HyperactivityoftheRhoA/ROKsignalingcascadehasbeenimplicatedinvariouspathologicalconditionssuchashypertensionandvasospasm.HyperactivityofRhoA/ROKinthevascularsmoothmuscleofhypertensiveanimals,forexample,wasmanifestedbyincreasedlevelsofactivatedRhoA,upregulationofROK,enhancementofagonist-inducedCa++ sensitizationofcontraction,andagreaterreductioninbloodpressurebyROKinhibitorsascomparedwithnormotensivecontrols.Asimilartrendwasobservedinhumans,inthatROKinhibitorsdecreasedforearmvascularresistanceinhypertensivepatientstoagreaterextentthaninnormotensivecontrols.ROKinhibitorshavealsobeenshowntoreverseorpreventexperimentallyinducedcerebralvasospasmandcoronaryvasospasm,aswellastheassociatedupregulationofRhoA/ROKandincreasedmyosinlight-chainphosphorylation.HyperactivityofRhoA/ROKhasadditionallybeenimplicatedinbronchialasthma,erectiledysfunction,andpretermlabor,asevidencedbytheeffectsofROKinhibitors.Inaddition,ROKinhibitorshavedecreasedvascularsmoothmuscleproliferationandreducedrestenosisafterballoonangioplastyinratcarotidartery.
During a phasic contraction, myoplasmic [Ca++], cross-bridge phosphorylation, and force reach a peak and then return to baseline (
Fig. 14.9 ). In contrast, during a tonic contraction, myoplasmic [Ca++] and cross-bridge phosphorylation decline after an initial spike but do not return to baseline levels. During this later phase, force slowly increases and is sustained at a high level (see
Fig. 14.9).
This sustained force is maintained with only 20% to 30% of the cross-bridges phosphorylated, and thus ATP utilization is reduced. The term latch state refers to this condition of tonic contraction during which force is maintained at low energy expenditure.