Sympathetic Adrenergic System Research Articles

(231) Endogenous Vasoactive Peptides in the Control of Human Penile Erectile Tissue: Is There a Significance of the Neuropeptide Y (NPY)?

Abstract Introduction Aside from the neurotransmitters of the sympathetic adrenergic system, vasoconstrictor peptides may also play a role in mediating the constant tone of the erectile tissue during penile flaccidity and in returning the erect penis to the flaccid state. Neuropeptide Y (NPY) is present in high concentrations in the male genital tract. The peptide has been shown to induce contraction of isolated human penile tissue (corpus cavernosum, penile arteries) and potentiate its response to noradrenaline. Objective The purpose of our study was to measure in the cavernous and systemic blood of healthy male volunteers the course of NPY through different stages of sexual arousal. Methods Whole blood was drawn from the corpus cavernosum and the cubital vein of 15 healthy male volunteers during penile flaccidity (Fl), tumescence (Tu), rigidity (Ri) and detumescence (Det). Penile tumescence and erection were induced by applying audiovisual and tactile stimulation. Plasma levels of NPY (given in pmol/L) were determined by means of an enzyme-linked immunoassay (ELISA, IBL GmbH, Hamburg, Germany). Results NPY significantly decreased in the cavernous blood with the beginning of sexual arousal, when the flaccid penis became tumescent and finally rigid (Fl: 88.8 ± 35.8, Tu: 62.4 ± 22.7, Ri: 62.3 ± 19.7). In the phase of detumescence, only a slight increase was noted (64.8 ± 23). In the systemic circulation, no pronounced alterations in the concentration of NPY were registered through the different penile stages (Fl: 64.4 ± 27, Tu: 65.8 ± 19, Ri: 59.6-25, Det: 67.6 ± 29.3). Conclusions Our findings are in favor of the hypothesis that NPY could contribute to the maintenance of the resting state of cavernous smooth muscle. It remains to be elucidated whether the peptide may play a role in the pathophysiology of erectile dysfunction. Disclosure No

Exploration of autonomic regulation reflecting on pathophysiological change of sepsis: a prospective observational study.

AimIt remains unclear how autonomic regulation modulates pathophysiological changes of sepsis. This study aims to analyze and clarify those in patients with suspected sepsis.MethodsIn this single‐centered, prospective, observational study, adult patients who had an infection, a quick Sequential Organ Failure Assessment score of 2 or more at the emergency department, and underwent intensive care were screened. Heart rate variability (HRV) and serum adrenaline were measured immediately after arrival. The primary outcome was defined as vasopressor dependence during 48 h after arrival.ResultsA total of 63 patients were included. All the patients had SOFA score of 2 or more on admission. Vasopressor dependence, renal replacement therapy, and in‐hospital mortality were associated with higher adrenaline (which reflects sympathetic adrenergic system activity). Bacteremia was associated with lower high‐frequency components of HRV (parasympathetic nerve activity). The HRV parameter of sympathetic nerve activity had no significant association with the outcomes. In the multivariate logistic regression model adjusted for age and sex, vasopressor dependence remained associated with higher adrenaline (cut‐off 0.11 ng/mL, odds ratio 9.71, 95% confidence interval 2.55–37; P = 0.000874), and lower high‐frequency components with bacteremia (17.2 ms2, odds ratio 4.86, 95% confidence interval 1.36–17.4; P = 0.0152). There were no significant correlations between parameters of HRV and serum adrenaline.ConclusionHypoperfusion, organ dysfunction, and in‐hospital mortality were associated with an increased sympathetic adrenergic activity. Bacteremia was associated with decreased parasympathetic nerve activity. The autonomic regulator may involve a multilayered and differentiated modulating process for sepsis.

Stress and the "extended" autonomic system.

This review updates three key concepts of autonomic neuroscience-stress, the autonomic nervous system (ANS), and homeostasis. Hans Selye popularized stress as a scientific idea. He defined stress variously as a stereotyped response pattern, a state that evokes this pattern, or a stimulus that evokes the state. According to the "homeostat" theory stress is a condition where a comparator senses a discrepancy between sensed afferent input and a response algorithm, the integrated error signal eliciting specific patterns of altered effector outflows. Scientific advances since Langley's definition of the ANS have incited the proposal here of the "extended autonomic system," or EAS, for three reasons. (1) Several neuroendocrine systems are bound inextricably to Langley's ANS. The first to be described, by Cannon in the early 1900s, involves the hormone adrenaline, the main effector chemical of the sympathetic adrenergic system. Other neuroendocrine systems are the hypothalamic-pituitary-adrenocortical system, the arginine vasopressin system, and the renin-angiotensin-aldosterone system. (2) An evolving body of research links the ANS complexly with inflammatory/immune systems, including vagal anti-inflammatory and catecholamine-related inflammasomal components. (3) A hierarchical network of brain centers (the central autonomic network, CAN) regulates ANS outflows. Embedded within the CAN is the central stress system conceptualized by Chrousos and Gold. According to the allostasis concept, homeostatic input-output curves can be altered in an anticipatory, feed-forward manner; and prolonged or inappropriate allostatic adjustments increase wear-and-tear (allostatic load), resulting in chronic, stress-related, multi-system disorders. This review concludes with sections on clinical and therapeutic implications of the updated concepts offered here.

Dopamine promotes the progression of AML via activating NLRP3 inflammasome and IL-1β

Mental stress has been shown to activate sympathetic adrenergic system to produce dopamine and finally promote the progression of cancer. Dopamine can also regulate the immune system through secreting kinds of cytokines. However, what role does dopamine play in acute myeloid leukemia (AML) remains unclear. Here, we investigated the effects and mechanisms of dopamine in NLRP3 inflammasome activation and cellular viability of acute myeloid leukemia U937 cells. Our results showed that dopamine enhanced the viability of U937 cells and activated the NLRP3 inflammasome in U937 cells. To further explore the mechanism of dopamine on U937 cells, we examined the expression level of dopamine receptors (DRs). We found that the mRNA expression level of DR5 in U937 cells was significantly higher than other dopamine receptors. Furthermore, we treated U937 cells with DR1/2/3/5 antagonist before dopamine, and it manifestly reversed the NLRP3 inflammasome activation and the viability-enhancing effect in U937 cells induced by dopamine. Anti-IL-1β antibody also could partly reversed the viability-enhancing effect by dopamine. We concluded that dopamine could enhance the viability of U937 cells through DR1/5 receptor pathway and activate NLRP3 inflammasome.

Nicotine supplementation enhances simulated game performance of archery athletes

BackgroundNicotine is beneficial to mood, arousal and cognition in humans. Due to the importance of cognitive functioning for archery athletes, we investigated the effects of nicotine supplementation on the cognitive abilities, heart rate variability (HRV), and sport performance of professional archers.MethodsEleven college archers were recruited and given 2 mg of nicotine supplementation (NIC group) and placebo (PLA group) in a crossover design.ResultsThe results showed that at 30 min after the intake of nicotine gum, the “correct rejection” time in the NIC group was significantly lower than that of the PLA group (7.29 ± 0.87 vs. 8.23 ± 0.98 msec, p < 0.05). In addition, the NIC group completed the grooved pegboard test in a shorter time than the PLA group (48.76 ± 3.18 vs. 53.41 ± 4.05 s, p < 0.05), whereas motor reaction times were not different between the two groups. Saliva α-amylase activity was significantly lower after nicotine supplementation (p < 0.01) but increased immediately after the archery test in the NIC group (p < 0.05). In addition, nicotine supplementation significantly decreased HRV and increased the archery score (290.58 ± 10.09 vs. 298.05 ± 8.56, p < 0.01).ConclusionsNicotine enhances the performance of archery athletes by increasing cognitive function and stimulating the sympathetic adrenergic system.

The possible association between COVID-19 and postural tachycardia syndrome

The possible association between COVID-19 and postural tachycardia syndrome

The extended autonomic system, dyshomeostasis, and COVID-19.

The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. This essay explores the possibility that the heightened risk may involve activation of the “extended autonomic system” (EAS). Traditionally, the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of “autonomic.” Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain network—the “central autonomic network”—regulates these systems; embedded within it are components of the Chrousos/Gold “stress system.” Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 and that treatments targeting specific abnormalities identified in individual patients may be beneficial.

Microcirculation of the skin with essential arterial hypertension

The review describes the skin microcirculation disorders with essential arterial hypertension by the capillaroscopy and laser Doppler flowmetry. The methods are complementary to each other and provide information about the structural and functional state of arteriolar, capillary and venular vessels in the microvasculature. The most common disorders in the skin microvasculature attending the arterial hypertension are vasomotor dysfunction of the microvascular endothelium, a decreasing of the dilator reserve, and capillary rarefaction. The bulk information was obtained in non-acral areas of the skin, where the tissue perfusion is has mainly nutritional pattern. The blood flow pattern in of the skin acral areas, where the sympathetic adrenergic system of regulation dominates, is still unexplored, and tissue perfusion is characterized by a thermoregulatory shunt orientation.

The Effects of a Marathon Effort on Psychomotor Performance and Catecholamine Concentration in Runners over 50 Years of Age

Long-distance running and, in particular, running marathons has become an increasingly popular activity among the elderly. The aim of the study was to examine the effects of a marathon effort on the psychomotor performance and catecholamine concentration in runners over 50 years of age. The participants were male runners (n = 28) who completed the 32nd Wrocław Marathon in Poland. The runners’ psychomotor performance was assessed on the basis of their choice reaction times (CRT), heart rate (HR) and running speed measurements. In addition, the adrenaline (A) and noradrenaline (NA) as well as lactate (LA) levels and anaerobic threshold (AT) were measured. The runners’ CRT after crossing the finish line was significantly longer by 50 ms (p &lt; 0.05) in response to each emitted audiovisual stimulus, as compared with baseline. The mean running speed was reduced by 1 km/h between the first speed measurement (5th km of the run) and the last (42.195 km) (p &lt; 0.05). The observed three-fold increase in adrenaline and noradrenaline levels indicates an intense activity of the sympathetic–adrenergic system. The cognitive function levels in the studied marathon runners returned to baseline after 30 min of recovery, and the function of the sympathetic–adrenergic system by seven days after completing the marathon race.

Regulation of Transepithelial Ion Transport in the Rat Late Distal Colon by the Sympathetic Nervous System

The colorectum (late distal colon) is innervated by the sympathetic nervous system, and many colorectal diseases are related to disorders of the sympathetic nervous system. The sympathetic regulation of colorectal ion transport is rarely reported. The present study aims to investigate the effect of norepinephrine (NE) in the normal and catecholamine-depleted condition to clarify the regulation of the sympathetic adrenergic system in ion transport in the rat colorectum. NE-induced ion transport in the rats colorectum was measured by short-circuit current (I(sc)) recording; the expression of beta-adrenoceptors and NE transporter (NET) were quantified by real-time PCR, and western blotting. When the endogenous catecholamine was depleted by reserpine, the baseline I(sc) in the colorectum was increased significantly comparing to controls. NE evoked downward deltaI(sc) in colorectum of treated rats was 1.8-fold of controls. The expression of beta(2)-adrenoceptor protein in the colorectal mucosa was greater than the control, though the mRNA level was reduced. However, NET expression was significantly lower in catecholamine-depleted rats compared to the controls. In conclusion, the sympathetic nervous system plays an important role in regulating basal ion transport in the colorectum. Disorders of sympathetic neurotransmitters result in abnormal ion transport, beta-adrenoceptor and NET are involved in the process.

Heat-stress-induced metabolic changes and altered male reproductive function.

Heat stress can cause systemic physiological and biochemical alterations in living organisms. In reproductive systems, heat stress induces germ cell loss and poor quality semen. However, until now, little has been known about such a complex regulation process, particularly in the perspective of metabolism. In this study, serum, hypothalamus, and epididymis samples derived from male SD (Sprague-Dawley) rats being exposed to high environmental temperature (40 °C) 2 h per day for 7 consecutive days were analyzed using metabonomics strategies based on GC/TOFMS. Differentially expressed metabolites reveal that the energy metabolism, amino acid neurotransmitters, and monoamine neurotransmitters pathways are associated with heat stress, in accordance with changes of the three upstream neuroendocrine system pathways in the SNS (sympathetic adrenergic system), hypothalamic pituitary adrenal axis (HPA), and hypothalamic pituitary testis axis (HPT) axis. Many of these metabolites, especially in the epididymis, were found to be up-regulated, presumably due to a self-preserving action to resist the environmental hot irritation to maintain normal functioning of the male reproductive system.

Mitochondrial production of reactive oxygen species contributes to the β‐adrenergic stimulation of mouse cardiomycytes

The sympathetic adrenergic system plays a central role in stress signalling and stress is often associated with increased production of reactive oxygen species (ROS). Furthermore, the sympathetic adrenergic system is intimately involved in the regulation of cardiomyocyte Ca2+ handling and contractility. In this study we hypothesize that endogenously produced ROS contribute to the inotropic mechanism of β-adrenergic stimulation in mouse cardiomyocytes. Cytoplasmic Ca2+ transients, cell shortening and ROS production were measured in freshly isolated cardiomyocytes using confocal microscopy and fluorescent indicators. As a marker of oxidative stress, malondialdehyde (MDA) modification of proteins was detected with Western blotting. Isoproterenol (ISO), a β-adrenergic agonist, increased mitochondrial ROS production in cardiomyocytes in a concentration- and cAMP–protein kinase A-dependent but Ca2+-independent manner. Hearts perfused with ISO showed a twofold increase in MDA protein adducts relative to control. ISO increased Ca2+ transient amplitude, contraction and L-type Ca2+ current densities (measured with whole-cell patch-clamp) in cardiomyocytes and these increases were diminished by application of the general antioxidant N-acetylcysteine (NAC) or the mitochondria-targeted antioxidant SS31. In conclusion, increased mitochondrial ROS production plays an integral role in the acute inotropic response of cardiomyocytes to β-adrenergic stimulation. On the other hand, chronically sustained adrenergic stress is associated with the development of heart failure and cardiac arrhythmias and prolonged increases in ROS may contribute to these defects.

Clinostatic Hypertension and Orthostatic Hypotension

The association of clinostatic hypertension (CH) and orthostatic hypotension (OH) is described as the "Hyp-Hyp phenomenon," and it has been found in about 5.5% of hypertensive patients and in up to 50% of patients with OH. The importance of CH/OH in clinical practice is mainly due to the presence of troublesome symptoms, end-organ damage, and difficulties in its clinical management. The review focuses on the clinical problem of CH and review the international literature for the best management, including the diagnostic work-up and the taylored treatment for this kind of patients. A systematic review of the literature was conducted through MEDLINE research to focus the main controversial issues about CH/OH. Included topics: (1) the diagnostic work-up, (2) the association with dysautonomic failure and syncope, and (3) the treatment options and prevention of end-organ damage. Current standard reference for OH diagnosis includes functional assessment of the cardiac vagal nervous system and the sympathetic adrenergic system. The association with dysautonomic failure and with syncope needs further investigation. Pharmacologic treatment of OH is aimed at controlling symptoms rather than restoring normotension. Midodrine is the only medication that has been put to multicenter placebo-controlled trial and subsequently approved by the U.S. Food and Drug Administration (FDA) for OH treatment. Short-acting oral antihypertensive agents at bedtime should be considered in patients with severe, sustained CH. Data obtained from the literature review showed that clinical diagnosis of the Hyp-Hyp phenomenon is relatively simple, but it remains more difficult to establish the causal disease. In our opinion, it is advisable to define simple diagnostic standards for the selection of patients at risk of dysautonomic impairment so that a subsequent highly specific diagnostic work-up could be initiated.

Review: β‐Blockade in Chronic Dialysis Patients

AbstractApproximately 50% of the mortality in chronic dialysis patients is due to cardiovascular diseases (CVD). Cardiomyopathy, coronary artery disease, and arrhythmia are all common conditions and predispose to sudden death, which accounts for 60% of all cardiac deaths in this population. Despite advances in dialysis therapy, the mortality from CVD remains substantially unchanged, partly due to the lack of evidence‐based strategies for improving the outcome of cardiac diseases in this population. Activation of the sympathetic adrenergic system is well documented in chronic dialysis patients and is likely involved in the pathogenesis of myocardial hypertrophy, coronary artery disease, heart failure, and arrhythmia. Given the proven benefit of β‐blockers in patients with normal kidney function with similar cardiac comorbidities, β‐blockers would seem to be attractive agents to reduce cardiovascular morbidity and mortality in the patient population with advanced chronic kidney disease. However, the value of β‐blockade in patients on chronic dialysis remains unclear. This uncertainty surrounding the efficacy is compounded by the risk of side effects to these patients, such as hypotension, bradycardia, and hyperkalemia. In addition, numerous studies have suggested suboptimal usage of β‐blockers in the dialysis population; this is seen even in high risk patients, such as those with established coronary artery disease. In this review, we will focus on sympathetic nervous system activation in kidney disease and highlight the benefit and risks of β‐blockers usage in the chronic dialysis patient population.

Expectation enhances autonomic responses to stimulation of the human subthalamic limbic region

Recent studies show that the placebo component of a treatment can be investigated by administering therapies either overtly or covertly, without the administration of any placebo. Here, we analyze the effects of open (i.e., expected) versus hidden (i.e., unexpected) stimulations of the human subthalamic region on autonomic responses in Parkinson patients. To do this, we mapped the whole subthalamic region, from the dorsal to the ventral part, and recorded both heart rate and sympathetic responses by using spectral analysis of heart rate variability. We found that open stimulations were more effective than hidden ones only in the ventral subthalamic region, whereas no difference between the two conditions was found in the dorsal aspect. By analyzing the stimulus–response curves in the dorsal, middle, and ventral subthalamic regions, we found that the autonomic response threshold was higher in the hidden than open condition for both heart rate and sympathetic responses only in the ventral part. As this ventralmost portion of the subthalamic region is involved in associative-limbic functions, these data suggest that expectation enhances autonomic responses only if these are elicited in the limbic system. These results extend previous findings on the open–hidden paradigm in deep brain stimulation [Benedetti, F., Colloca, L., Lanotte, M., Bergamasco, B., Torre, E., Lopiano, L., 2004a. Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res. Bull. 63, 203–211.], and indicate that expectation plays a major role in the therapeutic outcome. In light of the interactions between the sympathetic adrenergic system and the immune system, the open–hidden difference in autonomic responses might be relevant to the understanding of how expectations might affect the immune system.

Zinc transporter 3 and zinc ions in the rodent superior cervical ganglion neurons

Previous studies have revealed that zinc-enriched (ZEN) terminals are present in all parts of the CNS though with great differences in intensity. The densest populations of both ZEN terminals and ZEN somata are found in telencephalic structures, but also structures like the spinal cord demonstrate impressive ZEN systems spreading terminals several segments around the respective ZEN somata. The present study evaluates whether sympathetic neurons in the superior cervical ganglia (SCG) are ZEN neurons, i.e. contain vesicles that have zinc transporter 3 (ZnT3) proteins in their membranes and contain zinc ions. ZnT3 immunoreactivity (IR) was found in the somata and processes in the postganglionic neurons of mouse SCG. Only a small fraction of neurons (less than 5%), expressed varying degrees of ZnT3. Colchicine treatment, however, increased the number of ZnT3-positive neurons three-fold, suggesting an accumulation of ZnT3 protein in the somata. A small proportion of the postganglionic axons revealed dotted accumulations of ZnT3 IR along their courses. Double labeling showed that all ZnT3-positive neurons and axons were also tyrosine hydroxylase-positive with strong immunofluorescence, while no colocalization was found between ZnT3 and the vesicular acetylcholine transporter (VAChT) or neuropeptide Y IR. VAChT-positive preganglionic neurons were found to terminate on ZnT3 neuronal somata. 6-Methoxy 8-para toluene sulfonamide quinoline fluorescence and zinc selenium autometallography (ZnSe AMG) revealed that a subgroup of SCG cells contained free or loosely bound zinc ions. It is therefore concluded that ZnT3 and zinc ions are present in a subpopulation of TH-positive, NPY-negative neurons in the rodent SCG, supporting the notion that vesicular zinc ions may play a special role in the peripheral sympathetic adrenergic system.

Systemic and cavernous plasma levels of vasopressin in healthy males during different functional conditions of the penis.

The role of the sympathetic adrenergic system in mediating the constant tone of penile flaccidity and returning the erect penis to its flaccid state is fairly well established. However, it is not yet known whether additional nonadrenergic-noncholinergic transmitters are involved in this process. Arginine-vasopressin (AVP, ADH), a pituitary peptide hormone with potent vasoconstrictor activity, may be one of the factors contributing to such control. The present study was undertaken to determine whether or not plasma levels of AVP change during penile flaccidity, tumescence, rigidity, and detumescence. We determined the plasma levels of AVP in the systemic as well as the cavernous blood of 25 healthy adult male volunteers who were exposed to visual and tactile erotic stimuli in order to elicit penile tumescence and erection. Whole blood was aspirated from the corpus cavernosum and the cubital vein, and AVP was quantified in plasma aliquots obtained from the whole blood samples. A marked decline in mean AVP plasma levels from 5.4+/-2.7 ng/l during flaccidity to 2.9+/-2.5 ng/l during rigidity was registered in the systemic blood of the subjects. No further decline was observed when the rigid penis became detumescent. In contrast, no alterations in AVP plasma levels were detected in the cavernous blood under the different penile conditions. The results from our study are contrary to the hypothesis of a local release and uptake of AVP in the cavernous compartment in the control of penile flaccidity and detumescence. Moreover, our findings are not in favour of AVP as an important mediator involved in adrenergic neurotransmission in the corpus cavernosum penis. Nevertheless, our data indicate that the decrease in systemic AVP levels in response to sexual arousal might be a prerequisite to facilitate penile tumescence and rigidity in healthy males.

Leptin response to endogenous acute stress is independent of pituitary function

There are close interactions between the adipocyte-derived hormone, leptin, and the anterior pituitary, especially the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the relationship between the sympathetic adrenergic system and serum leptin levels, dependent on the function of anterior pituitary hormone axes, in 27 patients without a history of a hormone-secreting pituitary adenoma or other underlying endocrine disease. Based on responses in a routine insulin hypoglycemia test (ITT), the patients were classified as hypopituitary (HP; n=15), growth hormone deficient (GHD; n=6) or controls (CTR; 6 patients with normal responses). Nadir plasma glucose was 1.5+/-0.1 mmol/l at the time of maximum hypoglycemia. Each group had a significant increase in plasma epinephrine; however the magnitude of change was significantly higher in GHD (6.066+/-1.633 nmol/l) compared with HP patients (1.781+/-0.492 nmol/l) (P<0.01). The rise in norepinephrine was delayed (60 min) in the HP and CTR groups. However, in GHD patients there was a considerable increase at the time of hypoglycemia which was significantly different from HP (P<0.001) and CTR (P<0.05) patients. The increase in catecholamines was followed by a quick and significant decrease in serum leptin levels 45 min after an i.v. bolus injection of insulin in HP patients (-4.7+/-2.5%, P<0.05), which was significantly sustained after 60 min (-5.6+/-2.5%, P<0.05). In CTR patients there was a significant decrease in serum leptin levels 60 min after i.v. insulin (-14.4+/-6.9%, P<0.05), while no significant response was observed in the GHD group, although 5 of 6 patients had decreased levels at 45 and 60 min. No differences between the groups were found by ANOVA. In conclusion, an acute increase in endogenous circulating catecholamines is associated with a quick decrease in serum leptin levels. Intact anterior pituitary function seems not to be essential for this hitherto poorly understood mechanism.

Downregulation of Angiotensin II Receptor Type 1 in Heart Failure

Among the major consequences of reduced cardiac performance is the neurohumoral response, mediated primarily by activation of the sympathetic-adrenergic system and the renin-angiotensin system (RAS). These responses may contribute to maintain homeostasis and are considered to be adaptive mechanisms to a fall in cardiac output for the short term. If sustained in heart failure, however, the cellular and molecular abnormality within the heart induced by these changes can cause detrimental effects on cardiac function and thus plays a critical part in determining the poor prognosis of this condition.1 It is now apparent that cardiac hypertrophy, one of the most important responses of the failing heart, is a complex process that is both beneficial and detrimental. Although a growing number of molecular changes have been recognized in both compensatory hypertrophy and end-stage heart failure, it is poorly understood whether such changes contribute to or compensate for the deterioration of the heart or are simply associated with the failure and have nothing to do with the relevant processes. Thus, understanding the nature and mechanisms for the transition to heart failure after chronic overload has been a focus of considerable attention. During the last several years we have witnessed a great advance in our understanding with respect to the pathophysiological role of the local RAS in the heart. Evidence presented to date indicates that the local RAS is selectively activated despite the normal circulating RAS in the overloaded heart associated with hemodynamic overload and myocardial infarction. Since angiotensin II exerts direct cardiac effects, including trophic effect, long-term activation of cardiac RAS leads to cardiac hypertrophy independent of circulating levels of angiotensin II.2 3 Angiotensin II has also been shown to elicit a mitogenic response in neonatal and adult cardiac fibroblasts that may largely contribute to cardiac hypertrophy as well as interstitial …

Heart rate and blood pressure consequences of an afternoon SIESTA (Snooze-Induced Excitation of Sympathetic Triggered Activity)

With the increased interest shown in the area of arcadian variations in physiologic parameters and cardiovascular disease processes in recent years, it has been demonstrated that there are distinct circadian rhythms in cardiovascular events, with a surge in ischemia, 1 onset of acute myocardial infarction 2 and sudden cardiac death 3 in the morning waking hours, and a trough in such events at night. Such peaks in ischemia and onset of acute myocardial infarction are particularly related to actual time of waking and commencing activities. Because there are surges in heart rate (HR) and systolic blood pressure (BP) in the morning waking hours, 4 and because β-adrenergic blocking agents blunt the morning peaks in HR, 5 in addition to those of ischemia, 5 onset of acute myocardial infarction 2 and sudden cardiac death, 6 it has been suggested that activation of the sympathetic adrenergic system may play an important role in the increased cardiovascular event rate in the period soon after waking and commencing activities. We have assessed HR and BP responses before, during and after an afternoon siesta in apparently normal subjects, and compared the changes with those recorded on waking and commencing activities in the morning to establish whether the morning waking hours are particularly associated with increases in the determinants of myocardial oxygen demand, or whether this response is reproducible after any period of “sleep”.