Adrenergic Tone Research Articles

Depressive symptoms predict recurrence of atrial fibrillation after cardioversion

Objective The aim of this study was to evaluate whether depressive symptoms and the type-D personality are predictive of early recurrence of atrial fibrillation (or atrial flutter; AF) after successful electrical cardioversion (CV). Background Depressive symptoms are associated with an adverse prognosis in patients with coronary artery disease, congestive heart failure, and ventricular arrhythmias. Anger and hostility have been shown to be predictive of development of AF. However, little is known about the effects of depression on AF. Methods Fifty-four patients with persistent AF completed the Hospital Anxiety and Depression Scale (HADS) and the Type D Scale (DS-14) prior to elective electrical CV. Patients with a successful CV were followed for 2 months. Results During the follow-up period, 27 patients (50%) had recurrence of the arrhythmia. Depressive mood (HADS depression scale >7) was the only significant nonsomatic predictor of recurrence, which was observed in 85% of depressed versus 39% of nondepressed patients [odds ratio=8.6; 95% confidence interval (CI)=1.7–44.0, P=.004]. HADS anxiety scores and the presence of the type-D personality pattern were not associated with recurrence of AF. On multivariate Cox regression analysis, including variables with a prevalence >10% of the total study population and a univariate discriminative effect yielding a P value of <.2, a HADS depression score >7 was found to be the only independently predictive variable of arrhythmia recurrence (hazard ratio=2.7; 95% CI=1.05–7.2; P=.046). Conclusions Our results indicate that depressive mood is a major risk factor for recurrence of AF after electrical CV. Heightened adrenergic tone and a proinflammatory state are possible mechanisms responsible for the observed association. Identification of depression may be of value prior to the decision to perform electrical CV.

Regulation of [Ca 2+] i oscillations in mouse pancreatic islets by adrenergic agonists

[Ca 2+] i oscillations are an important cellular signal in glucose-induced insulin secretion. Isolated mouse pancreatic islets show a high degree of synchronization in their oscillatory pattern. Our comprehensive analysis revealed that 63% of the islets exhibited glucose-induced oscillations with low frequency (⩽0.5/min) and 37% with high frequency (>0.5/min). The catecholamines adrenaline and noradrenaline as well as clonidine, all known to inhibit insulin secretion, were studied for their ability to modulate the glucose-induced slow large amplitude [Ca 2+] i oscillations. All three adrenergic agonists reduced the frequency of the glucose-induced [Ca 2+] i oscillations in islets with glucose-induced high frequency [Ca 2+] i oscillations, but not in islets, in which glucose induced low frequency [Ca 2+] i oscillations. This effect of catecholamines is likely to be mediated via α 2-adrenoceptors, as supported by the observation that the agonistic effect could be antagonized by yohimbine, a selective α 2-adrenoceptor antagonist. Thus, whether an individual islet responds to glucose stimulation with high or low frequency [Ca 2+] i oscillations appears to be determined at least in part by the adrenergic tone. Furthermore, we could show that glucagon as well as IBMX and forskolin indeed significantly increased the frequency of the glucose-induced [Ca 2+] i oscillations. These results support a cAMP mediated regulation and indicate that glucagon release from pancreatic α-cells acts in a paracrine fashion as a modulator of glucose-induced [Ca 2+] i oscillations in mouse pancreatic islets.

Yohimbine Attenuates Baroreflex-Mediated Bradycardia in Humans

Alpha-2 adrenoreceptor stimulation profoundly augments baroreflex-mediated bradycardia presumably through parasympathetic activation. We tested the hypothesis that endogenous alpha-2 adrenergic tone mediates a similar response. In 10 healthy men (age: 33+/-3 years; body mass index: 24+/-1.3 kg/m(2)), we determined baroreflex control of heart rate and sympathetic traffic after ingestion of the selective alpha-2 adrenoceptor antagonist yohimbine (20 mg) or placebo. Testing was conducted in a randomized, double-blind, crossover fashion. We measured heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity. Sympathetic and parasympathetic baroreflex curves were determined using incremental phenylephrine and nitroprusside infusions (0.3, 0.6, 0.9, 1.2, and 1.5 microg/kg per minute). Plasma norepinephrine increased with yohimbine (50+/-38 ng/L; P<0.05) and was unchanged with placebo (2.2+/-7.6 ng/L). Blood pressure increased 13+/-4/8+/-1 mm Hg with yohimbine and 6+/-2/3+/-1 mm Hg with placebo (P<0.01). HR increased 5+/-1 bpm with yohimbine but did not change with placebo (P<0.01). Ninety minutes after drug ingestion, resting muscle sympathetic nerve activity was similar with yohimbine and with placebo. Baroreflex control of heart rate was decreased with yohimbine (6 ms/mm Hg versus 10 ms/mm Hg; P<0.01) and reset to higher blood pressure and heart rate values. In contrast, yohimbine did not alter the sympathetic baroreflex curve. Yohimbine selectively attenuates baroreflex heart rate control in normotensive young men possibly through parasympathetic mechanisms.

Amiodarone for Atrial Fibrillation Following Cardiac Surgery: Development of Clinical Practice Guidelines at a University Hospital

Atrial fibrillation (AF) usually develops within the first 72 h following cardiac surgery, and is often self-limiting. Within 48 h of acute onset of symptoms, approximately 50% of patients spontaneously convert to normal sinus rhythm. Thus, the relative risks and benefits of therapy must be carefully considered. The etiology of AF following cardiac surgery is similar to that in non-surgical patients except that pericardial inflammation and increased adrenergic tone play an increasingly important role. Further, AF after surgery may be associated with transient risk factors that resolve as the patient moves out from surgery, and the condition is less likely to recur compared to AF arising in other circumstances. Immediate heart rate control is important in preventing ischemia, tachycardia-induced cardiomyopathy, and left ventricular dilatation. At our institution, amiodarone is frequently used as a first-line drug for treating AF after cardiac surgery. Inconsistent prescribing practices, variable dosage regimens, and a lack of consensus regarding the appropriate use of amiodarone prompted the need for developing practice guidelines. Multidisciplinary collaboration between the departments of cardiac surgery, pharmacy, and anesthesiology led to the development of a protocol for postoperative AF. We review the clinical evidence from published trials and discuss our guidelines, defining amiodarone use for AF in the cardiac surgery setting.

Advances in the development of hormonal modulators for the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a leading disorder of the ageing male population and is characterized by a progressive enlargement of the prostate, resulting in the obstruction of the proximal urethra and hence the disturbance in normal urinary flow and further quality of life of the patients. Therefore, there is an imperative need to develop a therapeutic modality to combat the overgrowth of the prostate with improvements in both the urinary flow rate and the quality of life of the patients. At present, α-blockers, which act on the dynamic component of the disease to regulate the increased adrenergic tone of the lower urinary tract smooth muscles, and 5-α-reductase inhibitors, which control the overgrowth of the prostate and hence static component by regulating the levels of androgens, are the mainstay of therapies for the treatment of BPH and associated lower urinary tract symptoms. However, each target class has its own limitations in terms of compromised efficacy or tolerability. Therefore, it is pertinent to have an effective and safe therapeutic modality for the further improvement of life of the geriatric male population. Hormone modulators, which regulate the overgrowth of the prostate, represent one of the important categories that have been explored and that is still undergoing certain investigations towards the development of a therapeutic entity for the treatment of BPH. The key lies in achieving the differentiation in terms of improved tolerability with comparable or better efficacy over the existing class of drugs. Gonadotropin receptor modulators and vitamin D receptor agonists may represent promising druggable targets in this therapeutic area, due to the availability of proof of principles and concepts in preclinical animal models and human subjects.

Daytime sympathetic hyperactivity in OSAS is related to excessive daytime sleepiness

The aim of this study was to investigate the relationships among sympathetic hyperactivity, excessive daytime sleepiness (EDS) and hypertension in obstructive sleep apnoea syndrome (OSAS). Ten newly diagnosed OSAS patients with untreated EDS and daytime hypertension underwent polysomnography (PSG) and daytime measurements of plasma noradrenaline (NA), ambulatory blood pressure (BP), muscle sympathetic nerve activity (MSNA) by microneurography and objective assessment of EDS before and during 6 months of compliance-monitored continuous positive airway pressure (CPAP) treatment. One month after the start of CPAP, BP, MSNA and NA were significantly lowered, remaining lower than baseline also after 3 and 6 months of treatment. CPAP use caused a significant improvement of sleep structures, and reduced EDS. A statistical correlation analysis demonstrated that EDS was not correlated with sleep measures obtained from baseline PSG (% sleep stages, apnoea and arousal index, mean oxygen saturation value), whereas daytime sleepiness was significantly correlated with MSNA. Furthermore, MSNA and BP showed no correlation. Our data obtained from selected patients suggest that the mechanisms inducing EDS in OSAS are related to the degree of daytime sympathetic hyperactivity. Additionally, resting MSNA was unrelated to BP suggesting that factors other than adrenergic neural tone make a major contribution to OSAS-related hypertension. The results obtained in this pilot study need, however, to be confirmed in a larger study involving more patients.

Hypothalamic angiotensinergic–noradrenergic systems interaction in fructose induced hypertension

Objective Several studies suggest the importance of the interaction between the renin angiotensin and sympathetic nervous systems in blood pressure control, especially in clinical situations such as the metabolic syndrome. Previously, we have demonstrated changes in noradrenergic hypothalamic control of blood pressure in an animal model of insulin resistance and hypertension. The aim of the present study was to evaluate the effects of the interaction between the noradrenergic and angiotensinergic systems on hypothalamic blood pressure regulation in fructose hypertensive rats. Methods In control (C) and fructose-fed hypertensive (F) rats, we studied: 1) the effects of hypothalamic perfusion of irbesartan (AT 1 angiotensin receptor antagonist, 50 and 500 μg ml − 1) and metoprolol (β 1 adrenergic receptor antagonist, 10 and 100 μg ml − 1) on blood pressure, heart rate and noradrenaline intrahypothalamic levels, by means of the microdialysis technique; and 2) the effects of intrahypothalamic microinjection of angiotensin II alone or after metoprolol pre-administration, on blood pressure and heart rate. Results Meanwhile irbesartan perfusion did not modify neither mean arterial pressure (MAP) nor heart rate or noradrenaline hypothalamic levels in the C group, its highest dose diminished MAP (ΔMAP: F: − 16.3 ± 1 mm Hg, p < 0.05) and noradrenaline levels (% of basal levels: 58 ± 7%, p < 0.05) in the F group, without affecting heart rate. Intrahypothalamic perfusion of metoprolol diminished MAP only in the F group (ΔMAP: F: − 12.1 ± 1.1 mm Hg, p < 0.05), but did not modify heart rate in both groups. On the other hand, it diminished noradrenaline hypothalamic levels in C (% of basal levels: 53 ± 6%, p < 0.05) but not in the F group. The pressor response to angiotensin II microinjection was increased in F rats (ΔMAP: F: 13.3 ± 1.5 mm Hg vs. C: 6.9 ± 1.8 mm Hg; p < 0.05). Previous administration of metoprolol markedly abolished this increment. Conclusions Our results suggest the existence of an increase in AT 1 and β 1 adrenergic receptors tone in the hypothalamus of F rats, which could be related to the increase in blood pressure present in this experimental model. On the other hand, considering that the enhanced pressor response to angiotensin II intrahypothalamic injection in F rats was abolished by previous administration of a β 1 adrenergic receptor antagonist, these results would indicate that β 1 adrenergic receptors activation participates in the pressor response to angiotensin II in this experimental model of insulin resistance and hypertension.

Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by the absence of structural heart disease, syncope, and sudden cardiac death.1 Typically, acceleration of the heart rate during physical exercise or emotional distress provokes an increasing number of ventricular premature complexes followed by runs of bidirectional or polymorphic ventricular tachycardia (VT). During clinical testing, about 30–50% of the patients will reproducibly develop VT following exercise testing or catecholamine injection.1,2 The ECG morphology of ventricular tachyarrhythmias observed in patients with CPVT resembles that of VTs commonly described in digitalis toxicity (which is associated with cellular calcium overload), and in metabolic disturbances as seen in severe HF (which is associated with high adrenergic tone).3 In conditions of cytoplasmic Ca2+ overload or enhanced β-adrenergic signalling, cardiac myocytes exhibit greater ectopic activity. It has therefore been suggested that arrhythmias in CPVT are mediated by triggered activity and delayed afterdepolarizations (DADs), which are defined as oscillations in the membrane potential of the cardiac myocyte after repolarization of an action potential has been completed.1 The most common, autosomal-dominant form of CPVT is caused by genetic mutations in the gene encoding the cardiac ryanodine receptor ( RyR2 ), the principal intracellular Ca2+ release channel involved in excitation-contraction coupling.4 Although experimental studies have provided evidence that mutant RyR2 channels can give rise to DADs in isolated cardiomyocytes,5 the study by Paavola et al .6 demonstrates DADs in monophasic action potential (MAP) recordings for the first time in CPVT patients with RyR2 mutations. In contrast to conventional electrode catheter recordings, MAP recordings provide precise information not only about the local activation time, but also about the entire repolarization time course. Electrophysiological data for the occurrence of DADs in patients with CPVT have been scarce in the literature, with … *Corresponding author. Tel: +1 713 798 4261; fax: +1 713 798 3475. E-mail address : wehrens{at}bcm.edu

An Afferent Vagal Nerve Pathway Links Hepatic PPARα Activation to Glucocorticoid-Induced Insulin Resistance and Hypertension

Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvate carboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara(+/+) mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARalpha null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension.

Sympathetic overactivity and arrhythmias in tetanus: electrocardiographic analysis

As a result of the advances in the control of pulmonary insufficiency in tetanus, the cardiovascular system has increasingly been shown to be a determining factor in morbidity and mortality but detailed knowledge of the cardiovascular complications in tetanus is scanty. The 24h-Holter was carried out in order to detect arrhythmias and sympathetic overactivity in 38 tetanus patients admitted to an ICU. The SDNN Index (standard deviation from the normal R-to-R intervals), was useful in detecting adrenergic tonus, and ranged from 64.1 +/- 27 in the more severe forms of tetanus to 125 +/- 69 in the milder ones. Sympathetic overactivity occurred in 86.2% of the more severe forms of the disease, but was also detected in 33% of the milder forms. Half the patients had their sympathetic overactivity detected only by the Holter. The most frequent arrhythmias were isolated supraventricular (55.2%) and ventricular (39.4%) extrasystoles. There was no association of the arrhythmias with the clinical form of tetanus or with the presence of sympathetic overactivity. The present study demonstrated that major cardiovascular dysfunction, particularly sympathetic overactivity, occurs in all forms of tetanus, even in the milder ones. This has not been effectively detected with traditional monitoring in ICU and may not be properly treated.

Relation between Adrenergic Tone, Insulin Resistance and Left Ventricular Hypertrophy in Human Obesity

Relation between Adrenergic Tone, Insulin Resistance and Left Ventricular Hypertrophy in Human Obesity

Rat strain-related differences in myocardial adrenergic tone and the impact on cardiac fibrosis, adrenergic responsiveness and myocardial structure and function

Sprague–Dawley (SD) rats have been reported to have a higher sympathetic activity than Wistar–Kyoto (WKY) rats. In the present study we sought to determine if these rat strain-related differences in sympathetic activity exist at a myocardial level and whether they translate into changes in cardiac fibrosis, contractile responsiveness to adrenergic agonists, and cardiac structure and function. Coronary effluent noradrenaline concentrations, as determined in isolated, perfused heart preparations, were higher in 5-month-old SD as compared to age-matched WKY male rats. This difference was accompanied by higher resting heart rates in SD rats as assessed in vivo. However, increases in myocardial noradrenaline release in SD rats did not translate into enhanced myocardial fibrosis, cardiac hypertrophy or remodeling, changes in basal ventricular systolic and diastolic function, or to down-regulation of inotropic responses to the β-adrenoreceptor agonists, noradrenaline, isoproterenol and dobutamine. Although age-matched male SD rats were heavier, no differences in absolute heart weights were noted between rat strains. Moreover, left ventricular (LV) posterior wall thickness as assessed by echocardiography, as well as cardiac myocyte dimensions as determined by laser scanning confocal microscopy were similar between rat strains. Furthermore, LV internal diameters as determined in vivo, as well as LV diastolic volume intercept determined in isolated, perfused heart preparations were similar between rat strains. Increases in myocardial noradrenaline release in SD rats also did not translate into differences in LV systolic chamber and myocardial function as assessed in vivo (LV endocardial and midwall fractional shortening) and at controlled loads and heart rates ex vivo (the slope of the LV developed pressure–volume relation determined). Likewise, neither myocardial hydroxyproline content nor LV chamber stiffness as assessed by the slope of the LV end-diastolic pressure–volume relation were different in SD and WKY rats. In conclusion, rat strain-related differences in cardiac adrenergic tone do indeed exist, but in young animals these differences do not translate into cardiac phenotypes known to contribute to progressive cardiac dysfunction.

Vascular function in the metabolic syndrome and the effects on skeletal muscle perfusion: lessons from the obese Zucker rat

The increased prevalence of obesity in Western society has been well established for many years, and with this trend, the prevalence of other associated pathologies including insulin resistance, dyslipidaemia, hypertension and the genesis of a proinflammatory and prothrombotic environment within individuals is also rapidly increasing, resulting in a condition known as the~metabolic syndrome. From a physiological perspective, one of the most severe consequences of the metabolic syndrome is a progressive inability of the cardiovascular system to adequately perfuse tissues and organs during either elevated metabolic demand and, if sufficiently severe, under basal levels of demand. For the study of the metabolic syndrome, the OZR (obese Zucker rat) represents an important tool in this effort, as the metabolic syndrome in these animals results from a chronic hyperphagia, and thus can be an excellent representation of the human condition. As in afflicted humans, OZR experience an attenuated functional and reactive hyperaemia, and can ultimately experience an ischaemic condition in their skeletal muscles at rest. The source of this progressive ischaemia appears to lie at multiple sites, as endothelium-dependent vasodilator responses are strongly impaired in OZR, and specific constrictor processes (e.g. adrenergic tone) may be enhanced. Whilst these active processes may contribute to a reduction in blood flow under resting conditions or with mild elevations in metabolic demand, an evolving structural alteration to individual microvessels (reduced distensibility) and microvascular networks (reduced microvessel density) also develop and may act to constrain perfusion at higher levels of metabolic demand. Given that constrained muscle perfusion in the metabolic syndrome appears to reflect a highly integrated, multi-faceted effect in OZR, and probably in humans as well, therapeutic interventions must be designed to address each of these contributing elements.

Acetylcholinesterase Inhibition in Patients With Orthostatic Intolerance

The efficacy of current therapeutic measures in orthostatic intolerance (OI) varies among patients and is oftentimes unsatisfactory. New approaches to alleviate symptoms of OI are therefore clearly needed. Recent reports have demonstrated that acetylcholinesterase inhibition is effective in the treatment of orthostatic hypotension with the presumed mechanism of enhancing sympathetic ganglionic transmission. Based on the hypothesis that acetylcholinesterase inhibition, by improving the safety factor of cholinergic transmission, will result in enhanced vascular adrenergic tone and a vagal shift in cardiac sympathovagal balance, we evaluated the role of acetylcholinesterase inhibition in the treatment of patients with OI. We monitored heart rate (HR), blood pressure, and indexes for cardiac output, end-diastolic volume, and systemic resistance continuously in 18 patients with OI during supine rest and during 5 minutes of 70 degrees head-up tilt before and 1 hour after oral administration of 60 mg pyridostigmine. Plasma catecholamines and baroreflex sensitivity were determined for the supine and upright position before and after medication. Patients scored orthostatic symptoms for both tilt studies. The excessive HR response to orthostatic stress was significantly blunted after pyridostigmine administration. HR was significantly lower in the supine and more so in the upright position. Baroreflex sensitivity in the upright position was significantly higher after pyridostigmine. Norepinephrine was increased in both supine and upright position. These changes were associated with significant improvement of orthostatic symptoms. We conclude that pyridostigmine improves orthostatic tolerance in patients with OI. Our findings support the suggested mechanisms of enhanced sympathetic ganglionic neurotransmission and a vagal shift in cardiac sympathovagal balance. Acetylcholinesterase inhibition could be a new useful concept in the treatment of OI.

GNB3 TT Genotype Predicts Enhanced Benefit of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine in African Americans with Heart Failure: Results of the A-HeFT Trial

The G protein beta 3-subunit (GNB3) plays an important role in alpha adrenergic signaling. A common polymorphism (C825T) exists in exon 10. The T haplotype is linked to a splicing variant which results in enhanced alpha adrenergic tone and is more prevalent in African Americans than in whites. We examined the impact of the GNB3 T haplotype on heart failure (HF) outcomes and the effect of therapy with isosorbide dinitrate and hydralazine (I-H) for subjects in the African American Heart Failure Trial (A-HeFT).

Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo

Inhibition of the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) or depletion of sarcoplasmic reticulum (SR) Ca(2+) stores protects against apoptosis from excessive isoproterenol (Iso) stimulation in cultured ventricular myocytes, suggesting that CaMKII inhibition could be a novel approach to reducing cell death in conditions of increased adrenergic tone, such as myocardial infarction (MI), in vivo. We used mice with genetic myocardial CaMKII inhibition due to transgenic expression of a highly specific CaMKII inhibitory peptide (AC3-I) to test whether CaMKII was important for apoptosis in vivo. A second line of mice expressed a scrambled, inactive form of AC3-I (AC3-C). AC3-C and wild-type (WT) littermates were used as controls. AC3-I mice have reduced SR Ca(2+) content and are resistant to Iso- and MI-induced apoptosis compared with AC3-C and WT mice. Phospholamban (PLN) is a target for modulation of SR Ca(2+) content by CaMKII. PLN(-/-) mice have increased susceptibility to Iso-induced apoptosis. Verapamil pretreatment prevented Iso-induced apoptosis in PLN(-/-) mice, indicating the involvement of a Ca(2+)-dependent pathway. AC3-I and AC3-C mice were bred into a PLN(-/-) background. Loss of PLN increased and equalized SR Ca(2+) content in AC3-I, AC3-C, and WT mice and abolished the resistance to apoptosis in AC3-I mice after MI. There was a trend (P = 0.07) for increased Iso-induced apoptosis in AC3-I mice lacking PLN compared with AC3-I mice with PLN. These findings indicate CaMKII is proapoptotic in vivo and suggest that regulation of SR Ca(2+) content by PLN contributes to the antiapoptotic mechanism of CaMKII inhibition.

Mechanisms of atrial tachyarrhythmia induction in a canine model of autonomic tone fluctuation

The purpose of this study was to investigate the effect of cholinergic modulation in the presence of increased adrenergic tone (i. e., autonomic fluctuation) on atrial tachyarrhythmia (AT) induction. High-resolution optical mapping was used to measure action potentials from the left atrium in isolated arterially perfused canine atrial preparations. Optical recordings were made in the presence of isoproterenol during electrical stimulation of a fat pad at the right pulmonary veinatrial junction (Group I, n = 6), during electrical stimulation of a fat pad locating the superior vena cava contacted by the right pulmonary artery (Group II, n = 4), and during acetylcholine (ACh; Group III, n = 4) infusion. In the presence of isoproterenol,each of the three different transitory cholinergic interventions induced spontaneous AT in all preparations. In Group I, AT induced from the right atrium was sustained. However, AT induced from the left atrium was not sustained (RRB) in Group I. In Groups II and III, AT induced from the left atrium as well as the right atrium were also sustained (BAF-AT). The A1A2 coupling interval was shorter when BAF-AT was induced than it was when RRB was induced. Mean cycle length of repetitive focal excitation was shorter during the initiation of BAF-AT compared to RRB. Isochrone maps during the initiation of AT demonstrated a macroreentry with lines of conduction block following a single extrasystole (27 %) and focal repetitive excitation (73 %). These results suggest that transitory cholinergic activation in the presence of increased adrenergic drive in the left atrium causes a single premature extrasystole with a short coupling interval and a focal repetitive excitation with a short cycle length, which favors the generation of AT originating from the left atrium.

Evidence for a respiratory component, similar to mammalian respiratory sinus arrhythmia, in the heart rate variability signal from the rattlesnake,Crotalus durissus terrificus

Autonomic control of heart rate variability and the central location of vagal preganglionic neurones (VPN) were examined in the rattlesnake (Crotalus durissus terrificus), in order to determine whether respiratory sinus arrhythmia (RSA) occurred in a similar manner to that described for mammals. Resting ECG signals were recorded in undisturbed snakes using miniature datalogging devices, and the presence of oscillations in heart rate (fh) was assessed by power spectral analysis (PSA). This mathematical technique provides a graphical output that enables the estimation of cardiac autonomic control by measuring periodic changes in the heart beat interval. At fh above 19 min(-1) spectra were mainly characterised by low frequency components, reflecting mainly adrenergic tonus on the heart. By contrast, at fh below 19 min(-1) spectra typically contained high frequency components, demonstrated to be cholinergic in origin. Snakes with a fh >19 min(-1) may therefore have insufficient cholinergic tonus and/or too high an adrenergic tonus acting upon the heart for respiratory sinus arrhythmia (RSA) to develop. A parallel study monitored fh simultaneously with the intraperitoneal pressures associated with lung inflation. Snakes with a fh<19 min(-1) exhibited a high frequency (HF) peak in the power spectrum, which correlated with ventilation rate (fv). Adrenergic blockade by propranolol infusion increased the variability of the ventilation cycle, and the oscillatory component of the fh spectrum broadened accordingly. Infusion of atropine to effect cholinergic blockade abolished this HF component, confirming a role for vagal control of the heart in matching fh and fv in the rattlesnake. A neuroanatomical study of the brainstem revealed two locations for vagal preganglionic neurones (VPN). This is consistent with the suggestion that generation of ventilatory components in the heart rate variability (HRV) signal are dependent on spatially distinct loci for cardiac VPN. Therefore, this study has demonstrated the presence of RSA in the HRV signal and a dual location for VPN in the rattlesnake. We suggest there to be a causal relationship between these two observations.

The Influence of Tidal Volume on the Dynamic Variables of Fluid Responsiveness in Critically Ill Patients

Respiratory-related variabilities in stroke volume and arterial pulse pressure (Delta%Pp) are proposed to predict fluid responsiveness. We investigated the influence of tidal volume (Vt) and adrenergic tone on these variables in mechanically ventilated patients. Cyclic changes in aortic velocity-time integrals (Delta%VTI(Ao), echocardiography) and Delta%Pp (catheter) were measured simultaneously before and after intravascular volume expansion, and Vt was randomly varied below and above its basal value. Intravascular volume expansion was performed by hydroxyethyl starch (100 mL, 60 s). Receiver operating characteristic curves were generated for Delta%VTI(Ao), Delta%Pp and left ventricle cross-sectional end-diastolic area (echocardiography), considering the change in stroke volume after intravascular volume expansion (> or =15%) as the response criterion. Covariance analysis was used to test the influence of Vt on Delta%VTI(Ao) and Delta%Pp. Twenty-one patients were prospectively included; 9 patients (43%) were responders to intravascular volume expansion. Delta%VTI(Ao) and Delta%Pp were higher in responders compared with nonresponders. Predictive values of Delta%VTI(Ao) and Delta%Pp were similar (threshold: 20.4% and 10.0%, respectively) and higher than that of left ventricle cross-sectional end-diastolic area at the appropriate level of Vt. Delta%Pp was slightly correlated with norepinephrine dosage. Delta%Pp increased with the increase in the level of Vt both before and after intravascular volume expansion, contrasting with an unexpected stability of Delta%VTI(Ao). In conclusion, Delta%VTI(Ao) and Delta%Pp are good predictors of intravascular fluid responsiveness but the divergent evolution of these two variables when Vt was increased needs further explanation.

Immersion of the hand in ice water releases adrenergic vasoconstrictor tone in the ipsilateral temple

Immersion of the hand in painfully cold water induces cutaneous vasodilatation in the temples, more so ipsilaterally than contralaterally. To investigate the mechanism of this response, guanethidine or saline was administered by transcutaneous iontophoresis to a recording site in the temple of ten participants before they immersed one of their hands in ice water. Guanethidine displaces noradrenaline from sympathetic nerve terminals and inhibits sympathetic noradrenergic neurotransmission. Therefore, it was hypothesized that guanethidine pre-treatment would block vasodilatation mediated by release of sympathetic vasoconstrictor tone in cutaneous vessels in the temple. During hand immersion, increases in the amplitude of the pulse waveform detected by laser Doppler flowmetry were greater in the ipsilateral than contralateral temple (86% vs. 34% above baseline, p < 0.05), and pre-treatment with guanethidine prevented this asymmetric response (ipsilateral response 21% above baseline and contralateral response 32%, difference not significant). Guanethidine also inhibited ipsilateral increases in cutaneous blood flow during hand immersion in responsive participants. These findings suggest that limb pain inhibited ipsilateral adrenergic vasoconstrictor outflow in the temple. Thus, the findings challenge the concept of the sympathetic nervous system as a “mass action” system that discharges in unison to meet environmental demands. Instead, they suggest that the sympathetic nervous system is highly differentiated, with separate control of discrete reflex pathways on each side of the body.