T-TYPE CA2- POTENTIAL PATHOPHYSIOLOGICAL RELEVANCE( CHANNELS AND PHARMACOLOGICAL BLOCKADE )

Low-voltage-activated T-type Ca2+ channels are present in most excitab le tissues including the heart (mainly pacemaker cells), smooth muscle , central and peripheral nervous systems, and endocrine tissues, but a lso in non-excitable cells, such as osteoblasts, fibroblasts, glial ce lls, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (<10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical prop erties of T-type Ca2+ channels, which are less specific. T-type Ca2+ c hannels are weakly blocked by standard Ca2+ antagonists. Pharmacologic al blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT(1)-receptor), ATP, and is oproterenol (cAMP-independent), but are reduced by angiotensin II (AT( 2)-receptor), somatostatin and atrial natriuretic peptide. Norepinephr ine enhances these currents in some cells but decreases them in others . T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differenti ation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris . Its favorable pharmacological profile and limited side effects appea r to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiprolifer ative actions.