Voltage-gated cardiac Ca channels as a target for new positive inotropic drugs

The present state and future prospect of drug-induced activation of voltage-gated Ca channels as a means to improve cardiac contractility is shortly reviewed. All the presently available Ca channel activators are 1,4-dihydropyridine derivatives that bind with high affinity to both the open and the inactivated channel conformation. Nonselective simultaneous activation of cardiac and vascular smooth muscle L-type Ca channels prevents the use of these compounds as therapeutic agents. Possible strategies to overcome this dilemma include the use of suitable mixtures of a channel-activating drug with a channel-blocking drug and the exploitation of tissue-specific structural features of the channel for the development of new selective nondihydropyridine drugs. The development of functionally active, partially tissue-specific antibodies directed against Ca channel subunits suggests that in the near future the second approach may become feasible.