Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta blockade alone in chronic congestive heart failure

Kukin, Marrick; Kalman, Jill; Mannino, Michael M.; Freudenberger, Ronald S; C, Buchholz; Ocampo, Ofelia

doi:10.1016/s0002-9149(97)89342-3

Cited by 39 publications

(17 citation statements)

References 21 publications

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“…23 We previously studied whether ␣-blocking effects might persist in the presence of ␤-blockade during long-term use. 24 In that study, we compared chronic metoprolol therapy with combination therapy with metoprolol and the ␣-blocker doxazosin. After 3 months of therapy, there was no hemodynamic difference between ␤-blockade and combined ␣␤-blockade, which implied tolerance to ␣-blockade despite the presence of ␤-blockade.…”

Section: Discussionmentioning

confidence: 99%

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

et al. 1999

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Background-With ␤-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is ␤ 1 -selective, the third-generation compound carvedilol is ␤-nonselective, with ancillary pharmacological properties including ␣-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF. Methods and Results-Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of ␤-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18Ϯ6.3% to 23Ϯ8.7% (PϽ0.005) with metoprolol and from 19Ϯ8.5% to 25Ϯ9.9% (PϽ0.0005) with carvedilol (PϭNS between groups). With metoprolol, TBARS values decreased from 4.7Ϯ0.9 nmol/mL at baseline to 4.2Ϯ1.5 nmol/mL at month 4 to 3.9Ϯ1.0 nmol/mL at month 6 (PϽ0.0001). With carvedilol, there was a parallel decline from 4.7Ϯ1.4 to 4.2Ϯ1.3 to 4.1Ϯ1.2 nmol/mL over the same time frame (PϽ0.025), with no between-group difference in these changes. Conclusions-Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population. (Circulation. 1999;99:2645-2651.)

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Section: Discussionmentioning

confidence: 99%

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

et al. 1999

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“…10 Doxazosin mesylate, an α 1 -AR selective blocking agent, was started at 1 mg daily with a target of 8 mg daily. 11 All medications were up-titrated weekly until target doses were met or limiting side effects developed.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Kao

Lowes

Gilbert

et al. 2015

Circ Cardiovasc Genet

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volume) to the degree of eccentric hypertrophy (end-diastolic volume [EDV]). IDC in humans is associated with myocardial gene expression changes affecting contractile function and hypertrophy.2,3 Among these are upregulation in mRNA and protein abundances of β-myosin heavy chain (MYH7) and atrial natriuretic peptide (NPPA) with downregulation of α-myosin heavy chain (MYH6) and sarcoplasmic reticulum calcium-ATPase 2 (ATP2A2), a pattern also observed during fetal cardiac development.2,3 Reversal of these pathological changes is associated with ventricular reverse-remodeling in response to both β 1 -selective and nonselective β-adrenergic Background-When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca 2+ -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β 1 -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results-Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β 1-selective), metoprolol+doxazosin (β 1 /α 1 ), or carvedilol (β 1 /β 2 /α 1 ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β 1 -adrenergic signaling. Conclusions-In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β 1 -adrenergic receptor gene network. Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.

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“…The antioxidant and alpha-blocking activities of carvedilol have been suggested to contribute to its beneficial effects, but the benefits of antioxidants and alpha blockers have not been corroborated by clinical studies [87,88]. Zhou et al found that carvedilol is the only beta blocker tested that can effectively suppress arrhythmogenic store overloadinduced Ca 2+ release that can lead to triggered arrhythmias and sudden death [76,89].…”

Section: No In Chf-effects Of Carvedilolmentioning

confidence: 99%

Nitric Oxide and its Role in Cardiovascular Diseases

Dobutović¹

2011

TONOJ

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Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a free radical which reacts with various molecules to cause multiple biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are exquisitely regulated and extend to almost every cell type and function within the circulation. While the molecule mediates many physiological functions, an excessive presence of NO is toxic to cells. The enzyme NOS, constitutively or inductively, catalyses the production of NO in several biological systems. NO is derived not only from NOS isoforms but also from NOS-independent sources. In mammals, to date, three distinct NOS isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The molecular structure, enzymology and pharmacology of these enzymes have been well defined, and reveal critical roles for the NOS system in a variety of important physiological processes. This review focuses on recent advances in the understanding of the interactions between NOS enzymes and pathophysiology of cardiovascular diseases (CVD) and the role of NO agonists as potential therapeutic agents in treatment of CVD.

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Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta blockade alone in chronic congestive heart failure

Cited by 39 publications

References 21 publications

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Nitric Oxide and its Role in Cardiovascular Diseases

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