Impaired β‐adrenergic responsiveness accentuates dysfunctional excitationcontraction coupling in an ovine model of tachypacing‐induced heart failure (original) (raw)
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Mitigation of beta 1- and/or beta 2-adrenoceptor function in human heart failure
British Journal of Clinical Pharmacology, 1990
Patients with congestive heart failure (CHF) have an elevated activity of the sympathoadrenal system. We have investigated several aspects of P-adrenoceptor desensitization in such patients. 2 The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2-values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF.
Heart Function Challenged with β-Receptor Agonism or Antagonism in a Heart Failure Model
Cardiovascular Drugs and Therapy - CARDIOVASC DRUG THERAPY, 2001
We have shown that chronic treatment with carteolol, a non-selective ß-adrenergic receptor antagonist, improved left ventricular (LV) function and survival in an avian model of dilated cardiomyopathy (DCM). The aim of the present study was to compare ex vivo heart function with and without ß-agonist and antagonist challenge. We investigated whether intracoronary infusion of a ß-blocker, carteolol or ß-agonist, isoproterenol decreased contractility. In the DCM group, isoproterenol resulted in a significantly greater increase in heart rate (71% vs. 28% compared to control hearts). To investigate the mechanism for the increase in heart rate, we exposed spontaneously beating neonatal cardiomyocytes to serum immunoglobulin (IgG) isolated from DCM animals. Serum IgG resulted in a significant increase in spontaneous beating rate in neonatal rat cardiomyocytes that was blocked by pre-treatment with a ß-blocker. Carteolol challenge did not significantly change heart rate but did significantl...
Importance of receptor regulation in the pathophysiology and therapy of congestive heart failure
The American Journal of Medicine, 1986
The available data indicate that the beta-adrenergic receptors that mediate positive inotropic responses undergo "down-regulation," a cellularly mediated decrease in surface receptor number, in congestive heart failure. This decrease in beta-adrenergic receptor number is proportional to the degree of myocardial dysfunction and the loss of contractility that occurs in congestive heart failure. It appears to be chamber-specific, occurring to the greatest degree in the most severely affected ventricular chamber, and is specific to the beta1adrenergic receptor subtype. Beta-adrenergic receptor down-regulation may be the result of the excessively high levels of plasma catecholamines seen in congestive heart failure, inasmuch as a similar phenomenon of beta-adrenergic receptor down-regulation is seen in animals treated with high doses of catecholamines. The specific down-regulation in cardiac beta receptors may be, in part, the cause of the decrease in myocardial function observed during long-term beta-adrenergic receptor stimulation, and an actual decrease in beta-adrenergic receptor number has been observed in myocardial tissue from patients with congestive heart failure. Down-regulation of beta receptors in congestive heart failure results in a decrease or loss of efficacy of beta-adrenergic receptor agonists on long-term administration. This is especially evident for partial agonists, which are more dependent on receptor number for their positive inotropic effects than full agonists. Although beta receptors are down-regulated in congestive heart failure, myocardial alphal-adrenergic receptors and histamine H2 receptors do not appear to be subject to this same regulatory process. Inasmuch as stimulation of both of these receptors results in a positive inotropic effect, further study should be given to the potential therapeutic utility of selective stimulation of myocardial alpha~-adrenergic receptors and histamine H2 receptors in congestive heart failure. It is evident that the status of specific receptor subtypes in pathophysiologic states such as congestive heart failure must be considered when assessing the likelihood of success in treating patients with beta-adrenergic receptor agonists.
Journal of cardiovascular pharmacology, 2014
Alpha-1-adrenergic receptors (ARs) are G proteincoupled receptors activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the nonfailing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and beta-AR dysfunction. Decades of evidence from gain and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure.
Cardiac beta-Adrenergic Signaling: From Subcellular Microdomains to Heart Failure
Annals of the New York Academy of Sciences, 2006
-adrenergic signaling plays a central role in the neurohumoral regulation of the heart and the progression of heart failure. Initially thought to be a simple linear cascade, this complex network is now recognized to utilize cross-talk with numerous other pathways, spatial compartmentation, and feedback control to coordinate cardiac electrophysiology, contractility, and adaptive remodeling. Here, we review recent basic insights and novel quantitative approaches that are leading to a more comprehensive understanding of -adrenergic signaling and thus motivate new therapeutic strategies for cardiac disease. more complex than previously believed. Here, we briefly review conventional cardiac -AR signaling and then expand upon growing research areas that are casting a new light on -AR signaling and its consequences for the treatment of heart failure.
Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation
Trends in Molecular Medicine, 2007
Chronic heart failure (HF) is characterized by sympathetic hyperactivity reflected by increased circulating catecholamines (CAs), which contributes significantly to its morbidity and mortality. Therefore, sympatholytic treatments, that is, treatments that reduce sympathetic hyperactivity, are being pursued currently for the treatment of HF. Secretion of CAs from the adrenal gland, which is a major source of CAs, is regulated by alpha(2)-adrenoceptors (alpha(2)ARs), which inhibit, and by beta-adrenoceptors (betaARs), which enhance CA secretion. All ARs are G-protein-coupled receptors (GPCRs), whose signaling and function are regulated tightly by the family of GPCR kinases (GRKs). Despite the enormous potential of adrenal ARs for the regulation of sympathetic outflow, elucidation of their properties has only begun recently. Here, recent advances regarding the roles of adrenal ARs in the regulation of sympathetic outflow in HF and the regulatory properties of ARs are discussed, along with the potential benefits and challenges of harnessing their function for HF therapy.
Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade
American journal of physiology. Heart and circulatory physiology, 2003
Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using beta-adrenergic receptor antagonists (beta-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of beta-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective beta-receptor blocker (5 mg. kg-1. day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot ...
Neurohumoral activation in heart failure: the role of adrenergic receptors
Anais da Academia Brasileira de Ciências, 2006
Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.