A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure.

Abstract

Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.

• Authors: Masateru Kohno, Masafumi Yano, Shigeki Kobayashi, Masahiro Doi, Tetsuro Oda, Takahiro Tokuhisa, Shinichi Okuda, Tomoko Ohkusa, Michihiro Kohno, Masunori Matsuzaki
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 284 Issue 3 Pg. H1035-42 (Mar 2003) ISSN: 0363-6135 [Print] United States
• PMID: 12433661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Cardiotonic Agents
• Coumarins
• Fluorescent Dyes
• Immunosuppressive Agents
• Ryanodine Receptor Calcium Release Channel
• Thiazepines
• K201 compound
• Polylysine
• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B
• Calcium
• Tacrolimus

Topics

• Animals
• Binding, Competitive (drug effects)
• Calcium (metabolism, pharmacokinetics)
• Calcium Channel Blockers (pharmacology)
• Cardiac Pacing, Artificial
• Cardiotonic Agents (pharmacology, therapeutic use)
• Coumarins (chemistry)
• Disease Models, Animal
• Dogs
• Fluorescent Dyes (chemistry)
• Heart Failure (drug therapy, physiopathology)
• Hemodynamics (drug effects)
• Immunosuppressive Agents (pharmacology)
• Ion Channel Gating (drug effects)
• Polylysine (pharmacology)
• Protein Conformation (drug effects)
• Radioligand Assay
• Ryanodine Receptor Calcium Release Channel (chemistry, drug effects, metabolism)
• Sarcoplasmic Reticulum (chemistry, drug effects, metabolism)
• Tacrolimus (pharmacology)
• Tacrolimus Binding Proteins (metabolism)
• Thiazepines (pharmacology, therapeutic use)