Vasodilators tend to have effects on smooth muscle ion channels that oppose those of vasoconstrictors (Figure 3). In general, they reduce Ca2+ influx by a number of mechanisms (see Figure 3), leading to a reduction in intracellular Ca2+, smooth muscle relaxation, and vasodilation. The only exceptions to this pattern are vasodilators that act through the cAMP-PKA signaling cascade. Voltage-gated Ca2+ channels are phosphorylated by PKA, leading to their activation. Although counter to the general Ca2+-lowering trend induced by most dilators, this increased activity in voltage-gated Ca2+ channels may provide local Ca2+ to maintain the activity of BKCa channels (see Figure 1), despite a general lowering of intracellular Ca2+ by other means.
In skeletal muscle, cardiac muscle, and the brain, increases in tissue activity lead to release of K+ ions from the active cells, resulting in elevation of the extracellular concentration of K+ from 5 mM to between 8 and 20 mM. Such increases in extracellular K+ can activate smooth muscle KIR channels leading to membrane hyperpolarization and vasodilation (Figure 3). In arterioles where smooth muscle cells are electrically coupled to endothelial cells by myoendothelial gap junctions, endothelial KIR channels may contribute to K+-induced hyperpolarization and vasodilation through a similar mechanism (Figure 4).
Vasodilators such as acetylcholine, bradykinin, ATP, and histamine lead to relaxation of vascular smooth muscle and decreases in arteriolar tone in intact arterioles by stimulating the release of vasodilator substances from endothelial cells. Ion channels play an important part in this process, as outlined in Figure 4. Calcium-dependent activation of sKCa and IKCa channels hyperpolarizes endothelial cells and augments Ca2+ influx through SOC, providing a maintained increase in intracellular Ca2+ to support endothelial autacoid production. In addition, the endothelial hyperpolarization, per se, may be transmitted through myoendothelial gap junctions to hyperpolarize and relax the overlying smooth muscle (Figure 4). Shear stress and increases in extracellular K+ may also hyperpolarize endothelial cells by activation of Kir channels. These channels may also be recruited by membrane hyperpolarization caused by activation of other K+ channels serving to amplify the initial hyperpolarization. Hyperpolarization-induced activation of KIR channels also may allow conduction of hyperpolarization from endothelial cell to endothelial cell, that are coupled by gap junctions, providing a means to transmit hyperpolarization for long distances along arterioles. Similar to their effects on smooth muscle, vasodilators such as adenosine also may activate Katp channels on endothelial cells, providing another pathway for endothelial cell hyperpolarization and regulation of arteriolar tone (pathway not shown in Figure 4). Thus, ion channels significantly contribute to the mechanism of action of vasodilators both in smooth muscle and in endothelial cells.
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