T-type Ca2+ channel blockade prevents sudden death in mice with heart failure.

Abstract

BACKGROUND:

Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.

METHODS AND RESULTS:

We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.

CONCLUSIONS:

T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

• Authors: Hideyuki Kinoshita, Koichiro Kuwahara, Makoto Takano, Yuji Arai, Yoshihiro Kuwabara, Shinji Yasuno, Yasuaki Nakagawa, Michio Nakanishi, Masaki Harada, Masataka Fujiwara, Masao Murakami, Kenji Ueshima, Kazuwa Nakao
• Journal: Circulation (Circulation) Vol. 120 Issue 9 Pg. 743-52 (Sep 01 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19687356 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, L-Type
• Calcium Channels, T-Type
• Dihydropyridines
• Nitrophenols
• Organophosphorus Compounds
• Mibefradil
• efonidipine
• Nitrendipine

Topics

• Animals
• Arrhythmias, Cardiac (mortality, prevention & control)
• Autonomic Nervous System (drug effects, physiology)
• Blood Pressure
• Body Weight
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, L-Type (metabolism)
• Calcium Channels, T-Type (metabolism)
• Cardiomyopathy, Dilated (drug therapy, mortality)
• Death, Sudden, Cardiac (prevention & control)
• Dihydropyridines (pharmacology)
• Disease Models, Animal
• Female
• Mibefradil (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Infarction (drug therapy, mortality)
• Myocytes, Cardiac (physiology)
• Nitrendipine (pharmacology)
• Nitrophenols (pharmacology)
• Organophosphorus Compounds (pharmacology)
• Patch-Clamp Techniques