The hyperactivity of the RhoA/ROK signaling cascade has been linked to various pathological conditions such as hypertension and vasospasm. In hypertensive animals, an increased level of activated RhoA, upregulation of ROK, and enhanced agonist-induced Ca++ sensitization of contraction were observed in the vascular smooth muscle, along with a greater reduction in blood pressure when treated with ROK inhibitors compared to normotensive controls. Similar findings were observed in hypertensive patients, where ROK inhibitors were found to decrease forearm vascular resistance to a greater extent than in normotensive individuals. ROK inhibitors have also been shown to reverse or prevent experimentally induced cerebral vasospasm and coronary vasospasm, as well as the associated upregulation of RhoA/ROK and increased myosin light-chain phosphorylation. The hyperactivity of RhoA/ROK has also been implicated in bronchial asthma, erectile dysfunction, and preterm labor, as evidenced by the effects of ROK inhibitors. Additionally, ROK inhibitors have been found to decrease vascular smooth muscle proliferation and reduce restenosis after balloon angioplasty in the rat carotid artery.

During a phasic contraction, myoplasmic [Ca++], cross-bridge phosphorylation, and force all peak and then return to baseline (Fig. 14.9). On the other hand, during a tonic contraction, myoplasmic [Ca++] and cross-bridge phosphorylation initially spike but do not return to baseline levels. Instead, force gradually increases and remains at a high level (refer to Fig. 14.9). This sustained force is maintained with only 20% to 30% of the cross-bridges phosphorylated, resulting in reduced ATP utilization. The term "latch state" is used to describe this condition of tonic contraction where force is sustained with low energy expenditure.
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.