Valsartan restores sarcoplasmic reticulum function with no appreciable effect on resting cardiac function in pacing-induced heart failure.

Abstract

BACKGROUND:

Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure.

METHODS AND RESULTS:

SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of beta-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A-hyperphosphorylated, showed an abnormal Ca2+ leak, and had a decreased amount of ryanodine receptor-bound FKBP12.6. No such phenomena were seen in the valsartan-treated paced hearts. Both the SR Ca2+ uptake function and the amount of Ca2+-ATPase were decreased in the untreated failing SR, but both were restored in the valsartan-treated SR.

CONCLUSIONS:

During the development of pacing-induced heart failure, valsartan preserved the density of beta-receptors and concurrently restored SR function without improving resting cardiac function.

• Authors: Shinichi Okuda, Masafumi Yano, Masahiro Doi, Tetsuro Oda, Takahiro Tokuhisa, Masateru Kohno, Shigeki Kobayashi, Takeshi Yamamoto, Tomoko Ohkusa, Masunori Matsuzaki
• Journal: Circulation (Circulation) Vol. 109 Issue 7 Pg. 911-9 (Feb 24 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 14757694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Receptors, Adrenergic, beta
• Ryanodine Receptor Calcium Release Channel
• Tetrazoles
• Angiotensin II
• Dobutamine
• Valsartan
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B
• Calcium-Transporting ATPases
• Valine
• Norepinephrine

Topics

• Angiotensin II (antagonists & inhibitors)
• Angiotensin II Type 1 Receptor Blockers
• Animals
• Calcium Signaling (drug effects)
• Calcium-Transporting ATPases (metabolism)
• Cardiac Pacing, Artificial (adverse effects)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Dobutamine (pharmacology)
• Dogs
• Drug Evaluation, Preclinical
• Heart Failure (drug therapy, etiology, physiopathology)
• Myocardial Contraction (drug effects)
• Norepinephrine (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Receptors, Adrenergic, beta (metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (drug effects, physiology)
• Tachycardia, Ventricular (etiology, physiopathology)
• Tacrolimus Binding Proteins (metabolism)
• Tetrazoles (pharmacology, therapeutic use)
• Valine (analogs & derivatives, pharmacology, therapeutic use)
• Valsartan
• Ventricular Remodeling (drug effects)