Contribution of Rho-kinase to membrane excitability of murine colonic smooth muscle.
OBJECTIVE
The Rho-kinase pathway regulates agonist-induced contractions in several smooth muscles, including the intestine, urinary bladder and uterus, via dynamic changes in the Ca(2+) sensitivity of the contractile apparatus. However, there is evidence that Rho-kinase also modulates other cellular effectors such as ion channels.


METHODS
We examined the regulation of colonic smooth muscle excitability by Rho-kinase using conventional microelectrode recording, isometric force measurements and patch-clamp techniques.


RESULTS
The Rho-kinase inhibitors, Y-27632 and H-1152, decreased nerve-evoked on- and off-contractions elicited at a range of frequencies and durations. The Rho-kinase inhibitors decreased the spontaneous contractions and the responses to carbachol and substance P independently of neuronal inputs, suggesting Y-27632 acts directly on smooth muscle. The Rho-kinase inhibitors significantly reduced the depolarization in response to carbachol, an effect that cannot be due to regulation of Ca(2+) sensitization. Patch-clamp experiments showed that Rho-kinase inhibitors reduce GTPγS-activated non-selective cation currents.


CONCLUSIONS
The Rho-kinase inhibitors decreased contractions evoked by nerve stimulation, carbachol and substance P. These effects were not solely due to inhibition of the Ca(2+) sensitization pathway, as the Rho-kinase inhibitors also inhibited the non-selective cation conductances activated by excitatory transmitters. Thus, Rho-kinase may regulate smooth muscle excitability mechanisms by regulating non-selective cation channels as well as changing the Ca(2+) sensitivity of the contractile apparatus.
Department of Physiology and Cell Biology, University of Nevada Reno, School of Medicine, USA.
O
O
Bayguinov
L
L
Dwyer
H
H
Kim
A
A
Marklew
K M
KM
Sanders
S D
SD
Koh
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology*; D003106:Colon / Q000294:innervation / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials; D051379:Mice; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000294:innervation / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000577:Amides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011725:Pyridines; C108830:Y 27632; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002217:Carbachol; D054460:rho-Associated Kinases
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