Decreased Lymphocyte Beta-Adrenergic-Receptor Density in Patients with Heart Failure and Tolerance to the Beta-Adrenergic Agonist Pirbuterol

Colucci, Wilson S.; Alexander, R. Wayne; Williams, Gordon H.; Rude, Robert E.; Holman, B. Leonard; Konstam, Marvin A.; Wynne, Joshua; Mudge, Gilbert H.; Braunwald, Eugene

doi:10.1056/nejm198107233050402

Cited by 322 publications

(68 citation statements)

References 17 publications

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“…On the other hand, if isoprenaline-induced relaxations were not modified in the absence ofendothelium, in isolated coronary segments from young human beings as previously described (Furchgott, 1984;Forsterman et al, 1986) (Venter, 1979) has not been challenged, however, by other authors (Colucci et al, 1981;Bristow et al, 1982).…”

Section: Discussionmentioning

confidence: 96%

The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline

Berkenboom¹,

Depierreux

Fontaine³

1987

British J Pharmacology

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The responses to substance P. isoprenaline and noradrenaline were observed on human isolated coronary arteries removed from 30 human hearts, and were classified according to the age ofthe hearts, the presence or absence of cardiac failure and the degree of atherosclerosis.2 The endothelium-dependent vasodilator, substance P (0.1I M), relaxed rings precontracted with prostaglandin F2,, (PGF2,, 1 tM) when they were devoid of atherosclerosis. The presence of moderate or severe lesions of atherosclerosis abolished this response. There was no difference in the response, related to either the age of the hearts or to the presence or absence of cardiac failure. 3 The dose-response curves to isoprenaline (an endothelium-independent vasodilator) were also markedly altered by the presence of atherosclerotic lesions, while aging and the presence of cardiac failure did not alter the maximal relaxation. These last 2 factors induced only a rightward shift of the dose-response curves.4 On severely atherosclerotic rings, P-adrenoceptor-mediated responses were so altered that the effect of noradrenaline was wholly vasoconstrictor (via x-adrenoceptors). This response was not modified after pretreatment with atenolol (10 PM).5 It is concluded that atherosclerosis in human coronary arteries, induces alterations in the responses to substance P and to P-adrenoceptor agonists. The P-adrenoceptor-mediated relaxations seem more influenced by the presence of atherosclerosis than they are by aging or by the down-regulation induced by cardiac failure. Conversely, the x-adrenoceptor responses appear to be well preserved.

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Section: Discussionmentioning

confidence: 96%

The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline

Berkenboom¹,

Depierreux

Fontaine³

1987

British J Pharmacology

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“…53,58,59 Clinical pharmacological studies conducted in patients without heart failure also supported functional cardiac ␤ 2 -AR signaling. 60,61 In patients with heart failure, administration of ␤ 2 -agonists demonstrated evidence of arrhythmogenic 62 and possibly adverse remodeling 28 effects, providing evidence for functional ␤ 2 -ARs in the failing heart but also demonstrating the potential adverse effects of chronic ␤ 2 -AR signaling. The potential downside of chronic ␤ 2 -AR activation was further reinforced by transgenic overexpression of ␤ 2 -ARs in mice, 63 which, when studied for longer periods, produced preliminary evidence of cardiomyopathic effects that were eventually fully characterized (see below).…”

Section: Discovery Of Functional ␤ 2 -Ars On Cardiac Myocytes In Humamentioning

confidence: 98%

“…27 Such a regulatory change would predispose the failing heart to damage from the high circulating levels of catecholamines. On the other hand, there was evidence from lymphocyte ␤ 2 -receptor density 28 and agonist response 29 measurements that systemic ␤-adrenergic receptor desensitization was present in human heart failure. Thus, in the late 1970s, the status of ␤-receptor signal transduction mechanisms in the failing heart was an open question, which could be readily investigated in explanted human hearts.…”

Section: Pharmacological Characterization Of the ␤-Adrenergic Neuroefmentioning

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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“…Increased sympathetic activity occurs in heart failure as a compensatory mechanism and is associated with a decrease in cardiac Pi-adrenergic receptor density [1,2] and a decrease in 3i-adrenergic responsiveness [3]. The therapeutic attitude toward this phenomenon is not well defined: should the treatment reduce the sympathetic stimulation or directly reset a Pi-adrenergic responsiveness?…”

Section: Introductionmentioning

confidence: 99%

Evaluation of cardiac beta 1‐adrenergic sensitivity with dobutamine in healthy volunteers.

Pousset

Chalon

Thomare

et al. 1995

Brit J Clinical Pharma

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assessed by QS2i provided the best parameter for evaluation of Pi-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4 In heart failure patients such a dobutamine test should allow separation of altered contractility and 3-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.

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Decreased Lymphocyte Beta-Adrenergic-Receptor Density in Patients with Heart Failure and Tolerance to the Beta-Adrenergic Agonist Pirbuterol

Cited by 322 publications

References 17 publications

The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline

The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Evaluation of cardiac beta 1‐adrenergic sensitivity with dobutamine in healthy volunteers.

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