Quintessence of Vascular Ca2+ and K+ channels

Vascular tone and hence blood pressure are determined by the contractile state of vascular smooth muscle cells (VSMCs) within the blood vessel wall, which is regulated by intracellular calcium concentration ([Ca]i). Vasoconstrictors act through increasing [Ca]i as well as on the apparent calcium sensitivity of the contractile process in VSMCs, whereas relaxing factors have the opposite effect. In contrast, an elevation in endothelial [Ca]i induces relaxation of the adjacent VSMCs. Therefore, fine tuning of [Ca]i in both cell types is imperative for precise regulation of organ and tissue perfusion. The major pathways for an increase in myocyte [Ca]i are voltage-dependent Ca 2+ channels (VDCC) and nonselective cation channels at the plasmalemmal membrane or the internal store release channels, i.e., the ryanodine (RyR) and the inositol trisphosphate (IP3R) receptors found in the sarcoplasmic reticulum (SR) membrane (FIGURE 1). Global [Ca]i is mainly dictated by the open state probability of L-type VDCC, which are finely controlled by the membrane potential. Activity of different ion channels present at the plasma membrane such as K+, Cl–, and cation channels govern the membrane potential and therefore affect the VDCC activity and calcium entry. Opening of K+ channels such as the large-conductance Ca2+-activated K+ channel (BK) hyperpolarizes the membrane, promoting closure of VDCC and thus opposing vasoconstriction. In contrast to the VSMCs, an increase in endothelial [Ca]i results in vascular relaxation through endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF) (FIGURE 1). Furthermore, due to the absence of VDCC, hyperpolarization of the endothelial membrane by activation of Ca2+-sensitive K+ channels does not reduce calcium influx. In fact, membrane potential hyperpolarization would promote calcium entry possibly involving transient receptor potential channels (TRPC1, TRPC3, TRPC4, TRPC6, TRPV4, etc.) through an elevation of the electrochemical driving force for Ca2+ (2, 129).