Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure.

Abstract

Both beta-adrenergic blockade and bradycardia may contribute to the therapeutic effect of beta-blockers in chronic heart failure (CHF). This study tested the relative importance of bradycardia by comparing cilobradine (Cilo), a sinus node inhibitor, with a beta-blocker, metoprolol (Meto), in an established canine model of CHF. Dogs were chronically instrumented for hemodynamic and left ventricular (LV) volume measurements. CHF was created by daily coronary embolization via a chronically implanted coronary (left anterior descending coronary artery) catheter. After establishment of CHF, control (n=6), Meto (30 mg/day, n=5), Cilo (low) (1 mg/kg/day, n=5), or Cilo (high) (3 mg/kg/day, n=5) was given orally for 12 weeks. Systemic hemodynamics, echocardiography, and pressure volume analysis were measured at baseline, at CHF, and 3 months after treatment in an awake state. Protein levels of cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), ryanodine receptor (RyR2), and Na+-Ca2+ exchanger (NCX1) were measured by Western blot. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation. After 12 weeks, Meto and Cilo (high and low) produced similar bradycardic effects, accompanied by a significantly improved LV dP/dt versus control [Meto, 2602+/-70; Cilo (low), 2517+/-45; Cilo (high), 2579+/-78; control, 1922+/-115 mm Hg/s; p<0.05]. Both Meto and Cilo (high) normalized protein levels of SERCA2a and NCX1 and reversed PKA hyperphosphorylation of RyR2, in contrast to controls. High-dose cilobradine effectively produced bradycardia and improved cardiac function after CHF, comparable with metoprolol. Restored protein levels of SERCA2a and improved function of RyR2 may be important mechanisms associated with cilobradine therapy.

• Authors: Yanping Cheng, Isaac George, Geng-Hua Yi, Steven Reiken, Anguo Gu, Yuankai Kenny Tao, Jordan Muraskin, Siyi Qin, Kun-Lun He, Ilan Hay, Kenward Yu, Mehmet C Oz, Daniel Burkhoff, Jeffrey Holmes, Jie Wang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 321 Issue 2 Pg. 469-76 (May 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17277196 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Benzazepines
• Piperidines
• Sodium-Calcium Exchanger
• sodium-calcium exchanger 1
• cilobradine
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Metoprolol
• Calcium

Topics

• Adrenergic beta-Antagonists (therapeutic use)
• Animals
• Benzazepines (therapeutic use)
• Calcium (metabolism)
• Coronary Stenosis (complications)
• Dogs
• Echocardiography
• Female
• Heart Failure (drug therapy, etiology, physiopathology)
• Heart Rate (drug effects)
• Male
• Metoprolol (therapeutic use)
• Piperidines (therapeutic use)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (analysis)
• Sodium-Calcium Exchanger (physiology)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)