Calcium antagonism in vascular smooth muscle cells

Abstract

Ca2+ ions play critical roles in physiological and pathological signal transduction in vascular smooth muscle cells (VSMC). The control of Ca2+ homeostasis is an important means for modulating excitability and response. A pathological increase of Ca(2+)-dependent vascular tone causes vasospasm and arterial hypertension. Moreover, Ca(2+)-mediated migration, proliferation, matrix production and necrotization of VSMC are important components of atherogenic plaque formation. At least two physiological Ca2+ antagonists are known that compete for Ca2+ binding sites at VSMC: H+ and Mg2+. Effective pharmacological control of Ca2+ homeostasis is exerted by organic Ca2+ antagonists. The prototypical compounds verapamil, nifedipine and diltiazem and their derivatives represent three separate structural categories of drugs that block transsarcolemmal Ca2+ influx by specific interaction at a set of binding sites associated with the alpha 1-subunit of the L-type, voltage-gated Ca2+ channel protein. Selectivity of action of the Ca2+ antagonists may arise from pharmacokinetics, class and subclass of the Ca2+ channel activated, state-dependent interactions or pathological alterations. In human therapy they are the drugs of choice in the treatment of arterial spasms and hypertension. The extent to which their antiatherogenic properties are related to Ca2+ channel antagonism at VSMC remains to be elucidated further.