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Received June 25, 2004
Revised August 2, 2004
Accepted after revision August 25, 2004
1 The University of Liverpool
2 A.V. Palladine Institute of Biochemistry
3 University of Liverpool
* To whom correspondence should be addressed. E-mail: burdyga{at}liv.ac.uk.
Recent data have shown Ca2+-dependent activation of Rho-kinase by sustained depolarization of arterial smooth muscle. Visceral smooth muscles however contract phasically in response to action potentials and it is unclear whether Ca2+-dependent or independent Rho-kinase activation occurs. We have therefore investigated this, under physiologically relevant conditions, in intact ureter. Action potentials, ionic currents, Ca2+ transients, myosin light chain (MLC) phosphorylation and phasic contraction evoked by action potentials in guinea pig and rat ureter, were investigated. In rat, but not guinea pig ureter, three Rho-kinase inhibitors, Y-27632, HA-1077 and H-1152, significantly decreased phasic contractions and Ca2+ transients. Voltage and current clamp data showed that Rho-kinase inhibition, reduced the plateau component of the action potential, inhibited Ca2+-channels and, indirectly, Ca2+-activated Cl- channels. The Ca2+ channel agonist, Bay K8644, could reverse these effects. The K+ channel blocker TEA could also reverse the inhibitory effect of Y-27632 on the action potential and Ca transient. Ca2+ transients and inward current, activated by carbachol-induced SR Ca2+-release, were not affected by Rho-kinase inhibition. Rho-kinase inhibition produced a Ca2+-independent increase in the relaxation rate of contraction, associated with acceleration of MLC dephosphorylation, which was Calyculin A sensitive. These data show, for the first time, (1) Rho-kinase has major effects on Ca2+ signalling associated with the action potential, (2) that 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 Ca2+-dependent, involving ion channels and Ca2+-independent, involving MLCP activity.
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