Chronic Sympathetic Activation Research Articles

Reactive Oxygen Species in the Paraventricular Nucleus of the Hypothalamus Alter Sympathetic Activity During Metabolic Syndrome.

The paraventricular nucleus of the hypothalamus (PVN) contains heterogeneous populations of neurons involved in autonomic and neuroendocrine regulation. The PVN plays an important role in the sympathoexcitatory response to increasing circulating levels of angiotensin II (Ang-II), which activates AT1 receptors in the circumventricular organs (OCVs), mainly in the subfornical organ (SFO). Circulating Ang-II induces a de novo synthesis of Ang-II in SFO neurons projecting to pre-autonomic PVN neurons. Activation of AT1 receptors induces intracellular increases in reactive oxygen species (ROS), leading to increases in sympathetic nerve activity (SNA). Chronic sympathetic nerve activation promotes a series of metabolic disorders that characterizes the metabolic syndrome (MetS): dyslipidemia, hyperinsulinemia, glucose intolerance, hyperleptinemia and elevated plasma hormone levels, such as noradrenaline, glucocorticoids, leptin, insulin, and Ang-II. This review will discuss the contribution of our laboratory and others regarding the sympathoexcitation caused by peripheral Ang-II-induced reactive oxygen species along the subfornical organ and paraventricular nucleus of the hypothalamus. We hypothesize that this mechanism could be involved in metabolic disorders underlying MetS.

Null effect of ginsenoside Rb1 on improving glycemic status in men during a resistance training recovery.

BackgroundGinsenoside Rb1, a principle active ingredients of Panax ginseng, has been shown to lower blood glucose in animals and increase insulin secretion in cultured insulinoma cells. The aim of this study was to determine the effects of daily ginsenoside Rb1 supplementation on circulating glucose and insulin levels in men during a 5-day recovery period after an acute bout of resistance exercise.MethodsTwelve gymnasts (20.5 ± 0.3 years of age) participated in this double blind placebo-controlled crossover trial. They were challenged by a lower-limb resistance exercise at a weight load of 85 % one-repetition maximal (1-RM) for 10 repetitions, six sets of the movement. Rb1 (1 ng/kg) or Placebo was orally delivered to participants daily during a 5-day recovery period after challenge. Circulating insulin, glucose and heart rate variability (HRV) were measured under fasted condition in the morning at Days 1, Day 3, and Day 5 during recovery.ResultsNo significant effect of Rb1 on circulating glucose and insulin levels were found among participants during the 5-day recovery period. A persistent elevation in sympathetic nervous activity, indicated by increased HRV-low frequency/high frequency (HRV-LF/HF) power, during the Rb1 trial was observed.ConclusionsThe result of the study suggests that the null effect of Rb1 supplementation on lowering glucose and insulin levels of participants may be associated with chronic sympathetic activation.

Abstract B73: Adrenergic signaling promotes pancreatic tumor initiation and progression

Abstract Background/Aims: There is increasing evidence that chronic sympathetic nervous system activation can lead to increased noradrenaline levels in the tumor microenvironment. This process has been associated with proliferative signals largely mediated by beta-adrenergic signaling. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. In this study we aimed to investigate the role of locally and systemically delivered catecholamines to the tumor microenvironment in a well-established genetically engineered pancreatic cancer mouse model (PDx1-Cre/KRasG12D (KC) and PDx1-Cre/KRasG12D/Trp53R172H (KPC)). Methods: Adrenergic signaling was induced or inhibited in KC or KPC mice or 3D pancreatic spheres in culture using specific non-selective and selective agonists or antagonists. Adrenergic receptor expression was assessed by RT-PCR, Western blot and immunohistochemistry. Adrenergic signaling was also modeled in vivo applying restraint stress. To elucidate the crosstalk between nerve and cancer cells, pancreatic spheres and pancreatic cancer cells were co-cultured with dorsal root ganglia and neuronal plasticity was quantified by evaluating neurite outgrowth and number of branches. Denervation of the pancreas was performed using surgical or chemical neural ablation. Results: Adrenergic signaling receptors, in particular ADRB2, is upregulated during pancreatic cancer development. Furthermore, in vitro stimulation of cells harboring an oncogenic KRas mutation displayed a significantly increased sphere forming efficiency. This effect was blocked by the non-specific beta-blocker propranolol and the selective beta2-blocker ICI 188,551. Stimulation of pancreatic sphere formation from KC mice induced by adrenergic signaling from dorsal root ganglia in vitro was also prevented by selective blockage of the beta2-adrenergic signaling pathway. While surgical or chemical (Botulinum toxin A) denervation of the pancreas appeared not to retard the development precancerous lesions in KC mice, denervation significantly increased the survival when performed in mice after a tumor (3-5mm) was detected by high–resolution ultrasound imaging. In contrast, stress accelerated pancreatic cancer development in KC mice. The effects of stress were prevented by treatment with the selective ADRB2 antagonist ICI 188,551. Conclusions: Taken together, our data suggests that an increased level of stress and an increased level of systemic catecholamines may promote pancreatic carcinogenesis in its early stages. During this phase, patients might benefit from pharmacological inhibition of stress-induced signaling. The progression of pancreatic cancer seems to depend on the local delivery of catecholamines to the microenvironment, and thus patients might also benefit by additional targeting of the ADRB2 signaling pathway. Citation Format: Bernhard W. Renz, Christoph B. Westphalen, Xiaowei Chen, Yoku Hayakawa, Yoshihiro Takemoto, Marina Macchini, Daniel L. Worthley, Samuel Asfaha, Axel Kleespies, Helen Remotti, Kenneth P. Olive, Timothy C. Wang. Adrenergic signaling promotes pancreatic tumor initiation and progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B73.

Renal denervation for the treatment of atrial fibrillation in hypertensive patients or beyond?

The first-in-man study of catheter based renal denervation (RDN) suggests that this novel approach is associated with sustained blood pressure reduction without serious adverse events in patients with resistant hypertension [1]. Subsequent clinical studies show that RDN reduces renal [2] and whole-body sympathetic activities [3], and exerts beneficial effects in other disease states characterized by chronic sympathetic activation, such as heart failure [4] and left ventricular hypertrophy [5]. In consideration of the association between hypertension, sympathetic activation and atrial fibrillation (AF), Pokushalov et al.

EHMTI-0360. Chronic sympathetic activation in migraine headache: unique to migraine or common to sympathetic nervous system disorders?

The mechanisms of autonomic nervous system dysfunction in migraine are not well understood. It has been proposed that chronic/excessive SNS activation contributes to migraine episodes by rapidly depleting norepinephrine stores while increasing the release of dopamine, adenosine triphosphate, adenosine and prostaglandins. Research showing significantly colder hands in female migraineurs than healthy controls between headaches suggests evidence of chronic/excessive SNS activation in female migraineurs. A recent audit of standardized clinical assessment data collected over several years during a 26 minute psychophysiological mental stress assessment revealed interesting results which shed light on this dilemma. Data included hand skin temperature (HST), frontal sEMG, HR, SCR, respiration rate and the Anxiety Sensitivity Index. Ten female migraineurs (MH), 10 females with muscle contraction headache (MCH) and 10 females with panic disorder (PD) were compared. MCH controlled for the effects of having a distressing non-migraine/non SNS headache disorder. PD controlled for the effects of having a distressing non-headache, SNS disorder. There were no significant between-group differences for age and most test scores. A repeated measures ANOVA showed a significant between-groups difference for HST. The MCH group was in the normal range while the MH and PD groups were well below normal and significantly colder than the MCH group. The MH group results suggest chronic SNS arousal. However the PD group's similar result and the MCH normal result suggests that chronic SNS arousal is a characteristic of SNS disorders and is not unique to migraine. Alone, it appears insufficient to explain migraine episodes. Additional factors are proposed. No conflict of interest.

Nitric Oxide as a Target for Hypertension Management : a Review

High blood pressure is well-established as a leading cause of stroke, ischemic heart disease, and cardiovascular disease. Globally cardiovascular disease accounts for approximately 17 million deaths a year, nearly one third of the total. A number of pharmaceutical agents are available for initial treatment of high BP. These include older molecules such as diuretics and beta-blocking agents, and newer molecules such as dihydropyridine calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and direct acting vasodilators. Comprehensive hypertension management focuses on reducing overall cardiovascular risk and should be the preferred approach for initial management of hypertension. Nitric oxide is a gaseous signaling molecule that regulates various physiological and pathophysiological responses in the human body. Nitric oxide is a gaseous lipophilic free radical which reacts with various molecules to cause pleiotropic effects and it is generated by three distinct isoforms of nitric oxide synthase. The physiologic effects include circulation and blood pressure, platelet function, host defense, and neurotransmission in central nervous system and in peripheral nerves. The etiology of the association between impaired nitric oxide bioactivity and hypertension is complex, however, and has not been fully elucidated. Important mechanisms of hypertension and cardiovascular disease, in which impaired nitric oxide bioactivity plays a major role, include arterial stiffness and increased systolic pulse wave velocity, and possibly chronic sympathetic nervous system activation to be investigated in-depth. NO plays a vital role in a wide variety of pathophysiological and biochemical reactions. Nitric oxide is a critically important mediator in the pathophysiology of different cardiac diseases. Nitric oxide has been identied as one of the key targets for novel therapeutic interventions to minimize irreversible tissue damage associated with complications of hypertension and other cardiovascular disorders.

Abstract 18032: Increased Late Sodium Current During Early Heart Failure Development Induced by Chronic Sympathetic Activation

Chronic sympathetic activation promotes myocardial hypertrophy and heart failure. In mice overexpressing the human β1-adrenoreceptor (β1-OE), cytosolic [Na+]i increases during early stages of cardiac remodeling (8-12 weeks), thereby slowing relaxation and increasing diastolic [Ca2+]i due to increased Na+/Ca2+ exchanger (NCX) reverse mode activity. Here we investigate whether reduced Na+ efflux via Na+/K+ ATPase (NKA) regulation, or enhanced Na+ influx (voltage-dependent Na+ current or TRPC channel regulation) may account for increased [Na+]i in young β1-OE mice. In β1-OE mice (8-12 weeks) and their wild-type (WT) littermates protein expression of NKA and phospholemman (PLM) was determined by Western blot in ventricular homogenates or isolated ventricular myocytes (TRPC 1, 3, 6) and normalized to GAPDH. NKA current (Ipump, whole cell voltage clamp) was measured as the difference in outward current after rapid solution switch to 0 K+ external solution. The persistent component of the Na+ current, INa,late, was measured as the current sensitive to 30 μm Tetrodotoxin (TTX). In β1-OE, NKA α1 subunit expression was unchanged, whereas the α2 subunit was reduced (0.87±0.09 in β1-OE, n=5 vs. 1.24±0.08 in WT, n=4; p<0.05; mean±s.e.). Phosphorylated PLM was increased (1.3±0.05 in β1-OE, n=5 vs. 0.748±0.06 in WT, n=4; p<0.001), and total PLM was reduced in β1-OE mice (0.71±0.08 in β1-OE, n=5 vs. 1.23±0.18 in WT, n=4;p<0.05). TRPC 1, 3 and 6 expression was unaltered. Maximal Ipump density (100 mM [Na+]i in the pipette) was unchanged. With 10 mM [Na+]i, Ipump was significantly increased, indicating a higher Na+ affinity of NKA in β1-OE myocytes. INa,late was increased in β1-OE myocytes: at the end of pulse amplitude was -0.149 ± 0.034 pA/pF in β1-OE, n=10 vs. -0.063± 0.018 pA/pF in WT, n=9; p<0.05; integrated current was 138 ± 17 pC/pF in β1-OE, n=10 vs 85 ± 17 pC/pF in WT, n =9; p<0.05. In conclusion, in β1-OE mice, increased INa,late contributes to elevated [Na+]i during chronic sympathetic activation. Higher Na+ affinity of NKA due to less inhibition by phospholemman only partially compensates increased Na+ influx at this early stage of heart failure development.

Physiology's Impact: Exploring the Mysteries of Life

The discipline of physiology explores the mysteries of life. How is it possible that the same organism can live in a dangerous environment, where extreme ambient temperatures, gravitational forces, oxygen availability, or other abiotic factors impose serious challenges to the maintenance of

Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma

Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.

Hypothalamic mTORC1 Signaling Controls Sympathetic Nerve Activity and Arterial Pressure and Mediates Leptin Effects

The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular functions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous system and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dramatic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sympathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypothalamic mTORC1 activity may influence the development of cardiovascular diseases.

Sympathetic Neural and Hemodynamic Responses to Upright Tilt in Patients With Pulsatile and Nonpulsatile Left Ventricular Assist Devices

Left ventricular assist devices (LVADs) are now widely accepted as an option for patients with advanced heart failure. First-generation devices were pulsatile, but they had poor longevity and durability. Newer generation devices are nonpulsatile and more durable, but remain associated with an increased risk of stroke and hypertension. Moreover, little is understood about the physiological effects of the chronic absence of pulsatile flow in humans. We evaluated patients with pulsatile (n=6) and nonpulsatile (n=11) LVADs and healthy controls (n=9) during head-up tilt while measuring hemodynamics and muscle sympathetic nerve activity. Patients with nonpulsatile devices had markedly elevated supine and upright muscle sympathetic nerve activity (mean±SD, 43±15 supine and 60±21 bursts/min at 60° head-up tilt) compared with patients with pulsatile devices (24±7 and 35±8 bursts/min; P<0.01) and controls (11±6 and 31±6 bursts/min; P<0.01); however, muscle sympathetic nerve activity was not different between patients with pulsatile flow and controls (P=0.34). Heart rate, mean arterial pressure, and total peripheral resistance were greater, whereas cardiac output was smaller, in LVAD patients compared with controls in both supine and upright postures. However, these hemodynamic variables were not significantly different between patients with pulsatile and nonpulsatile flow. Heart failure patients with continuous, nonpulsatile LVADs have marked sympathetic activation, which is likely due, at least in part, to baroreceptor unloading. We speculate that such chronic sympathetic activation may contribute to, or worsen end-organ diseases, and reduce the possibility of ventricular recovery. Strategies to provide some degree of arterial pulsatility, even in continuous flow LVADs may be necessary to achieve optimal outcomes in these patients.

Psychophysiological Reactivity to Abuse-Related Stimuli in Sexually Revictimized Women

Prior research shows discrepant findings in relation to psychophysiological reactivity to threat in women with histories of sexual victimization. Women ages 18 to 22 (N = 123) with histories of sexual abuse were categorized into child sexual abuse (CSA), adult sexual victimization, revictimization, or nonvictimization groups. Low- and high-frequency heart rate variability were measured at baseline and during an Emotional Stroop task of abuse-related words. Revictimized women showed a significant decrease from baseline to task in both parasympathetic and sympathetic measures when compared to the CSA group. The CSA group demonstrated chronic sympathetic activation at both baseline and task, relative to the revictimization group. Groups did not differ on performance (i.e., reaction time) on the Emotional Stroop task (i.e., more threatening stimuli, slower performance). Cardiovascular responses reported might point to biological reactivity patterns needed for women with a history of sexual abuse to cope with abuse-related stimuli.

Cerebro-afferent vessel and pupillary basal diameter variation induced by stomatognathic trigeminal proprioception: a case report

IntroductionA patient affected by asymmetric hemodynamics of cerebro-afferent vessels underwent duplex color scanner investigations in occlusal proprioceptive un- and rebalance conditions. Pupillometric video-oculographic examinations were performed in order to spot connected trigeminal proprioceptive motor patterns able to interfere on sympathetic autonomic activity. The aim of this case report is to verify if involuntary jaw closing during swallowing, executed in unbalance and rebalance myoelectric activity, would be able to modify cerebral hemodynamics.Case presentationA 56-year-old Caucasian Italian woman affected by asymmetric blood flow of cerebro-afferent vessels underwent an electromyographic investigation of her occlusal muscles in order to assess their occlusal functional balance. The extreme asymmetry of myoelectric activity in dental occlusion evidenced by electromyographic values suggested the rebalancing of the functions of occlusal muscles through concurrent transcutaneous stimulation of the trigeminal nerve supra- and submandibular motor branches. The above-mentioned method allowed the detection of a symmetric craniomandibular muscular relation that can be kept constant through the use of a cusp bite modeled on the inferior dental arch: called orthotic-syntropic bite for its peculiar use of electrostimulation. A few days later, the patient underwent a duplex color scanner investigation and pupillometric video-oculographic examinations in occlusal unbalance and rebalance conditions.ConclusionsA comparative data analysis showed that an unbalanced dental occlusal function may represent an interferential pattern on cerebral hemodynamics velocity and pupillometric evaluations have proved useful both in the analysis of locus coeruleus functional modalities and as a diagnostic tool in the assessment of pathologies involving locus coeruleus and autonomic systems. The inclusion of myoelectric masseter examinations can be useful in patients with asymmetric hemodynamics of cerebro-afferent vessels and dental occlusal proprioceptive rebalance can integrate the complex therapy of patients with increased chronic sympathetic activity.

Abstract 201: Direct but not Indirect Activation of Sympathetic Ganglia Leads to Higher Neuronal Activation in Normotensive Than Deoxycorticosterone-salt Hypertensive Rats

Sympathetic activity is chronically elevated in hypertensive human patients and in many animal models of hypertension, including the deoxycorticosterone (DOCA)-salt rat model. Sympathetic ganglia receive signals from the central nervous system and relay them to blood vessels and peripheral organs. How sympathetic ganglia respond to activation signals differently in hypertension is not fully understood. We examined how direct and indirect activators of sympathetic ganglia would influence neuronal activation. 2-deoxy-D-glucose (2-DG) is a glucose analog that causes hypoglycemia leading to centrally-mediated, indirect activation of celiac ganglia, a prevertebral sympathetic ganglion. Nicotine directly activates sympathetic ganglia by acting on cholinergic receptors found on most sympathetic neurons. Acute neuronal activation was examined by measuring c-fos immunoreactivity (ir). We hypothesized that since there is higher chronic sympathetic activity in DOCA-salt hypertensive than normotensive rats, both direct and indirect acute activators will induce higher c-fos expression in sympathetic ganglia of normotensive than hypertensive rats. Maximal c-fos expression for 2-DG (800mg/kg i.p.) and nicotine (2mg/kg s.c.) treatments was observed 2hrs post-treatment and for all following experiments, celiac ganglia were dissected and fixed 2hrs post-treatment. Following nicotine treatment, c-fos expression was significantly higher in celiac ganglia of normotensive (25.5 ± 9.7 c-fos ir neurons/m^2) than hypertensive (12.0 ± 4.8 c-fos ir neurons/m^2) rats. However, following 2-DG treatment, c-fos expression was similar in celiac ganglia of normotensive (49.1 ± 17.6 c-fos ir neurons/m^2) and hypertensive (49.4 ± 16.0 c-fos ir neurons/m^2). In contrast with our hypothesis, only the direct but not the indirect activation of sympathetic ganglia induced higher sympathetic neuronal activation in normotensive than hypertensive rats. Thus, a centrally-mediated metabolic stimulus does not activate pathways to sympathetic ganglia differentially in normotension versus hypertension. However, direct ganglionic stimulation leads to greater neuronal activation in normotensive than hypertensive ganglia.

Association of sleep apnea with coronary slow-flow phenomenon

Both obstructive sleep apnea (OSA) and coronary slow-flow phenomenon (CSFP) are known to share similar etiopathogenic mechanisms, such as chronic sympathetic activation, upregulation of inflammatory pathways, oxidative stress and, finally, endothelial dysfunction. We evaluated whether there is an association between OSA and coronary flow rates. We retrospectively reviewed medical records of all patients who underwent diagnostic nocturnal polysomnography for suspected OSA. Those who had coronary angiography performed within the same year of polysomnography were divided into two main groups: those with (group 1) and without (group 2) OSA; also, angiographic coronary TIMI (thrombolysis in myocardial infarction) frame counts (TFC) were compared between the groups. Patients with coronary arterial stenosis and angiograms with inadequate filling of the coronary arteries or visualization of the distal landmarks for frame counting were excluded from the study. There was a statistically significant difference between the groups regarding TFCs. We found a significant positive correlation between mean TFC and apnea-hypopnea index (r=0.611, P<0.001). The current study demonstrated that sleep apnea impairs coronary flow rates and is associated with CSFP.

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

It is uncertain if downregulation of β-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400μgkg(-1)h(-1) over 16days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute β-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G(sα)) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G(iα2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sα)-protein expression.

Myocardial structural, contractile and electrophysiological changes in the guinea-pig heart failure model induced by chronic sympathetic activation

Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea-pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a β-adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg(-1), i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross-sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure-volume and stress-strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute β-adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular-to-LV difference in action potential duration was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed right ventricular-to-LV difference in repolarization time. In summary, we establish the guinea-pig model of ISO-induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.

The Role of Carvedilol in the Treatment of Dilated and Anthracyclines-Induced Cardiomyopathy

Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration.

Choroidal blood flow response to isometric exercise in patients with obstructive sleep apnea syndrome.

Abstract Purpose Obstructive sleep apnea syndrome (OSA) has been recently reported to be associated with ischemic and glaucomatous optic neuropathy. The physiopathology of these diseases includes an abnormal regulation in the optic nerve head vasculature. The aim of our study was to characterize the choroidal vascular reactivity to acute increase in ocular perfusion pressure due to exercise in OSA patients. Methods Fourteen newly diagnosed OSA patients were included in this prospective study. Control subjects were matched with OSA patients for body mass index (BMI), gender and age. At the screening visit, each subject underwent a general exam, cardiovascular, neurologic and ophthalmological examinations, and underwent complete overnight polysomnography. The LDF instrument used in this study to measure subfoveal choroidal blood flow (ChBF) measured the following parameters: ChBVel (kHz); volume, ChBVol (in arbitrary units, AU) and the relative flow, ChBF = ChBVel  ChBVol (in AU). Vascular choroidal reactivity was tested during squatting. Results OSA patients exhibited a similar choroidal reactivity during increase in OPP (i.e. stability of choroidal blood flow) than controls until an increase of OPP about 145%. We found a similar vascular resistance increase in both groups during increase of OPP. Conclusion This prospective comparative study explored for the first time the choroidal blood flow of OSA patients and showed that subfoveal ChBF reactivity to gas in OSA patients differed from that of healthy control subjects. These preliminary results suggest that choroidal vasculature of OSA patients remained vasoconstricted when OPP increased, due to a chronic sympathetic activation.

CaM Kinase IIδ Is Required for Catecholamine-Induced Cardiac Fibrosis but Not Hypertrophy

Chronic sympathetic activation is a well established feature of human heart failure. Catecholamine stimulation causes adaptive and maladaptive events. We used a knock-out mouse model to test the hypothesis that CaMKIIδ, the most abundant CaMKII isoform in the heart, is required for the onset of pathological features resulting from catecholamine stress. CaMKIIδ-deficient (KO) and littermate control (WT) mice were infused with 60 mg/kg/d isoproterenol (ISO) or vehicle via osmotic mini pump for two weeks.