Cardiovascular calcium channel blockers: historical overview, development and new approaches in design

Abstract

Role of calcium and calcium channels in vascular smooth muscle contraction. Calcium is a key component of the excitation–contraction coupling process, which occurs within the cardiovascular system. It acts as a cellular messenger to link internal or external excitation with cellular response. Increased cytosolic concentrations of Ca2+ result in the binding of Ca2+ to a regulatory protein, either troponin C in cardiac and skeletal muscle or calmodulin in vascular smooth muscle. This initial binding of Ca2+ uncovers myosin binding on the actin molecule, and subsequent interaction between actin and myosin result in muscle contraction. All these events are reversed once the cytosolic concentration of Ca2+ decreases. In this situation, Ca2+ binding troponin C or calmodulin is diminished or removed, binding sites are concealed, actin and myosin no longer interact and muscle contraction ceases [1,2]. Mechanisms of calcium movement and storage. The regulation of cytosolic calcium levels occurs via specific influx, efflux, and sequestering mechanism (Fig. 1) [3]. Intracellular calcium increases via the voltage-gated channels, receptor-mediated channels, Na2+/Ca2+and Na2+/H+-exchangers store-operated channels. Influx via either receptor-operated or voltage-dependent channels has been proposed to be the major entry pathway for Ca2+. Receptor-operated channels have been defined as those associated with cellular membrane receptors and activated by specific agonist-receptor interactions. In contrast, potential-dependent channels, also known as voltage-dependent or voltage-gated calcium channels, have been defined as those activated by membrane depolarization. The Na+/Ca2+ exchange process can promote either influx or efflux because the direction of Ca2+ movement depends upon the relative intracellular and extracellular ratio of Na+ and Ca2+. The «leak» pathways, which include unstimulated Ca2+ entry as well as entry during the fast inward Na+ phase of an action potential, play only a minor role in calcium influx. Ca2+ decreases via the sarco/endoplasmic reticulum calcium ATPase (SERCA) pump, plasma membrane calcium ATPase pump, permeability transition pore, and Na2+/Ca2+ exchangers. In addition to these influx and efflux mechanisms, the sarcoplasmic reticulum and the mitochondria function as internal storage/release sites. These storage sites work in concert with the influx and efflux processes to assure that cytosolic calcium level are appropriate for cellular needs. While influx and release processes are essential for excitation–contraction coupling, efflux and sequestering processes are equally important for terminating the contractile process and for protecting the cell from the deleterious effects of Ca2+ overload [4–6].