MECHANISMS OF VASORELAXATION

The regulation of vascular resistance is critical to the maintenance of circulatory homeostasis. The primary regulator of this resistance is the level of contraction of vascular smooth muscle, which is determined by the balance of factors that cause contraction with those that cause relaxation of this muscle. This review will feature the latter. However, to do this in a meaningful manner, specific contractile factors will also be considered. Under physiological conditions, vascular smooth muscle (VSM) contraction requires a concentration of ionized calcium ([Ca2+]i) in the cytosol greater than 10(-7) M and an energy source, ATP. Normally, [Ca2+]i is the regulated variable that determines the magnitude of contraction (VSM tone). Relaxation is effected by mechanisms represented in Fig. 1 that reduce [Ca2+]i and are therefore relevant to this review. Two of the mechanisms utilize active pumps requiring energy from ATP to move calcium out of the cytosol against large concentration gradients. These are the ATPase of the calcium efflux pump in the plasma membrane and the ATPase that sequesters calcium into the sarcoplasmic reticulum (SR). The third calcium-lowering mechanism is the sodium-calcium exchanger. This exchanger couples the energy derived from the movement of sodium down its concentration gradient into the cell to the extrusion of calcium from the cell. The concentration of ionized calcium inside the cell is a net value determined by the relative rates of calcium movement into the cell and the sum of the activities of these three [Ca2+]i-lowering mechanisms. The nature of this balance indicates yet another means by which [Ca 2+]i may be reduced to produce VSM relaxation. This is obviously a reduction in the rate of calcium entry into the cytosol, as would result from the action of a calcium channel antagonist, or, indirectly, by hyperpolarization of the plasma membrane or interference with other calcium delivery systems.