rats (-1.53+/-0.1 vs. -2.36+/-0.13 beats x min(-1) x mmHg(-1); p < 0.05) but similar BRS(NP) (-2.60+/-0.20 vs. -2.29+/-0.17 beats x min(-1) x mmHg(-1)). Blockade of cardiac muscarinic receptors with atropine methyl bromide elicited greater attenuation of BRS(PE) in male than in female rats (72+/-4.6 vs. 53+/-6.7% inhibition; p < 0.01) and abolished the gender difference. In male rats cardiac muscarinic blockade attenuated BRS(PE) significantly more than did cardiac beta-adrenergic receptor blockade with propranolol (72+/-4.6 vs. 43+/-2.7; p < 0.01), which suggests greater dependence of BRS(PE) on the parasympathetic component. In females, muscarinic and beta-adrenergic blockade elicited similar attenuation of BRS(PE). The findings suggest that (i) BRS is differentially influenced by gender; female rats exhibit substantially lower BRS(PE) but similar BRS(NP) compared with age-matched male rats and (ii) the sexual dimorphism in BRS(PE) results, at least partly, from a smaller increase in vagal outflow to the heart in response to baroreceptor activation.     

Predominance of Intrinsic Mechanism of Resting Heart Rate Control and Preserved Baroreflex Sensitivity in Professional Cyclists after Competitive Training

Different season trainings may influence autonomic and non-autonomic cardiac control of heart rate and provokes specific adaptations on heart’s structure in athletes. We investigated the influence of transition training (TT) and competitive training (CT) on resting heart rate, its mechanisms of control, spontaneous baroreflex sensitivity (BRS) and relationships between heart rate mechanisms and cardiac structure in professional cyclists (N = 10). Heart rate (ECG) and arterial blood pressure (Pulse Tonometry) were recorded continuously. Autonomic blockade was performed (atropine—0.04 mg.kg^-1; esmolol—500 μg.kg^-1 = 0.5 mg). Vagal effect, intrinsic heart rate, parasympathetic (n) and sympathetic (m) modulations, autonomic influence, autonomic balance and BRS were calculated. Plasma norepinephrine (high-pressure liquid chromatography) and cardiac structure (echocardiography) were evaluated. Resting heart rate was similar in TT and CT. However, vagal effect, intrinsic heart rate, autonomic influence and parasympathetic modulation (higher n value) decreased in CT (P≤0.05). Sympathetic modulation was similar in both trainings. The autonomic balance increased in CT but still showed parasympathetic predominance. Cardiac diameter, septum and posterior wall thickness and left ventricular mass also increased in CT (P<0.05) as well as diastolic function. We observed an inverse correlation between left ventricular diastolic diameter, septum and posterior wall thickness and left ventricular mass with intrinsic heart rate. Blood pressure and BRS were similar in both trainings. Intrinsic heart rate mechanism is predominant over vagal effect during CT, despite similar resting heart rate. Preserved blood pressure levels and BRS during CT are probably due to similar sympathetic modulation in both trainings.     

Baroreflex Function in Females: Changes With the Reproductive Cycle and Pregnancy

This review briefly describes the changes in baroreflex function that occur during female reproductive life, specifically during the reproductive cycle and pregnancy. The sensitivity or gain of baroreflex control of heart rate and sympathetic activity fluctuates during the reproductive cycle, reaching a peak when gonadal hormone levels increase, during the follicular phase in women and proestrus in rats. The increase in baroreflex sensitivity (BRS) is likely mediated by estrogen because ovariectomy in rats eliminates the BRS increase, the cyclic profile of changes in BRS mirror the changes in estrogen, and estrogen acts in the brainstem to increase BRS. In contrast, pregnancy depresses both BRS and the maximal level of sympathetic activity and heart rate evoked by severe hypotension. The decrease in BRS may be mediated by a reduction in the actions of insulin in the arcuate nucleus to support the baroreflex. In addition, increased levels of the neurosteroid progesterone metabolite 3α-OH-DHP act downstream in the rostral ventrolateral medulla to suppress maximal baroreflex increases in sympathetic activity. Consequently, these changes in baroreflex function impair blood pressure regulation in the presence of hypotensive challenges such as orthostasis and hemorrhage, a common event during delivery. As a result, peripartum hemorrhage is a major cause of human maternal death.     

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na(+) channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or beta-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not beta-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.     

Lecithinized brain-derived neurotrophic factor promotes the differentiation of embryonic stem cells in vitro and in vivo

The addition of lecithin molecules to brain-derived neurotrophic factor (BDNF) has been reported to markedly enhance its pharmacological effect in vivo. In the current study, we show that lecithinized BDNF (PC-BDNF) has a higher affinity than BDNF for neural precursor cells. Although BDNF only slightly increased the expression of the genes for Mash-1, p35, 68 kDa neurofilament, and TrkB receptor, PC-BDNF caused a significant increase in their expression. PC-BDNF also increased the level of neurofilament protein and dramatically increased TrkB mRNA gene expression, which was followed by a sustained activation of the p42/p44 extracellular-regulated kinases. Finally, transplantation of PC-BDNF-treated cells was more effective than BDNF-treated cells at improving impaired motor function caused by spinal cord injury. These findings showed that PC-BDNF has a better potential than BDNF for promoting neural differentiation, partly due to a higher cellular affinity. Furthermore, PC-BDNF-treated cells could be useful for transplantation therapy for central nervous system injuries.     

Central actions of angiotensin II on spontaneous baroreflex sensitivity in the trout Onc orhynchus mykiss

The goal of the present study was to investigate the central action of native angiotensin II (ANG II) on the spontaneous baroreflex sensitivity (BRS) in unanesthetized trout. The animals were equipped with two subcutaneous electrocardiographic (ECG) electrodes, a dorsal aorta catheter and an intracerebroventricular (ICV) cannula which was inserted within the third ventricle of the brain. The ECG and the systolic blood pressure (SBP) signals were recorded during a pre-injection period of 5 min and during five post-injection periods of 5 min. All injections were made at the fifth minute of the test. The time-series were processed with a sequence technique in order to detect the sequences of three or more consecutive increases in the SBP pulse, or three or more decreases in the SBP pulse correlated respectively with one delay beat increase of the RR interval of the ECG signal or shortening of this interval. The slope of the average regression line between the SBP and the RR intervals for each type of sequence was taken as a measure of the spontaneous BRS. Compared with pre-injection values, the ICV injection of vehicle (0.5 microl) had no effect on heart rate (HR), SBP, the total number of positive or negative sequences or on the spontaneous BRS during the post-injection periods. By contrast, ANG II at doses of 5 and 50 pmol increased HR but only 50 pmol ANG II elevated SBP. For all doses, ANG II depressed the spontaneous BRS, but the peptide had no effect upon the number of each baroreflex sequences. Intra-arterial injections of atropine dramatically reduced the number of positive and negative baroreflex sequences and decreased the sensitivity of the few remaining sequences, suggesting that the autonomic control of the cardiac BRS was solely due to vagal parasympathetic control. In atropinized trout the ICV injection of 5 pmol ANG II had no effect upon HR, SBP and the baroreflex parameters. This study determines for the first time the spontaneous BRS in a non-mammalian species and demonstrates an inhibitory action of ICV injection of ANG II upon this variable through a probable control of the vagal parasympathetic activity.     

Attenuated autonomic function in multiple organ dysfunction syndrome across three age groups.

Multiple organ dysfunction syndrome (MODS) is the failure of several organs after a trigger event. The mortality is high, at up to 70%. We hypothesize that autonomic dysfunction may substantially contribute to the development of MODS and speculate that there is an age dependence of autonomic dysfunction in MODS. A total of 90 consecutively admitted MODS patients were assigned to this study. Three variables of autonomic function were analyzed: heart rate variability (HRV), baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS). The patient cohort was divided into three age groups. The main finding was that BRS, CRS and almost all indices of HRV were attenuated in comparison to normal range data and there was no age dependence for HRV indices or CRS, but there was for BRS. In conclusion, autonomic function in MODS is attenuated. The influence of MODS on autonomic function overwhelms the age dependence of autonomic function observed in healthy subjects.     

Arterial baroreflex function is an important determinant of acute cerebral ischemia in rats with middle cerebral artery occlusion

AIMS: To clarify whether arterial baroreflex function is an important determinant of acute cerebral ischemia in rats. MAIN METHODS: Three animal models were used in this study. In the first, saponin conjugated with substance P (SP-SAP) was injected into the nucleus tractus solitarii (NTS) of Sprague-Dawley (SD) rats to block the central baroreflex arc. In the second model, sinoaortic denervation (SAD) was performed to destroy the peripheral baroreflex arc in SD rats. In the third model, SD rats were divided into two groups according to their naturally occurring BRS values. After determining hemodynamic indexes and baroreflex sensitivity (BRS), we subjected the animals to middle cerebral artery (MCA) occlusion. Levels of interleukin (IL)-1beta and IL-6 were detected both in SAD/sham operation groups and low/high BRS groups. KEY FINDINGS: In all three animal models, baroreflex dysfunction significantly increased the infarct volume and weight. The levels of inflammatory factors were markedly elevated in SAD and low BRS groups. SIGNIFICANCE: These results demonstrate that the function of arterial baroreflex is an important determinant of acute cerebral ischemia in rats with MCA occlusion. Inflammation might be an important mechanism for the arterial baroreflex dysfunction-induced increase in brain damage in rats with MCA occlusion.     

Autonomic control of the respiratory-hemodynamic system in 8-to 11-year-old children with different baroreflex sensitivities

The efficiency of baroreflex control depends on the baroreflex sensitivity (BRS), which is defined as the ratio of the change in the heart rate (HR) to the change in the blood pressure (BP). The BRS value may be used for assessing the autonomic control of the cardiovascular system and the degree of autonomic dysfunction. Until recently, the baroreflex had not been assessed in a large population of healthy subjects. In this study, the BRS was estimated by the ratio of the low-frequency component of the HR spectrum and the low-frequency component of the rhythm of the systolic BP. For assessing the arterial baroreflex in children, the BRSs for spontaneous and induced baroreflexes were compared. Sex-and age-related differences in BRS were found in 8-to-11-year-old children, and correlations between BRS and some spectral components of HR variability (HRV) and BP rhythm variability were determined. Cluster analysis of the BRS calculated for the spontaneous baroreflex at rest was used to distinguish three clusters of subjects (with high, medium, and low BRSs). These clusters differed in the variability of the basic parameter and size and showed sex-related differences.     

Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system

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(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(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(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.     

Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats

An early dietary intervention in the form of a high-carbohydrate (HC) milk formula in neonatal rat pups results in immediate onset of hyperinsulinemia. While increased insulin secretion in HC rats has been shown to be related to hypersensitivity to glucose, the immediate onset of hyperinsulinemia and its persistence throughout the suckling period suggest involvement of multiple systems that enhance insulin secretion in response to increased demand. Evidence presented here in 12-day-old HC rats indicates that altered activity of the autonomic nervous system contributes to enhanced insulin secretory responses to glucose stimulation through increased parasympathetic and decreased sympathetic signaling. Both in vivo and in vitro studies have shown that HC rats secrete significantly higher levels of insulin in response to glucose in the presence of acetylcholine, a cholinergic agonist, while sensitivity to inhibition of insulin secretion by oxymetazoline, an alpha(2a)-adrenergic receptor (alpha(2a)AR) agonist, was reduced. In addition, HC rats showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic type 3 receptor (M3R) antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide, as well as increased potentiation of glucose-stimulated insulin secretion by treatment with yohimbine. Increases in islets levels of M3R, phospholipase C-beta1, and protein kinase Calpha mRNAs, as well as decreased alpha(2a)AR mRNA, in 12-day-old HC rats provide a mechanistic connection to the changes in insulin secretion seen in HC rats. In conclusion, altered autonomic regulation of insulin secretion, due to the HC nutritional intervention, contributes to the development of hyperinsulinemia in 12-day-old HC rats.     

Time course analysis of baroreflex sensitivity during postural stress

Postural stress requires immediate autonomic nervous action to maintain blood pressure. We determined time-domain cardiac baroreflex sensitivity (BRS) and time delay (tau) between systolic blood pressure and interbeat interval variations during stepwise changes in the angle of vertical body axis (alpha). The assumption was that with increasing postural stress, BRS becomes attenuated, accompanied by a shift in tau toward higher values. In 10 healthy young volunteers, alpha included 20 degrees head-down tilt (-20 degrees), supine (0 degree), 30 and 70 degrees head-up tilt (30 degrees, 70 degrees), and free standing (90 degrees). Noninvasive blood pressures were analyzed over 6-min periods before and after each change in alpha. The BRS was determined by frequency-domain analysis and with xBRS, a cross-correlation time-domain method. On average, between 28 (-20 degrees) to 45 (90 degrees) xBRS estimates per minute became available. Following a change in alpha, xBRS reached a different mean level in the first minute in 78% of the cases and in 93% after 6 min. With increasing alpha, BRS decreased: BRS = -10.1.sin(alpha) + 18.7 (r(2) = 0.99) with tight correlation between xBRS and cross-spectral gain (r(2) approximately 0.97). Delay tau shifted toward higher values. In conclusion, in healthy subjects the sensitivity of the cardiac baroreflex obtained from time domain decreases linearly with sin(alpha), and the start of baroreflex adaptation to a physiological perturbation like postural stress occurs rapidly. The decreases of BRS and reduction of short tau may be the result of reduced vagal activity with increasing alpha.     

Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

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 Cbeta1, and protein kinase C-alpha and decreased levels of alpha(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.     

Phenotypic screening for heart rate variability in the mouse

We developed a technology for heart rate (HR) variability (HRV) analysis in the mouse for characterization of HR dynamics, modulated by vagal and sympathetic activity. The mouse is the principal animal model for studying biological processes. Mouse strains are now available harboring gene mutations providing fundamental insights into molecular mechanisms underlying cardiac electrical diseases. Future progress depends on enhanced understanding of these fundamental mechanisms and the implementation of methods for the functional analysis of mouse cardiovascular physiology. By telemetric techniques, standard time and frequency-domain measures of HRV were computed with and without autonomic blockade, and baroreflex sensitivity testing was performed. HR modulation in the high-frequency component is predominantly mediated by the parasympathetic nervous system, whereas the low-frequency component is under the influence of both the parasympathetic and sympathetic systems. The presented technology and protocol allow for assessment of autonomic regulation of the murine HR. Phenotypic screening for HR regulation in mice will further enhance the value of the mouse as a model of heritable electrophysiological human disease.     

Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation.

Cardiovascular autonomic modulation during 36 h of total sleep deprivation (SD) was assessed in 18 normal subjects (16 men, 2 women, 26.0 +/- 4.6 yr old). ECG and continuous blood pressure (BP) from radial artery tonometry were obtained at 2100 on the first study night (baseline) and every subsequent 12 h of SD. Each measurement period included resting supine, seated, and seated performing computerized tasks and measured vigilance and executive function. Subjects were not supine in the periods between measurements. Spectral analysis of heart rate variability (HRV) and BP variability (BPV) was computed for cardiac parasympathetic modulation [high-frequency power (HF)], sympathetic modulation [low-frequency power (LF)], sympathovagal balance (LF/HF power of R-R variability), and BPV sympathetic modulation (at LF). All spectral data were expressed in normalized units [(total power of the components/total power-very LF) x 100]. Spontaneous baroreflex sensitivity (BRS), based on systolic BP and pulse interval powers, was also measured. Supine and sitting, BPV LF was significantly increased from baseline at 12, 24, and 36 h of SD. Sitting, HRV LF was increased at 12 and 24 h of SD, HRV HF was decreased at 12 h SD, and HRV LF/HF power of R-R variability was increased at 12 h of SD. BRS was decreased at 24 h of SD supine and seated. During the simple reaction time task (vigilance testing), the significantly increased sympathetic and decreased parasympathetic cardiac modulation and BRS extended through 36 h of SD. In summary, acute SD was associated with increased sympathetic and decreased parasympathetic cardiovascular modulation and decreased BRS, most consistently in the seated position and during simple reaction-time testing.     

Selective quantification of the cardiac sympathetic and parasympathetic nervous systems by multisignal analysis of cardiorespiratory variability

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-->HR) and fluctuations in ABP to HR (ABP-->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-->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.