Vasoconstrictors bind to their receptors on the cell surface to activate phospholipase C and Ca²⁺ channels, resulting in the mobilization of Ca²⁺ from intracellular are extracellular Ca²⁺ pools and protein kinase C activation. Vasoconstrictors are also thought to activate a distinct cellular mechanism for downregulating 20kDa myosin light chain (MLC₂₀) phosphatase activity, which involves Rho p21 and protein kinase C, resulting in an increase in the Ca²⁺ sensitivity of MLC₂₀ phosphorylation. Protein kinase C also appears to activate a MLC₂₀ phosphorylation-independent mechanism for contraction, contributing to the maintenance of agonist-induced contraction. On the other hand, vasorelaxants inhibit activation of phospholipase C and gating of Ca²⁺ channels, or stimulate Ca²⁺ extrusion across the plasma membrane, leading to a decrease in the [Ca²⁺]i. Vasorelaxants also appear to stimulate MLC₂₀ phosphatase activity, resulting in a further reduction of contractile response. The modulatory mechanism for changing the Ca²⁺ sensitivity, together with the major regulatory mechanism for cellular Ca²⁺metabolism, plays an important role in regulating vascular smooth muscle tone.