Related Experiment Videos
Voltage-gated T-type Ca2+ channels and heart failure
J P Clozel1, E A Ertel, S I Ertel
1Actelion Ltd, Innovation Center, Allschwil, Switzerland.
Insights
T-type calcium channels are implicated in cardiac hypertrophy and arrhythmia. While T-type channel blockade showed promise in animal heart failure models, drug interactions halted human trials.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
Background:
- T-type calcium channels regulate vascular tone and cardiac automaticity.
- Upregulation of T-type channels in cardiac hypertrophy may promote arrhythmia.
- These channels influence cell proliferation and neurohormonal secretion, potentially impacting myocardial remodeling.
Purpose of the Study:
- To investigate the pathophysiological role of T-type calcium channels in heart failure.
- To evaluate the efficacy of T-type selective calcium channel blockers in heart failure models.
Main Methods:
- Utilized mibefradil, a potent T-type calcium channel antagonist.
- Tested mibefradil in experimental models of cardiac hypertrophy and heart failure, including the Pfeffer rat model.
- Compared mibefradil's effects to classic L-type calcium channel antagonists.
Main Results:
- Mibefradil demonstrated beneficial effects in multiple animal heart failure models.
- Unlike L-type antagonists, mibefradil did not induce negative inotropic effects or stimulate the neurohormonal system.
- Blockade of T-type channels with mibefradil improved survival rates in the Pfeffer rat model.
Conclusions:
- T-type calcium channels play a significant role in the pathophysiology of heart failure.
- Selective T-type channel blockade holds therapeutic potential for heart failure, as evidenced by animal studies.
- Drug interactions in humans led to the withdrawal of mibefradil, preventing definitive clinical efficacy assessment for heart failure treatment.
Abstract:
In the cardiovascular system, two types of voltage-gated Ca2+ channels are present: the L-type and the T-type. Under normal conditions, T-type Ca2+ channels are involved in the maintenance of vascular tone and cardiac automaticity but, since they are not present in contractile myocardial cells, they do not contribute significantly to myocardial contraction. In experimental models of cardiac hypertrophy, myocardial T-type Ca2+ channels are upregulated, which could contribute to the increased incidence of ventricular arrhythmia. In addition, T-type Ca2+ channels participate in the regulation of cell proliferation and neurohormonal secretion; through these pathways, T-type Ca2+ channels might participate in myocardial remodeling. The pathophysiological role of T-type Ca2+ channels in heart failure has been investigated using mibefradil, a Ca2+ antagonist that is 10-50 times more potent at blocking T-type than L-type Ca2+ channels. In contrast with classic L-type Ca2+ channel antagonists, miberfradil appears beneficial in many animal models of heart failure; in particular, it does not exert negative inotropic effects nor does it stimulate the neurohormonal system. Furthermore, in the Pfeffer rat model, blockade of T-type Ca2+ channels with mibefradil is associated with an improved survival rate. In humans, however, major metabolic drug interactions independent of T-type Ca2+ channel blockade made it impossible to determine the efficacy of mibefradil in treating heart failure; indeed, these interactions led to the withdrawal of the drug from the market.