Voltage-gated T-type Ca2+ channels and heart failure

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+ ch annels are involved in the maintenance of vascular tone and cardiac automat icity 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 upregul ated, which could contribute to the increased incidence of ventricular arrh ythmia. In addition, T-type Ca2+ channels participate in the regulation of cell proliferation and neurohormonal secretion; through these pathways, T-t ype Ca2+ channels might participate in myocardial remodeling. The pathophys iological role of T-type Ca2+ channels in heart failure has been investigat ed using mibefradil, a Ca2+ antagonist that is 10-50 times more potent at b locking T-type than L-type Ca2+ channels. In contrast with classic L-type C a2+ channel antagonists, mibefradil appears beneficial in many animal model s of heart failure; in particular, it does not exert negative inotropic eff ects nor does it stimulate the neurohormonal system. Furthermore, in the Pf effer rat model, blockade of T-type Ca2+ channels with mibefradil is associ ated with an improved survival rate. In humans, however, major metabolic dr ug interactions independent of T-type Ca2+ channel blockade made it impossi ble to determine the efficacy of mibefradil in treating heart failure; inde ed, these interactions led to the withdrawal of the drug from the market.