Paradoxical Role of T-type Calcium Channels in Coronary Smooth Muscle

Abstract

Of the ten mammalian voltage-gated calcium channels (VGCCs), those belonging to the L-type family have been best studied for the development of useful therapeutics for hypertension. Other studies on drugs that target the T-type family of VGCCs suggest that T-type channels might also be relevant to clinically directed modulation of hypertension; however, the selectivity of one such drug (i.e., mibefradil) has been called into question. CacnaH1 encodes Ca_v3.2, one of the three T-type channels. Recently, Cacna1H^−/− mice were developed to ascertain the normal roles of T-type channels. Ca_v3.2-null mice possess continually constricted arterioles in the heart. The smooth muscle and arterioles from isolated knockout mice are able to contract normally in vitro; however, in the presence of acetylcholine (ACh) or other relaxing agents, the mutant vasculature is unable to relax to the same degree as does wild-type vasculature. Similarly, blocking wild-type T-type channels prevents ACh-mediated relaxation. These results suggest an important role of T-type channels in normal cardiovascular function. But is hope for a specific and useful T-type channel–targeted drug premature?