Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing.

Marzo, Kevin; Frey, Martin J.; Wilson, John R.; Liang, Bruce T.; Manning, David R.; Lanoce, V.; Molinoff, Perry B.

doi:10.1161/01.res.69.6.1546

Cited by 95 publications

(44 citation statements)

References 49 publications

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“…It has been proposed that these decreases in adenylate cyclase activity could partially be caused by a generalized membrane dysfunction, independent of G proteins. [26][27][28] Differences between the previous studies and ours might be dependent on a time factor. If the pulmonary arteries had been studied after a longer duration of CHF, we might also have observed generalized membrane dysfunction.…”

Section: Relaxation Response To Forskolincontrasting

confidence: 60%

Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.

et al. 1993

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BACKGROUND Alterations in myocardial function and systemic vascular tone are well documented in congestive heart failure (CHF), but little information is available on the effects of CHF on pulmonary vessels. We examined the mechanisms of tone regulation of canine pulmonary arteries during pacing-induced CHF. METHODS AND RESULTS Rings 3-4 mm wide from lobar pulmonary arteries were prepared from normal dogs, dogs paced at 210 beats per minute for 3 weeks (paced group, nonfailure), and dogs also paced at 240 beats per minute during the fourth week to induce severe heart failure (CHF group). Contractile responses to 60 mmol/L KCl and phenylephrine and relaxation responses to acetylcholine, bradykinin (endothelium-dependent cyclic GMP [cGMP]-mediated), isoproterenol, arachidonic acid, prostacyclin (receptor-dependent cyclic AMP [cAMP]-mediated), forskolin (direct stimulator of adenylate cyclase), a forskolin analogue (devoid of adenylate cyclase-dependent activity), and RO 20-1724 (phosphodiesterase inhibitor) were characterized. The paced group did not show alterations in vascular reactivity. Contractile response to phenylephrine and cGMP-mediated relaxation responses were not altered in the CHF group; however, receptor-mediated cAMP-induced relaxation responses were significantly inhibited (p < 0.05). Relaxation responses to isoproterenol (10(-6) mol/L), arachidonic acid (10(-5) mol/L), and prostacyclin (10(-5) mol/L) were reduced by 56%, 72%, and 74%, respectively. The relaxation response to RO 20-1724 was not affected by CHF, and this probe did not enhance the impaired relaxation response to isoproterenol. Forskolin-induced relaxation was not altered, and the forskolin analogue produced minimal relaxation compared with forskolin. CONCLUSIONS These findings suggest that in pacing-induced CHF, canine pulmonary arteries show a selective defect in receptor coupling to cAMP-dependent relaxation mechanisms. There is no evidence of enhanced degradation of cAMP.

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Section: Relaxation Response To Forskolincontrasting

confidence: 60%

Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.

et al. 1993

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“…Increased expression of Gi␣ proteins was also observed in human diseased heart and in numerous animal models of heart failure. [37][38][39][40][41][42] These data suggest that elevated Gi␣ signaling and negative regulation of PKA in heart is a common feature associated with the onset of heart failure. However, most of the studies focused on the Gi␣2 and Gi␣3 subunits.…”

Section: Discussionmentioning

confidence: 86%

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

et al. 2007

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Background-Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear. Methods and Results-Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf-mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca 2ϩ defects, and loss of protein kinase A-dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G␣ inhibiting subunit 1 (Gi␣1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals. Conclusions-These data suggest that selective induction of G␣ inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy. Key Words: hypertrophy Ⅲ cardiomyopathy Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ signal transduction H ypertrophic cardiomyopathy is the most common form of heart disease caused by genetic mutations of cardiac proteins, whereas left ventricular hypertrophy can be caused by mechanical overload associated with hypertension and valvular disease. Both may be characterized by myocyte hypertrophy, interstitial fibrosis, and induction of fetal gene expression. [1][2][3][4] Both the genetic and acquired forms of cardiac hypertrophy are risk factors for sudden cardiac death associated with electrophysiological remodeling and resultant cardiac arrhythmias. [5][6][7][8] Investigation of the underlying mechanisms of these manifestations has been the main focus of the field in recent years. Clinical Perspective p 605Ventricular arrhythmias are the most common cause of sudden cardiac death in hypertrophic cardiomyopathy and other cardiac diseases, including heart failure. 9 -11 Abnormal conduction and heterogeneous action potential propagation are the main causes of reentrant arrhythmias in ischemic hearts. In contrast, triggered arrhythmias caused by early or delayed afterdepolarizations are thought to be a major cause of ventricular arrhythmias in nonischemic cardiomyopathies. 12 Although prolonged action potential duration (APD), repressed outward K ϩ currents, and increased sodium...

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“…65 Downregulation of beta-adrenergic receptors and a resultant decreased sympathetic responsiveness has also been described in animals with TIC. 66,67 This reduction in beta receptor density and responsiveness to beta-adrenergic stimulation has been shown to be independent of haemodynamic and neurohormonal factors. 68 It has also been shown to normalise in the setting of rate control.…”

Section: Cellular Changesmentioning

confidence: 95%

What About Tachycardia-induced Cardiomyopathy?

Ellis¹,

Josephson²

2013

Arrhythmia &Amp; Electrophysiology Review

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Cardiomyopathies are heterogeneous heart muscle disorders with a wide range of aetiologies and clinical manifestations. They are often defined by their causes (i.e. hypertension, prior myocardial infarction, valvular heart disease), although current major society definitions describe cardiomyopathy as the presence of abnormal myocardial structure and/or function in the absence of underlying structural heart disease. Long-standing tachycardia is a well-recognised cause of heart failure and left ventricular dysfunction, and has led to the nomenclature, tachycardia-induced cardiomyopathy (TIC). TIC is generally a reversible cardiomyopathy if the tachycardia can be treated effectively, either with medications, surgery or catheter ablation. TIC can also manifest in patients with baseline left ventricular dysfunction from underlying structural heart disease that develop a worsening of their myocardial dysfunction in the setting of prolonged tachycardia, which can be reversed with control of the tachycardia. The diagnosis is usually made after demonstrating recovery of left ventricular function with normalisation of heart rate in the absence of other identifiable aetiologies.TIC was first described in 1913 in a young patient who presented with congestive heart failure (CHF) and atrial fibrillation (AF) with rapid ventricular response.1 In the subsequent decades, further reports were written documenting cases of complete resolution of CHF after cardioversion of AF to sinus rhythm.2-4 A century after the first reported case, we are still working to expand our understanding of the mechanisms underlying this disorder. A variety of chronic or incessant tachyarrhythmias have been implicated in the pathogenesis of TIC, the most classic being AF, 5-7 atrial flutter, 8 incessant supraventricular tachycardia, 9-12 ventricular tachycardia [13][14][15][16] and premature ventricular depolarizations 17 (see Table 1). The most common presentation is a dilated cardiomyopathy with or without the causative tachycardia.Given that this diagnosis represents a potentially reversible cause of heart failure, its recognition is critically important. In this review, we will discuss the proposed mechanisms of TIC, the causative tachycardias and their treatment, outcomes for patients diagnosed with TIC, and future directions for research and clinical care. Experimental Models BackgroundThe first experimental model of TIC was described by Whipple et al. in 1962 where he demonstrated that rapid, prolonged atrial pacing resulted in low output heart failure.18 This model has since become widely used as a model to study CHF. Animal studies, primarily in dogs and pigs, have shown that sustained rapid atrial or ventricular pacing results in systolic heart failure that is neurohormonally and haemodynamically similar to left ventricular systolic dysfunction in humans. [19][20][21][22][23] The majority of what is known about the pathophysiologic mechanisms underlying TIC is supported by pacing-induced heart failure in animal models (see Table 2). It is ...

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Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing.

Abstract: Changes in the ,-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing.

Cited by 95 publications

References 49 publications

Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.

Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.

Giα1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

What About Tachycardia-induced Cardiomyopathy?

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