REGULATION OF VASCULAR SMOOTH-MUSCLE TONE

Vascular smooth muscle tone is regulated primarily by the sarcoplasmic free Ca2+ concentration, which determines the level of myosin phospho rylation. Stimulation of the muscle results in an increase in free [Ca 2+], whereupon Ca2+ binds to calmodulin, inducing a conformational cha nge enabling calmodulin to interact with and activate myosin light cha in kinase. The active Ca2+ . calmodulin . myosin light chain kinase co mplex catalyses the phosphorylation of serine-19 of the two 20-kDa lig ht chains of myosin; this triggers cross-bridge cycling and the develo pment of force. Relaxation follows restoration of free [Ca2+] to the r esting level, whereupon calmodulin dissociates from myosin light chain kinase, which is thereby inactivated, and myosin is dephosphorylated by myosin light chain phosphatase and remains detached from actin. Ove rwhelming evidence now exists in favour of the central role of myosin phosphorylation-dephosphorylation in smooth muscle contraction - relax ation. However, considerable evidence supports the existence of additi onal, secondary mechanisms that can modulate the contractile state of smooth muscle either by altering the Ca2+ sensitivity of the contracti le response or otherwise modulating one of the molecular events occurr ing downstream of the Ca2+ signal, e.g., the interaction of phosphoryl ated myosin heads with actin. The interplay of several regulatory elem ents confers on the contractile response of vascular smooth muscle the high degree of flexibility and adaptability required for the effectiv e regulation of blood pressure.