The Role of Cyclic Adenosine Monophosphate in Adrenergic Effects on Ventricular Vulnerability to Fibrillation in the Isolated Perfused Rat Heart

Lubbe, Welma; Podzuweit, T.; Daries, P. S.; Opie, Lionel H.

doi:10.1172/jci109042

Cited by 104 publications

(21 citation statements)

References 30 publications

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“…130,131 On the other hand, PKA-dependent signaling can be beneficial, as evidenced by the remodeling prevention effects of overexpression of Type VI adenylyl cyclase, 132 the cardiomyopathic effects of CREB genetic inhibition, 133 and the antihypertrophic effects of PKA on Class II histone deacetylases. 134 To be sure, PKA-mediated signaling can also be adverse, both on the myocardium 135 and in promoting arrhythmias, 136 but, as depicted in Figure 6, PKA signaling has elements of both benefit and harm and encompasses most of the upside effects of ␤-adrenergic activation.…”

Section: Pka-dependent and Pka-independent Signalingmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

151

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ReviewTranslational Success Stories highlight how basic discoveries have led to clinical advances (such as the use of new drugs or diagnostic modalities in patients). This initiative reflects the renewed emphasis of our journal on translational research. It is hoped that these articles will stimulate efforts to translate basic insights into clinical practice. Treatment of Chronic Heart Failure With ␤-AdrenergicReceptor Antagonists A Convergence of Receptor Pharmacology and Clinical CardiologyMichael R. BristowAbstract: Despite the absence of a systematic development plan, ␤-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that ␤-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into Phase 3 trials. Success then came relatively quickly, and within 8 years multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy, through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting. (Circ Res. 2011;109:1176-1194.)Key Words: heart failure Ⅲ adrenergic receptors Ⅲ ␤-blockers Ⅲ norepinephrine Ⅲ drug development "I love it when a plan comes together" -Colonel John "Hannibal" Smith, The A-Team ␤ -Adrenergic blocking agents are now considered firstline therapy for chronic heart failure. 2 Between 1971 and 2001, ␤-blockers as a drug class went from contraindicated to being universally declared a highly effective new therapy for chronic heart failure with systolic dysfunction. As depicted in Figure 1, this 180-degree turn required the convergence of initially disconnected lines of basic and clinical investigation, none of which was systematically planned by the usual purveyors of drug development, large pharmaceutical companies. However, as for the typical outcome of Colonel Hannibal Smith's unconventional and dubious tactical schemes, 1 the end result was highly successful. This review provides some of the historical highlights, summarizes current knowledge, and provides thoughts on the future of ␤-blocker and antiadrenergic therapy. Historical Highlights Discovery of Adrenergic ReceptorsIn 1948, Raymond Ahlquist reported evidence for two types of adrenergic receptors, 3 which, "for convenience," he termed alpha and beta. The evidence was based on 2 distinct rank orders of agonist potency for a variety of pharmacological responses, plus the ability to inhibit the vasoconstrictor or uterine contraction responses of the ␣ group, with 3 different compounds (dibenamine, ergotoxine, or tolazoline) that would later be termed ␣-blocking agents. At the time of Ahlquist's landmark work, the...

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Section: Pka-dependent and Pka-independent Signalingmentioning

confidence: 99%

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Bristow

2011

Circulation Research

151

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“…13 The heart was mounted on the aortic cannula, and two thin platinum electrodes were inserted into the base and apex of the left ventricle. These electrodes recorded the electrocardiogram on an oscilloscope and delivered square-wave stimuli of 2-msec duration (Grass S88 Physiologic Stimulus Generator).…”

Section: Experimental Protocolsmentioning

confidence: 99%

Exercise training after experimental myocardial infarction increases the ventricular fibrillation threshold before and after the onset of reinfarction in the isolated rat heart.

Posel¹,

Noakes²,

Kantor³

et al. 1989

Circulation

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Previous work has shown that exercise training increases the ventricular fibrillation threshold of the isolated perfused rat heart. The aim of our study was to determine whether exercise training that begins after myocardial infarction can similarly increase the ventricular fibrillation threshold. Rats that had suffered an experimental myocardial infarction were subject to a running training program. Thereafter, the ventricular fibrillation threshold was measured before and after the onset of acute reinfarction induced by a second coronary artery ligation. Ventricular fibrillation thresholds were significantly elevated in trained rats during normoxia (13.7±2.2 vs. 4.7±0.8 mA, p<0.01) and during acute ischemia (6.8±1.6 vs. 3.0±0.7 mA, p<0.02). The myocardial cyclic AMP level was lower in the nonischemic zone of the trained hearts (0.21±0.01 vs. 0.28±0.01 nmol/g,p<0.05), which also had lower cyclic AMP levels after epinephrine challenge (0.50±0.05 vs. 0.73±0.09 nmol/g, p<0.01; 1.41±0.11 vs. 1.85±0.09 nmol/g, p<0.02 after epinephrine 10`M and 5 X 10-6 M injection, trained vs. untrained). Both propranolol 10-6 M and epinephrine 5 x 10-7 M attenuated the difference in ventricular fibrillation thresholds before and after second coronary artery ligation and eliminated any difference in cyclic AMP content of both the nonischemic and ischemic myocardial tissue. We conclude that exercise training increases the ventricular fibrillation threshold of the previously infarcted isolated rat heart before and after the onset of reinfarction and that the training effect may be mediated by a decrease in myocardial sympathetic tone, an increase in parasympathetic tone, or both. (Circulation 1989;80:138-145) E pidemiologic evidence shows an association between exercise and a reduced incidence of sudden cardiac death.1-4 We have previously shown that the exercise-trained rat heart has an increased resistance to ventricular fibrillaFrom the MRC Ischaemic

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“…There was an increase in the ischemic tissue level of cAMP, which hypothetical ly plays a role in the genesis of ventricular arrhythmias. 27 During the 30-minute period of coronary ligation, all Table 1). Figure 2) Ryanodine 10"' to 10" 7 M prevented ventricular premature beats, ventricular tachycardia, and ventricular fibrillation during coronary artery ligation.…”

Section: Effect Of Coronary Artery LI Gat Ion (Tables 1-4)mentioning

confidence: 99%

“…27 The elevated levels of cAMP in the ischemic myocardium are likely to augment intracellular calcium oscillations since this cyclic nucleotide increases calcium ion influx 30 and enhances calcium uptake by the sarcoplasmic reticulum. 31 The antiarrhythmic property of ryanodine occurred independently of reduction in the ischemic tissue level of cAMP.…”

Section: Energy Statusmentioning

confidence: 99%