Increase In Sympathetic Outflow Research Articles

Heart or Mind? Unexplained Chest Pain in Patients with and Without Coronary Disease

Patients with unexplained chest pain continue to present a difficult challenge for clinicians, especially for cardiologists. Approximately 20% of patients undergoing diagnostic coronary arteriography for acute or chronic cardiac ischemia have angiographically normal coronary arteries. In these cases, patients with chest pain are usually reassured by their physician and other causes of substernal chest pain are searched. However, apart from a sizeable proportion of patients with gastroesophageal disorders, the remaining patients remain symptomatic without apparent reasons. The mechanism behind this phenomenon is likely to be the result of a combination of functional or anatomical abnormalities in the coronary microcirculation, a metabolic disorder which affects the handling of energy substrates by the heart, insulin resistance and neuropsychological components affecting pain perception. These patients often exhibit an increase in sympathetic outflow to the cardiovascular system, which might account for the reduction in coronary flow reserve, changes in metabolic utilization and development of insulin resistance that are seen in some of these patients. Therapeutically, beta-blockers appear to be most effective in controlling the symptoms associated with this condition, although those calcium antagonists which do not affect the neurohormonal system may be of some utility in patients with primary microvascular angina, in which microvascular spasm is operating or in whom excessive constriction of the distal component of the coronary circulation limits the vasodilatory reserve. This article reviews the clinical presentation, differential diagnosis, and approach to evaluation and therapy of this complex group of patients.

Abstract 022: mTORC1 is Required for the Cardiovascular but Not the Metabolic Actions of Leptin

Obesity represents a major risk factor for the development of hypertension, and inappropriate leptin action has been implicated as an essential mediator of obesity-associated hypertension. Leptin plays a critical role in energy homeostasis, acting through the brain to stimulate energy expenditure and suppress food intake. Leptin also increases sympathetic outflow to a variety of target organs, including those involved in blood pressure regulation. Here, we investigate the role of mTORC1 as a potential mediator of leptin’s cardiovascular and metabolic actions. For this, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb) expressing cells (LRb Cre /Rap fl/fl ). LRb Cre /Rap fl/fl displayed similar body weight, food intake and body composition as compared to littermate controls when fed a normal chow diet (body weight=29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Control and LRb Cre /Rap fl/fl mice also developed diet-induced obesity to a similar extent when fed either a 45% high-fat (37.2±3.1g g vs 40.9±2.2) or high-fat/high-sucrose diet (35.4±1.1g vs 35.2±2.7g). Additionally, fasting blood glucose (77.3±6.7mg/dL vs. 71.8±4.3mg/dL) as well as insulin (AUC=7788 ±1013, n=3 vs. 8964±884, n=4) and glucose (AUC=39750±2075, n=3 vs. 44259±1948, n=4) tolerance in high fat/high-sucrose diet fed mice were not changed in LRb Cre /Rap fl/fl mice as compared to littermate controls. Conversely, while baseline mean arterial pressure (MAP) was comparable between LRb Cre /Rap fl/fl mice (108±9 mmHg) and controls (103±7 mmHg), intracerebroventricular administration of leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRb Cre /Rap fl/fl mice (1±9 mmHg, P<0.05 vs controls). Consistent with this, LRb Cre /Rap fl/fl mice displayed a blunted renal sympathetic nerve response to leptin (-4±15%, n=9 vs. 127±16%, n=9, P<0.05) but a preserved increase in sympathetic outflow to brown adipose tissue (109±27%, n=5 vs. 173±52%, n=4). Together, our data indicate a critical role for mTORC1 in mediating the cardiovascular but not the metabolic effects of leptin.

Cyclical blood flow restriction resistance exercise: a potential parallel to remote ischemic preconditioning?

Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow due to greater activation of the exercise pressor reflex. Because of the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow [assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)] and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg press exercise interventions: 1) BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and 2) CE-65% 1RM without occlusion. Each condition consisted of 4 × 5-min cycles of exercise, with 3 × 10-reps in each cycle. Five minutes of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P < 0.001) and was 4-5 mmHg higher with CE versus BFRE (P ≤ 0.09). Mean MCAv also increased with exercise (P < 0.001) and was higher with CE compared with BFRE during the first bout of exercise only (P = 0.07). Plasma NE concentration increased with CE only (P < 0.001) and was higher than BFRE throughout exercise (P ≤ 0.02). The attenuated sympathetic response, combined with similar cerebrovascular responses, suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting.

Combining remote ischemic preconditioning and aerobic exercise: a novel adaptation of blood flow restriction exercise.

Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE) when performed at the same relative intensity. We also assessed the cerebrovascular responses due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% maximal heart rate with and without intermittent BFR (4 × 5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher concentration NE compared with CE (1249 ± 170 vs. 962 ± 114 pg/ml; P = 0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P = 0.33), and MAP was 4-5 mmHg lower with BFRE versus CE during the reperfusion periods (P ≤ 0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P ≥ 0.22), suggesting equivalent cerebrometabolic demand. The exaggerated sympathoexcitatory response with BFRE was not accompanied by higher MAP, likely because of the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac or stroke rehabilitation, where exercising patients could benefit from the cardio and cerebro protection associated with RIPC.

Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats.

Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho-vagal imbalance. Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood. We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre-sympathetic regions of the brainstem. Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho-vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF. Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho-vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague-Dawley rats (n=32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho-vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean±SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2±4.0 vs. 9.7±2.6eventsh-1 ), autonomic imbalance [0.6±0.2 vs. 0.2±0.1 low/high frequency heart rate variability (LF/HFHRV )] and cardiac arrhythmias (196.0±239.9 vs. 19.8±21.7eventsh-1 ). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6±43.2% vs. 296.0±43.9% LF/HFHRV , normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0±239.9 vs. 576.7±472.9eventsh-1 ) and diastolic dysfunction (0.008±0.004 vs. 0.027±0.027mmHgμl-1 ). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF.

Abstract WP157: Sympathetic and Cerebrovascular Responses to Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Introduction: Remote ischemic preconditioning (RIPC) is characterized by the cyclic application of limb blood flow restriction and reperfusion, and has been shown to protect the brain during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) is a novel training modality that similarly combines bouts of blood flow restriction and reperfusion with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with clinical application of BFRE is the potential for an augmented exercise pressor reflex, resulting in an unsafe rise in sympathetic outflow. Due to the use of lower workloads, however, we hypothesized that BFRE would exhibit an attenuated increase in sympathetic outflow, mean arterial pressure (MAP), and brain blood flow. Methods: 11 subjects (6M/5F; age 28±2 yrs) underwent 2 leg press exercise interventions separated by ≥1 month: 1. BFRE - 220 mmHg thigh occlusion during 4 cycles x 5-min of exercise, consisting of 3 x 10 reps at 20% of 1 rep-max (1RM), and; 2. Conventional exercise (CE) - 4 cycles x 5-min of exercise, consisting of 3 x 10 reps at 65% 1RM without occlusion. 5-min of rest and reperfusion (for BFRE) followed each cycle. MAP, mean middle cerebral artery velocity (MCAv), cerebral oxygen saturation (ScO 2 ), and plasma norepinephrine concentrations ([NE]) were compared between trials. Results: MAP increased with exercise under both conditions (P&lt;0.001) and was higher (P≤0.03) with CE vs. BFRE for each cycle (1. 107±3 vs. 103±2 mmHg, 2. 107±2 vs. 103±2 mmHg, 3. 107±2 vs. 103±2 mmHg, 4. 107±2 vs. 104±2 mmHg). MCAv and ScO 2 (N=10) increased over time (P&lt;0.001) with no difference between conditions for MCAv (P=0.83), while ScO 2 was higher for CE vs. BFRE (65±1 vs. 62±1%, P=0.05). Plasma [NE] (N=7) increased over time for both conditions (P=0.08) and was higher for CE vs. BFRE (757±103 vs. 524±71 pg/ml, P=0.09). Conclusions: BFRE elicited an attenuated sympathetic response compared to CE as evidenced by lower MAP and plasma [NE]. The lower ScO 2 (i.e., increased oxygen extraction) and no difference in MCAv responses suggests greater cerebral metabolic demand with BFRE. These findings indicate that BFRE could be explored as an alternative to CE in the clinical setting such as stroke-rehabilitation.

Neurovascular mechanisms underlying augmented cold-induced reflex cutaneous vasoconstriction in human hypertension.

In hypertensive adults (HTN), cardiovascular risk increases disproportionately during environmental cold exposure. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in HTN. The findings of the present study show that whole-body cold stress elicits greater increases in sympathetic outflow directed to the cutaneous vasculature and, correspondingly, greater reductions in skin blood flow in HTN. We further demonstrate an important role for non-adrenergic sympathetic co-transmitters in mediating the vasoconstrictor response to cold stress in hypertension. In the context of thermoregulation and the maintenance of core temperature, sympathetically-mediated control of the cutaneous vasculature is not only preserved, but also exaggerated in hypertension. Given the increasing prevalence of hypertension, clarifying the mechanistic underpinnings of hypertension-induced alterations in neurovascular function during cold exposure is clinically relevant. Despite ample evidence of dysregulated sympathetic control of the peripheral vasculature in hypertension, no studies have examined integrated neurovascular function during cold stress in hypertensive adults (HTN). We hypothesized that (i) whole-body cooling would elicit greater cutaneous vasoconstriction and greater increases in skin sympathetic nervous system activity (SSNA) in HTN (n=14; 56±2years) compared to age-matched normotensive adults (NTN; n=14; 55±2years) and (ii) augmented reflex vasoconstriction in HTN would be mediated by an increase in cutaneous vascular adrenergic sensitivity and a greater contribution of non-adrenergic sympathetic co-transmitters. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry; dorsum of foot) were measured during whole-body cooling (water-perfused suit). Sympathetic adrenergic- and non-adrenergic-dependent contributions to reflex cutaneous vasoconstriction and vascular adrenergic sensitivity were assessed pharmacologically using intradermal microdialysis. Cooling elicited greater increases in SSNA (NTN: +64±13%baseline vs. HTN: +194±26%baseline ; P<0.01) and greater reductions in skin blood flow (NTN: -16±2%baseline vs. HTN: -28±3%baseline ; P<0.01) in HTN compared to NTN, reflecting an increased response range for sympathetic reflex control of cutaneous vasoconstriction in HTN. Norepinephrine dose-response curves showed no HTN-related difference in cutaneous adrenergic sensitivity (logEC50 ; NTN: -7.4±0.3log Mvs. HTN: -7.5±0.3log M; P=0.84); however, non-adrenergic sympathetic co-transmitters mediated a significant portion of the vasoconstrictor response to cold stress in HTN. Collectively, these findings indicate that hypertension increases the peripheral cutaneous vasoconstrictor response to cold via greater increases in skin sympathetic outflow coupled with an increased reliance on non-adrenergic neurotransmitters.

Intracranial mechanisms for preserving brain blood flow in health and disease.

The brain is an exceptionally energetically demanding organ with little metabolic reserve, and multiple systems operate to protect and preserve the brain blood supply. But how does the brain sense its own perfusion? In this review, we discuss how the brain may harness the cardiovascular system to counter threats to cerebral perfusion sensed via intracranial pressure (ICP), cerebral oxygenation and ischaemia. Since the work of Cushing over 100years ago, the existence of brain baroreceptors capable of eliciting increases in sympathetic outflow and blood pressure has been hypothesized. In the clinic, this response has generally been thought to occur only in extremis, to perfuse the severely ischaemic brain as cerebral autoregulation fails. We review evidence that pressor responses may also occur with smaller, physiologically relevant increases in ICP. The incoming brain oxygen supply is closely monitored by the carotid chemoreceptors; however, hypoxia and other markers of ischaemia are also sensed intrinsically by astrocytes or other support cells within brain tissue itself and elicit reactive hyperaemia. Recent studies suggest that astrocytic oxygen signalling within the brainstem may directly affect sympathetic nerve activity and blood pressure. We speculate that local cerebral oxygen tension is a major determinant of the mean level of arterial pressure and discuss recent evidence that this may be the case. We conclude that intrinsic intra- and extra-cranial mechanisms sense and integrate information about hypoxia/ischaemia and ICP and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, to optimize cerebral perfusion.

Sympathetic Activation is Associated with Exercise Limitation in COPD

ABSTRACTExercise intolerance, skeletal muscle dysfunction, and reduced daily activity are central in COPD patients and closely related to quality of life and prognosis. Studies assessing muscle exercise have revealed an increase in sympathetic outflow as a link to muscle hypoperfusion and exercise limitation. Our primary hypothesis was that muscle sympathetic nerve activity (MSNA) correlates with exercise limitation in COPD.MSNA was evaluated at rest and during dynamic or static handgrip exercise. Additionally, we assessed heart rate, blood pressure, CO2 tension, oxygen saturation (SpO2), and breathing frequency. Ergospirometry was performed to evaluate exercise capacity.We assessed MSNA of 14 COPD patients and 8 controls. In patients, MSNA was negatively correlated with peak oxygen uptake (VO2% pred) (r = −0.597; p = 0.040). During dynamic or static handgrip exercise, patients exhibited a significant increase in MSNA, which was not observed in the control group. The increase in MSNA during dynamic handgrip was highly negatively correlated with peak exercise capacity in Watts (w) and peak oxygen uptake (VO2/kg) (r = −0.853; p = 0.002 and r = −0.881; p = 0.002, respectively).Our study reveals an association between increased MSNA and limited exercise capacity in patients with COPD. Furthermore, we found an increased sympathetic response to moderate physical exercise (handgrip), which may contribute to exercise intolerance in COPD.

Characteristics of renal sympathetic nerve single units in rabbits with angiotensin‐induced hypertension

We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors.

Putative Links Between Sleep Apnea and Cancer: From Hypotheses to Evolving Evidence

In recent years, the potentially adverse role of sleep-disordered breathing in cancer incidence and outcomes has emerged. In parallel, animal models of intermittent hypoxia (IH) and sleep fragmentation (SF) emulating the two major components of OSA have lent support to the notion that OSA may enhance the proliferative and invasive properties of solid tumors. Based on several lines of evidence, we propose that OSA-induced increases in sympathetic outflow and alterations in immune function are critically involved in modifying oncologic processes including angiogenesis. In this context, we suggest that OSA, via IH (and potentially SF), promotes changes in several signaling pathways and transcription factors that coordinate malignant transformation and expansion, disrupts host immunologic surveillance, and consequently leads to increased probability of oncogenesis, accelerated tumor proliferation, and invasion, ultimately resulting in adverse outcomes.

Obstructive sleep apnea and cardiovascular comorbidities: a large epidemiologic study.

Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic cessation of airflow for 10 seconds or more. There is growing awareness that OSA is related to the development and progression of cardiovascular disease. However, only a few studies have associated OSA directly to major cardiovascular events. The aim of this study was to evaluate the relationship between OSA and cardiovascular morbidity in a well defined population of patients.The electronic database of the central district of a major health management organization was searched for all patients diagnosed with OSA in 2002–2010. For each patient identified, an age- and sex-matched patient was randomly selected from the members of the same health management organization who did not have OSA. Data on demographics, socioeconomic status, and relevant medical parameters were collected as well.The study population included 2797 patients, average age 58.1, in which 76.6% were males. There was a significant correlation between OSA and the presence of ischemic heart disease (P < 0.001), pulmonary hypertension (P < 0.001), congestive heart failure (P < 0.001), cardiomyopathy (P = 0.003), and arrhythmia (P < 0.001). OSA was also significantly correlated with low socioeconomic status (P < 0.001).OSA and cardiovascular disease were strongly correlated. As such, early diagnosis and treatment of OSA may change the course of both diseases. We suggest that sleep disordered breathing should be routinely assessed in patients with cardiovascular problems. An ear–nose–throat evaluation may also be important to rule out anatomic disorders that cause upper airway obstruction.

Yes! Sex matters: sex, the brain and blood pressure.

The role of the brain in hypertension between the sexes is known to be important especially with regards to the effects of circulating sex hormones. A number of different brain regions important for regulation of sympathetic outflow and blood pressure express estrogen receptors (ERα and ERβ). Estradiol, acting predominantly via the ERα, inhibits angiotensin II activation of the area postrema and subfornical organ neurons and inhibits reactive oxygen generation that is required for the development of Angiotensin II-induced neurogenic hypertension. Estradiol activation of ERβ within the paraventricular nucleus and the rostral ventral lateral medulla inhibits these neurons and inhibits angiotensin II, or aldosterone induced increases in sympathetic outflow and hypertension. Understanding the cellular and molecular mechanisms underlying ERα and ERβ actions within key brain regions regulating blood pressure will be essential for the development of "next generation" selective estrogen receptor modulators (SERMS) that can be used clinically for the treatment of neurogenic hypertension.

Increases in sympathetic activity during cold pressor test does not cause cerebral vasoconstriction (1183.8)

The objective of this work was to determine whether increased sympathetic activity results in cerebral vasoconstriction. To assess the role of sympathetic activity, 10 healthy individuals participated in a cold pressor test in which they immersed their hand in ice cold water for 57.5±16.6 seconds. We continuously monitored beat‐by‐beat blood pressure, cerebral flow velocity in the middle (MCA) and anterior cerebral artery (ACA), common carotid artery (CCA) flow and end tidal CO2. As expected the cold pressor test produced a significant increase in sympathetic outflow causing mean arterial pressure to increase from 104±7 to 117±10 mmHg, P=0.005. In contrast CCA diameter did not change (6.7±0.2 to 6.7±0.2 mm), and flow increased slightly but non‐significantly (+6.0±6.2%). Similarly, we saw slight increases in flow velocity in the MCA (+3.0±6.7 %) and ACA (+7.5±4.9 %) but non‐significant. End tidal CO2 values did not change from baseline to end of cold pressor (40.3±1.1 vs 40.0±1.2 mmHg). In contrast, cerebrovascular resistance increased in the MCA (+9.7±5.7 %) and ACA (+11.5±5.0 %), likely due to the cerebral autoregulatory response to the increase mean arterial pressure. These data demonstrate that increased sympathetic activity was associated with a slight increase in common carotid, middle and anterior cerebral flow, all ~5%, indicating there was no cerebral vasoconstriction to reduce flow. The increase in cerebral flow was likely in response to increased neural activation due to pain and sensory inputs. Our finding that CCA flow increased the same amount as MCA and ACA supports the concept that sympathetic activity does not cause vasoconstriction at either the arteriolar or MCA level.Grant Funding Source: Supported by Dept of Veteran Affairs and NIH R21 DC009900

Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus

Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of U-II and its receptor at this level. We report here that U-II produces an increase in cytosolic Ca(2+) concentration in retrogradely labeled cardiac vagal neurons of nucleus ambiguus via two pathways: (i) Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptor; and (ii) Ca(2+) influx through P/Q-type Ca(2+) channels. In addition, U-II depolarizes cultured cardiac parasympathetic neurons. Microinjection of increasing concentrations of U-II into nucleus ambiguus elicits dose-dependent bradycardia in conscious rats, indicating the in vivo activation of the cholinergic pathway controlling the heart rate. Both the in vitro and in vivo effects were abolished by the urotensin receptor antagonist, urantide. Our findings suggest that, in addition, to the previously reported increase in sympathetic outflow, U-II activates cardiac vagal neurons of nucleus ambiguus, which may contribute to cardioprotection.

Elevation of Cardiac Troponins in Prolonged Status Epilepticus: A Retrospective Chart Analysis

To determine the clinical significance of elevation of Troponin-I [cTn-I] during prolonged status epilepticus [pSE] SE is known to be accompanied by an increase in sympathetic outflow. Elevation of cTn-I has been linked to myocardial stress. We hypothesize that in patients with risk factors for coronary artery disease[CAD], pSE may lead to myocardial stress and an elevation of cTn-I. This is a retrospective study of patients over the age of 18 years who were presented to Virginia Commonwealth University with SE between 2005 and 2010. Data was evaluated using the 30-minute definition for SE and 30 day mortality. Risk factors for CAD and cTn-I levels within the first 24 hours of diagnosis of pSE were analyzed. There were a total of 435 patients with a confirmed diagnosis of pSE, of which 266 had cTn-I concentrations reported. Statistical analysis showed a significant association between CAD risk factors and cTn-I elevation (χ2 =12.87, p-value <0.01), with Crude Odds Ratio of 4.7. In patients with a CAD risk factor, an elevation of cTn-I is associated with a significantly increased risk of mortality, with an Odds ratio of 8.0, (χ2 =40, [95% CI 4.1-15.9] p-value < 0.01). Mortality was higher in those with an elevation of cTn-I [54.65%] as opposed to those who did not have an elevation [15.08%], irrespective of CAD risk factors. OR=6.7, (χ2 =45, [95% CI=3.7-12.2] p-value < 0.01). In patients with pSE values, elevated cTn-I values are seen four to five time more often in those with CAD risk factors, as opposed to those without the risks. An elevation of cTn-I in this subgroup of patients with CAD risk factors was associated with an eight to nine fold increase in their 30 day mortality as compared to patients with pSE, who did not have an elevation of cTn-I.

Effects of aging and propofol on the cardiovascular component of the autonomic nervous system

Study ObjectivesTo determine the combined effects of aging and propofol on autonomic nervous system activity using heart rate variability (HRV) analysis. DesignProspective, two-parallel group, repeated-measures study. SettingOperating room of an academic hospital. PatientsASA physical status 1, 2, and 3 patients, including 14 young (< 65 yrs) and 14 elderly (> 65 yrs) patients. All patients were scheduled for general surgical procedures with general anesthesia. InterventionsEach patient received two successive propofol doses during induction (0.5 mg/kg and 1.5 mg/kg) with a time interval allowing the return of Bispectral Index (BIS) to awake values. MeasurementsPrimary outcomes were HRV parameters, which included normalized power spectral density at low frequency (LFnorm) and high frequency (HFnorm) bands and the ratio LF/HF. Secondary outcomes were BIS values, blood pressure, heart rate, respiratory rate, and body temperature. Main ResultsThe interaction of age and propofol dose level was significant [multivariate analysis of variance, F (3,74) = 4.72, P = 0.005], representing a combined effect of age and propofol dose level on the mean HRV parameters. Propofol induction decreased the HFnorm component and enhanced LFnorm and LF/HF in the younger group, but had no significant effect in the older group. Such an effect was not associated with a significant difference in systolic blood pressure (SBP) decrements between the younger and older groups. Within each group, propofol caused significant decreases in SBP compared with preinduction values. Heart rate did not change significantly during propofol administration between groups or within groups. ConclusionsPropofol and aging act in synergy to depress the activity of the cardiovascular component of the autonomic nervous system. However, a compensatory increase in sympathetic outflow was seen in young patients. Such counterbalance was not observed in the older group.

Relative contributions of the thalamus and the paraventricular nucleus of the hypothalamus to the cardiac sympathetic afferent reflex

The cardiac sympathetic afferent reflex (CSAR) is induced by stimulating the cardiac sympathetic afferents, which evokes increases in sympathetic outflow and arterial pressure. In the present study, we attempted to identify the contribution of thalamic and hypothalamic nuclei involved in the CSAR. First, we observed that there was an increase in the number of c-Fos-labeled cells in the paraventricular nucleus (PVN) (190 ± 18 vs. 101 ± 15; P < 0.05), the paraventricular nucleus of the thalamus (PVT) (239 ± 23 vs. 151 ± 15; P < 0.05), and the mediodorsal thalamic nucleus (MD) (92 ± 9 vs. 63 ± 6; P < 0.05) following epicardial application of bradykinin (BK) compared with the control group (P < 0.05). Second, using extracellular single-unit recording, we found 25% of spontaneously active neurons in the thalamus were stimulated by epicardial application of BK or capsaicin in intact rats. However, 24% of spontaneously active neurons in the thalamus were still stimulated by epicardial application of BK or capsaicin despite vagotomy and sinoaortic denervation. None of the neurons in the thalamus responded to baroreflex changes in arterial pressure, induced by intravenous injection of phenylephrine or sodium nitroprusside. The CSAR was inhibited by microinjection of muscimol or lidocaine into the PVN. However, it was not inhibited or blocked by microinjection of muscimol or lidocaine into the thalamus. Taken together, these data suggest that the thalamus, while activated, is not critical for autonomic adjustments in response to activation of the CSAR. On the other hand, the PVN is critically involved in the central pathway of the CSAR.

Augmented response of renal sympathetic nerve single units to chemoreceptor stimuli in rabbits with angiotensin induced hypertension

We examined the effect of angiotensin (AngII) hypertension on the activity of post‐ganglionic renal sympathetic units to determine whether elevated whole renal nerve activity is due to recruitment or increased firing frequency. Rabbits were treated with AngII for 4 weeks (50ng/kg/min, high dose) or for 8 weeks (20ng/kg/min, low dose) and then chloralose‐urethane anesthetized to test unitary responses to altered chemoreceptor activity. Units were detected from multi‐unit recordings using a novel algorithm that separated units by action potential shape characteristics using templates that matched spikes within a prescribed SD. Resting firing frequency was similar in sham (1.0±0.04 spikes/s, n=144) and high AngII rabbits (1.1±0.04 spikes/s, n=112) but was lower with low AngII (0.65±0.04 spikes/s, n=149). Firing frequency increased markedly to hypoxia (8% O2) in the high AngII group (+103%) but only by +39% in low AngII and +82% in sham group. The increase in firing rate with hypercapnia (8% CO2) was also greatest in the high AngII group whilst 100% O2 suppressed unitary firing in high AngII and sham groups. This study suggests that increases in sympathetic outflow in low dose AngII hypertension are most likely due to recruitment of individual neurons but high dose AngII markedly increases firing frequency to chemoreceptor stimuli. Supported by grants from National Health and Medical Research Council of Australia.

Somatosympathetic Vasoconstrictor Reflexes in Human Spinal Cord Injury: Responses to Innocuous and Noxious Sensory Stimulation below Lesion

It is known that the sudden increases in blood pressure associated with autonomic dysreflexia in people with spinal cord injury (SCI) are due to a spinally mediated reflex activation of sympathetic vasoconstrictor neurons supplying skeletal muscle and the gut. Apart from visceral inputs, such as those originating from a distended bladder, there is a prevailing opinion that autonomic dysreflexia can be triggered by noxious stimulation below the lesion. However, do noxious inputs really cause an increase in blood pressure in SCI? Using microelectrodes inserted into a peripheral nerve to record sympathetic nerve activity we had previously shown that selective stimulation of small-diameter afferents in muscle or skin, induced by bolus injection of hypertonic saline into the tibialis anterior muscle or the overlying skin, evokes a sustained increase in muscle sympathetic nerve activity and blood pressure and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects. We postulated that these sympathetic responses would be exaggerated in SCI, with a purely noxious stimulus causing long-lasting increases in blood pressure and long-lasting decreases in skin blood flow. Surprisingly, though, we found that intramuscular or subcutaneous injection of hypertonic saline into the leg caused negligible changes in these parameters. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large-diameter cutaneous afferents, caused a marked increase in blood pressure in SCI but not in able-bodied subjects. This suggests that it is activation of large-diameter somatic afferents, not small-diameter afferents, that triggers increases in sympathetic outflow in SCI. Whether the responses to activation of large-diameter afferents reflect plastic changes in the spinal cord in SCI is unknown.