Extrusion of calcium from the smooth muscle cell occurs through the sarcolemmal Ca++-ATPase and a 3Na+-1Ca++ antiporter. This process competes with the sequestration of calcium in the sarcoplasmic reticulum (SR) by SERCA, resulting in a reduction of calcium accumulation in the SR. When the calcium concentration in the SR decreases, the SR initiates calcium influx into the cell through store-operated calcium entry (SOCE), a process that facilitates refilling of the SR. Specifically, the protein STIM1, located in the SR, monitors the calcium concentration and initiates calcium influx through the sarcolemmal channel protein Orai via protein-protein interaction. This calcium influx during SOCE is believed to occur in the confined space between the caveolae and peripheral SR of smooth muscle. Recent studies suggest that STIM1-Orai mediated SOCE may also contribute to the increase in intracellular calcium following stimulation of the α1-adrenergic receptor. The STIM1-Orai complex is also implicated in the remodeling of smooth muscle in pathological conditions such as restenosis after balloon angioplasty.

Apart from the stimulatory effects of various agents on sarcolemma calcium channels and InsP3 cascades, there are several inhibitory factors that decrease myoplasmic calcium concentration, leading to smooth muscle relaxation. For instance, drugs belonging to the dihydropyridine class, which block calcium channels, decrease calcium influx through sarcolemmal L-type voltage-gated calcium channels and reduce vasomotor tone. Similarly, drugs that open potassium channels in the sarcolemma, like hydralazine, promote relaxation by hyperpolarizing the membrane potential, thereby reducing calcium influx through voltage-gated calcium channels. On the other hand, agents that decrease potassium permeability of the sarcolemma may induce vasoconstriction by inducing membrane depolarization, leading to increased calcium influx through the same voltage-gated calcium channels. Smooth muscle also contains receptor-activated calcium channels, and the conductance of these channels is linked to receptor occupancy.

Various drugs and hormones relax smooth muscle by increasing the cellular concentrations of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Nitric oxide (NO), produced by nerves and vascular endothelial cells, induces smooth muscle relaxation by increasing cGMP levels. Acetylcholine released from parasympathetic fibers causes vasodilation by stimulating the production of NO by vascular endothelial cells. Shear stress and adenosine, released from exercising muscle, can also promote NO release from vascular endothelial cells. The molecular mechanisms underlying the cGMP-dependent relaxation of vascular smooth muscle are intricate and involve the inhibition of inositol trisphosphate (InsP3) production, inhibition of the InsP3 receptor, activation of myosin light-chain phosphatase, and activation of the calcium-activated potassium channel (BKCa), which promotes hyperpolarization of the cells and inhibits calcium influx through voltage-gated calcium channels.
Calcium is extruded from the smooth muscle cell by the activity of sarcolemmal Ca++-ATPase and by a 3Na+-1Ca++ antiporter (i.e., 3 Na+ ions enter the cell for each Ca++ ion extruded). Extrusion of Ca++ from the cell competes with sequestration of Ca++ in the SR by SERCA and thus reduces the accumulation of Ca++ in the SR. When the [Ca++] in the SR decreases, the SR is thought to initiate Ca++ influx into the cell through a process called store-operated Ca++ entry (SOCE) to facilitate refilling of the SR. Specifically, stromal interaction molecule 1 (STIM1) in the SR is hypothesized to monitor SR [Ca++] and then initiate Ca++ influx through the sarcolemmal channel protein Orai through a protein-protein interaction. Thus the influx of Ca++ during SOCE is thought to occur in the confined space between the caveolae and peripheral SR of smooth muscle. Recent studies raise the possibility that STIM1-Orai–mediated SOCE may also contribute to the rise in intracellular Ca++ transient in smooth muscle following α1-adrenergic receptor stimulation. The Stim1-Orai complex has also been implicated in remodeling of smooth muscle in pathological conditions such as restenosis following balloon angioplasty.
In addition to the stimulatory effects of various agents on sarcolemma Ca++ channels and InsP3 cascades, there are several inhibitory factors that lower myoplasmic [Ca++] and thereby relax smooth muscle. For example, the dihydropyridine class of Ca++ channel blocking drugs decreases the influx of Ca++ through sarcolemmal L-type voltage-gated Ca++ channels and reduces vasomotor tone. Similarly, drugs that open K+ channels in the sarcolemma (e.g., hydralazine) promote relaxation (e.g., vasodilation) by hyperpolarizing the membrane potential, which reduces the influx of Ca++ through voltage-gated Ca++ channels. Conversely, agents that decrease K+ permeability of the sarcolemma may promote vasoconstriction by inducing membrane depolarization, which then increases influx of Ca++ through these same voltage-gated Ca++ channels. Smooth muscle also contains receptor-activated Ca++ channels. Conductance of these receptor-activated Ca++ channels is linked to receptor occupancy.
A variety of drugs and hormones relax smooth muscle by increasing the cellular concentrations of cAMP or cGMP.
Nitric oxide (NO) is produced by nerves and vascular endothelial cells and relaxes smooth muscle by increasing cGMP (
Fig. 14.12 ). Acetylcholine released from parasympathetic fibers causes vasodilation in some vascular beds as a result of stimulating the production of NO by vascular endothelial cells. Shear stress and adenosine (e.g., released from exercising muscle) may also promote NO release from vascular endothelial cells. The molecular mechanisms underlying the cGMP-dependent relaxation of vascular smooth muscle are complex and have been reported to involve (1) inhibition of InsP3 production, (2) inhibition of the InsP3 receptor, (3) activation of myosin light-chain phosphatase, and (4) activation of the Ca++-activated K+ channel (BKCa), which promotes hyperpolarization of the cells and thus inhibits Ca++ influx through voltage-gated Ca++ channels.