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T-Type Ca2+ Channels and Pharmacological Blockade: Potential Pathophysiological Relevance

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Abstract

Low-voltage–activated T-type Ca2+ channelsare present in most excitable tissues including the heart (mainly pacemakercells), smooth muscle, central and peripheral nervous systems, and endocrinetissues, but also in non-excitable cells, such as osteoblasts, fibroblasts,glial cells, etc. Although they comprise a slightly heterogeneouspopulation, these channels share many defining characteristics: smallconductance (<10 pS), similar Ca2+ andBa2+ permeabilities, slow deactivation, and avoltage-dependent inactivation rate. In addition, activation at lowvoltages, rapid inactivation, and blockade by Ni2+ areclassical properties of T-type Ca2+ channels, which areless specific. T-type Ca2+ channels are weakly blocked bystandard Ca2+ antagonists. Pharmacological blockers arescarce and often lack specificity and/or potency. The physiologicalmodulation of T-type Ca2+ currents is complex: they areenhanced by endothelin-1, angiotensin II (AT1-receptor), ATP,and isoproterenol (cAMP-independent), but are reduced by angiotensin II(AT2-receptor), somatostatin and atrial natriuretic peptide.Norepinephrine enhances these currents in some cells but decreases them inothers. T-type Ca2+ currents have many known or suggestedphysiological and pathophysiological roles in growth (protein synthesis,cell differentiation, and proliferation), neuronal firing regulation, someaspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis,cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is anew Ca2+ antagonist that is effective in hypertension andangina pectoris. Its favorable pharmacological profile and limited sideeffects appear to be related to selective block of T-typeCa2+ channels: mibefradil reduces vascular resistance andheart rate without negative inotropy or neurohormonal stimulation, and italso has significant antiproliferative actions.

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Ertel, S.I., Ertel, E.A. & Clozel, JP. T-Type Ca2+ Channels and Pharmacological Blockade: Potential Pathophysiological Relevance. Cardiovasc Drugs Ther 11, 723–739 (1997). https://doi.org/10.1023/A:1007706022381

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