Rho‐kinase inhibition and electromechanical coupling in rat and guinea‐pig ureter smooth muscle: Ca²⁺‐dependent and ‐independent mechanisms

Abstract

2+ -independent increase in the relaxation rate of contraction, associated with acceleration of MLC dephosphorylation, which was sensitive to calyculin A. These data show for the first time that: (1) Rho-kinase has major effects on Ca 2+ signalling associated with the action potential, (2) this effect is species dependent and (3) Rho-kinase controls relaxation of phasic contraction of myogenic origin. Thus Rho-kinase can modulate phasic smooth muscle in the absence of agonist, and the mechanisms are both Ca 2+ -dependent, involving ion channels, and Ca 2+ -independent, involving MLC phosphorylation activity.

Calcium Sensitization in Human Esophageal Muscle: Role for RhoA Kinase in Maintenance of Lower Esophageal Sphincter Tone

“…Both Y-27632 and HA-1077 significantly attenuated contraction over a range of concentrations 100-fold lower than that found to inhibit PKC, consistent with their selective inhibition of RhoA kinase in other smooth muscles (Rattan et al, 2003;Somlyo and Somlyo, 2003;Shabir et al, 2004;Gokina et al, 2005;Harnett et al, 2005). Contractions elicited by different stimuli showed similar sensitivity, showing internal consistency.…”

“…7B). However, attenuation in the evoked rise of [Ca 2ϩ ] i also accompanied treatment with RhoA-kinase blockers, similar to a previous report (Shabir et al, 2004). We examined the concentration dependence of this effect and found that the reduction in contraction was most apparent with 10 M Y-27632 (Fig.…”

“…In an elegant series of experiments, Shabir et al (2004) demonstrated that blockade of RhoA kinase did decrease phasic contraction of ureter smooth muscle, in part due to reduction of voltage-dependent Ca 2ϩ current. This effect of RhoA-kinase blockers was evident in rats, but not guinea pig ureters, indicating species differences and meriting investigation of human tissues.…”

Role of Protein Kinase Cζ and Calcium Entry in KCl-Induced Vascular Smooth Muscle Calcium Sensitization and Feedback Control of Cellular Calcium Levels

“…In most studies, the ROCK inhibitor Y-27632 has been shown to inhibit KCl-induced F without inhibiting KCl-induced increases in calcium (for review, see Ratz et al, 2005). However, 1 M Y-27632 dramatically inhibits VOCC activity in the phasic rat ureter (Shabir et al, 2004), and Y-27632 can inhibit nonselective cation channels that are distinct from VOCCs (Ghisdal et al, 2003). Our data showed that Y-27632 caused inhibition of the early phase of the KCl-induced increase in calcium, but HA-1077 and H-1152, ROCK inhibitors structurally distinct from Y-27632 (Hidaka and Kobayashi, 1992;Uehata et al, 1997;Sasaki et al, 2002), did not.…”

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

“…Many smooth muscle tissues display plateau-like electrical activity, which dictates the amplitude and duration of contraction [22][23][24][25] , and this includes the circular muscle layer of the mouse myometrium 24 . While the level of the plateau in many cases is close to that observed in human myometrium, À 25 to À 30 mV, a striking feature of the AP plateau in human myometrium is the rapidity of repolarization.…”