Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure

Gaffney, Thomas E.; Braunwald, Eugene

doi:10.1016/0002-9343(63)90118-9

Cited by 209 publications

(55 citation statements)

References 10 publications

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“…24 These observations were interpreted as representing increased generalized adrenergic activity in heart failure, which could progress to the point of causing tissue NE depletion profound enough to compromise the major contractile support mechanism of the heart. 24 These investigators also emphasized that in heart failure patients, the impaired adrenergic support mechanism could be further compromised by the administration of antiadrenergic agents, 25 including propranolol, 26 which could lead to clinical decompensation.…”

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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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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“…Acute administration of first-generation compounds, such as propranolol, causes a decrease in contractile state. 6 This, plus a concomitant increase in systemic vascular resistance, 53,67,68 leads to a profound decrease in cardiac output, 6,53,57 which results in a drug intolerance rate of Ͼ20%. 69 On the other hand, second-generation, ␤ 1 -selective compounds can be administered in low starting doses to subjects with mild to moderate heart failure and moderate to severe left ventricular dysfunction.…”

Section: Effects On Initiation Of Therapymentioning

confidence: 99%

β-Adrenergic Receptor Blockade in Chronic Heart Failure

2000

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“…(Circulation 1989;80:658-668) L eft ventricular (LV) failure is generally characterized by elevated circulating levels and reduced myocardial stores of catecholamines and by reduced responsiveness to infusions of sympathomimetic amines. [1][2][3][4][5][6][7] In fact, /3-adrenergic blockers have been suggested as one potential therapeutic intervention in patients with LV failure.8 '9 The mechanism for the lack of efficacy of potent sympa-thomimetic amines remains controversial. One mechanism, which has been postulated, involves alterations in either /3-adrenergic receptor density10 or /3-adrenergic receptor coupling.11 '12 Also, in certain models of LV hypertrophy and failure, for example, severe pressure overload, relative subendocardial ischemia may be involved in the mechanism of depressed functional response to sympathomimetic amines.…”

Section: Isoproterenol-induced Alterations Inmentioning

confidence: 99%

Isoproterenol-induced alterations in myocardial blood flow, systolic and diastolic function in conscious dogs with heart failure.

et al. 1989

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The effects of isoproterenol were examined in 10 conscious, chronically instrumented adult dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by aortic banding at 8-10 weeks of age (LV free wall plus septum-to-body weight ratio, 8.6±f.0.5 g/kg) and also in eight control dogs (LV free wall plus septum-to-body weight ratio, 5.1±0.3 g/kg). Baseline values of heart rate, LV end-diastolic pressure, LV end-diastolic stress, and LV systolic wall stress were greater in the LV failure dogs (p<0.01), whereas the ejection phase index, rate of change of LV short-axis diameter, LV dD/dt, was depressed compared with control animals. In the control animals, isoproterenol infusion increased Vcf and LV dD/dt significantly (p<0.05), whereas LV systolic wall stress did not change. In the LV failure dogs, the increases in Vcf and LV dD/dt were less (p<0.01), and LV systolic wall stress increased (p<0.01). In the control animals, LV end-diastolic pressure, LV end-diastolic stress, LV end-diastolic stressdimension ratio, diastolic radial myocardial stiffness, and the time constant of isovolumic relaxation decreased (p<0.05), whereas in the LV failure dogs, LV end-diastolic pressure, LV end-diastolic stress, diastolic radial myocardial stiffness, and the LV end-diastolic stressdimension ratio increased. In the LV failure group, the endocardial to epicardial blood flow ratio fell to 0.59±0.06 during isoproterenol infusion, that is, significantly lower than in control dogs (0.93+±0.06). These data support the concept that potent sympathomimetic amines exert deleterious effects on systolic and diastolic function in the failing heart, potentially related to subendocardial hypoperfusion. (Circulation 1989;80:658-668) L eft ventricular (LV) failure is generally characterized by elevated circulating levels and reduced myocardial stores of catecholamines and by reduced responsiveness to infusions of sympathomimetic amines. [1][2][3][4][5][6][7] In fact, /3-adrenergic blockers have been suggested as one potential therapeutic intervention in patients with LV failure.8'9 The mechanism for the lack of efficacy of potent sympa- thomimetic amines remains controversial. One mechanism, which has been postulated, involves alterations in either /3-adrenergic receptor density10 or /3-adrenergic receptor coupling.11'12 Also, in certain models of LV hypertrophy and failure, for example, severe pressure overload, relative subendocardial ischemia may be involved in the mechanism of depressed functional response to sympathomimetic amines.The purpose of this study was to determine the responses of LV systolic and diastolic function to an inotropic and chronotropic stress induced by isoproterenol in conscious dogs with pressure overload LV hypertrophy and failure. A second goal was to determine whether or not these alterations in myocardial function were associated with alterations in transmural myocardial blood flow. These studies were conducted in conscious dogs in the absence of the complicating effects of general anes...

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Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure

Cited by 209 publications

References 10 publications

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

β-Adrenergic Receptor Blockade in Chronic Heart Failure

Isoproterenol-induced alterations in myocardial blood flow, systolic and diastolic function in conscious dogs with heart failure.

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