Inhibitory mechanisms for cross-bridge cycling: the nitric oxide cGMP signal transduction pathway in smooth muscle relaxation

Relaxation follows sequestration of Ca2+ mobilized by an excitatory stimulu s in striated muscle. Removal of excitatory stimuli also relaxes smooth mus cle in vitro after reductions in the myoplasmic [Ca2+] and dephosphorylatio n of the myosin regulatory light chains. However, there are several experim ental procedures that produce relaxation in the presence of excitatory stim uli and elevated Ca2+-dependent cross-bridge phosphorylation. Of potential widespread physiological importance are treatments that increase myoplasmic [cGMP] owing to the ubiquity of nitric oxide (NO) as a signalling molecule for endothelial-mediated vasodilation and inhibitory nerves in most types of smooth muscle. Several mechanisms are implicated in the NO-cGMP mediated relaxation. Most studies support reductions in myoplasmic Ca2+. However. t here is evidence that increases in cGMP also lower the Ca2+-sensitivity of cross-bridge phosphorylation. This would contribute to a decline in force t hrough actions on the myosin light chain kinase/phosphatase system. In addi tion, changes in the dependence of force on phosphorylation are observed in tissues partially relaxed by treatments that elevate cGMP. This demonstrat es that either the attachment and cycling of phosphorylated crossbridges is impaired or blocked, or that the formation of dephosphorylated, force-gene rating crossbridges ('latch-bridges') is reduced. Protein kinase G-catalyse d phosphorylation of either a thin filament protein that blocks attachment of cross-bridges or a protein that inhibits myosin light chain phosphatase may explain the NO-induced relaxation with elevated cross-bridge phosphoryl ation.