Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β<sub>1</sub>-Adrenoceptors in Human Myocardium

Bundkirchen, Andreas; Brixius, Klara; Bölck, Birgit; Schwinger, Robert H. G.

doi:10.1124/jpet.300.3.794

Cited by 24 publications

(28 citation statements)

References 37 publications

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“…Not necessarily alternative to this, it is also to be considered that having shown the prominent profibrotic role of ␣-adrenoceptors makes it less likely, but cannot rule out, the possibility of a contribution to fibrosis by catecholamine-mediated activation of those ␤-adrenergic pathways known to be resistant to propranolol (a drug we selected for the present study as the prototype of the ␤-blockers used in the clinical setting rather than as a sophisticated pharmacological tool), namely those operated through the ␤ 3 -adrenoceptor or the so called ␤ 4 -adrenoceptor (later and more properly referred to as the propranolol-insensitive state of the ␤ 1 -adrenoceptor). 21,22 It may also be that other synaptic mechanisms (which would be disrupted by sympathectomy and not by ␤-blockade) play an inhibitory role on collagenolytic processes. These mechanisms may relate to adrenergic cotransmitters such as neuropeptide Y, ATP, or others.…”

Section: Discussionmentioning

confidence: 99%

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

et al. 2005

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Abstract-The adaptive changes that develop in the pressure-overloaded left ventricular (LV) myocardium include cardiomyocyte hypertrophy and interstitial fibrosis. Although the former is known to depend to a sizeable extent on sympathetic (over)activity, little information exists whether the same applies to the latter, ie, whether excess catecholamine exposure contributes to the imbalance between collagen deposition by fibroblasts and degradation by matrix metalloproteases (MMPs), eventually leading to LV collagen accumulation. Sprague-Dawley rats were subjected to abdominal aortic banding (B) or sham operation (S) and treated with ␤-blockade (Bb, oral propranolol, 40 mg/kg per day), chemical sympathectomy (Sx, 6-hydroxydopamine, 150 mg/kg intraperitoneal twice per week) or vehicle (Vh). Ten weeks later, systolic blood pressure, LV weight, collagen abundance (computer-aided histology), zymographic matrix metalloproteinase (MMP)-2 activity and its specific tissue inhibitor concentration (TIMP-2) were measured. Both sympathectomy and ␤-blockade failed to attenuate the banding-induced blood pressure elevation but significantly attenuated the attendant LV hypertrophy. As expected, pressure-overload hypertrophy was associated with interstitial fibrosis (collagen: 4.37Ϯ1.23% BVh versus 1.23Ϯ0.44% SVh, PϽ0.05), which was abolished by sympathectomy (2.55Ϯ1.31%, Pϭnot significant versus SSx) but left unchanged by ␤-blockade (4.11Ϯ1.23%, PϽ0.05 versus both SBb and BSx). ␤-blockade, but not sympathectomy, was also associated with an increased TIMP-2/MMP-2 ratio (PϽ0.05), indicating reduced interstitial collagenolytic activity. In separate groups of banded and sham-operated rats, treatment with the ␣-receptor blocker doxazosin (10 mg/kg per day) displayed similar antifibrotic and biochemical effects as sympathectomy. Thus in the course of experimental pressure overload, the sympathetic nervous system plays a major pro-fibrotic role, which is mediated via ␣-adrenergic but not ␤-adrenergic receptors. Key Words: collagen Ⅲ extracellular matrix Ⅲ fibrosis Ⅲ heart failure Ⅲ hypertrophy Ⅲ sympathectomy T here is extensive evidence that sympathetic nerve overactivity consistently accompanies hypertension in its uncomplicated stage and even more so after the progressive development of left ventricular (LV) hypertrophy, dysfunction, and failure. 1,2 This has deleterious consequences on the severity of hypertension itself, because it produces peripheral vasoconstriction, as well as on the heart, because: (1) it favors activation of other potentially cardiotoxic neurohumoral systems (renin-angiotensin system, endothelin, etc) 3,4 ; (2) it increases myocardial oxygen consumption; and (3) it directly exerts toxic (pro-apoptotic, pro-necrotic) effects on the myocardium. 5-7 Accordingly, it is now firmly established that administration of ␤-adrenergic receptor blockers favorably affects hypertension and heart failure, 8 most likely via correction of the aforementioned pathophysiological alterations.However, although it is well documented ...

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Section: Discussionmentioning

confidence: 99%

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

et al. 2005

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“…Their role in cardiac myocyte apoptosis remains to be investigated. Of note, activation of the β 3 -AR pathway by catecholamines may contribute to the myocardial dysfunction during sepsis [22], and putative β 4 -AR may represent propranolol-insensitive state of β 1 -AR [23, 24]. …”

Section: Adrenergic Receptors (Ars) and Cardiac Myocyte Apoptosismentioning

confidence: 99%

β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis: Role of β1 Integrins

Amin

Singh

2011

Journal of Signal Transduction

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Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Accumulation of catecholamines plays an important role in the pathogenesis of heart disease. Acting via β-adrenergic receptors (β-AR), catecholamines (norepinephrine and isoproterenol) increase cardiac myocyte apoptosis in vitro and in vivo. Specifically, β 1-AR and β 2-AR coupled to Gαs exert a proapoptotic action, while β 2-AR coupled to Gi exerts an antiapoptotic action. β1 integrin signaling protects cardiac myocytes against β-AR-stimulated apoptosis in vitro and in vivo. Interaction of matrix metalloproteinase-2 (MMP-2) with β1 integrins interferes with the survival signals initiated by β1 integrins. This paper will discuss background information on β-AR and integrin signaling and summarize the role of β1 integrins in β-AR-stimulated cardiac myocyte apoptosis.

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“…In vitro, in isolated canine atria, nebivolol has no positive chronotropic or inotropic effects. Also, in human ventricular papillary muscle strips nebivolol does not increase contractile force (8,29). These findings indicate that nebivolol is devoid of intrinsic sympathomimetic activity.…”

Section: Pharmacology Basic Pharmacological Characteristics Of Nebivololmentioning

confidence: 86%

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist, Nebivolol

Kuroedov

Cosentino

Lüscher

2004

Cardiovascular Drug Reviews

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Nebivolol is a racemic mixture of d- and l-enantiomers. The drug is characterized by beta(1)-adrenoceptor selectivity and long-acting beta-blockade exerted predominantly by d-enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial-dependent mechanism involving stimulation of beta(3)-adrenoceptors as well as by endothelial-independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium-dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion-induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional beta-adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24-h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough-to-peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo-controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.

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Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β₁-Adrenoceptors in Human Myocardium

Cited by 24 publications

References 37 publications

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis: Role of β1 Integrins

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist, Nebivolol

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Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β1-Adrenoceptors in Human Myocardium

Cited by 24 publications

References 37 publications

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy

β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis: Role of β1 Integrins

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist, Nebivolol

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Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of β₁-Adrenoceptors in Human Myocardium