Role of Rho-kinase in guinea-pig gallbladder smooth muscle contraction.
Guinea-pig gallbladder smooth muscle contractions can be elicited pharmacologically by a range of mechanisms. The involvement of Rho-kinase in contractions mediated by receptor-dependent and receptor-independent mechanisms was investigated using the Rho-kinase inhibitor (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide (Y-27632). In a separate series of experiments, the role of Rho-kinase in the contractile response to Ca2+ entry through store-operated Ca2+ channels and to electrical field stimulation was also examined. Y-27632 (10 microM), which caused a significant decrease (P<0.0005) in basal resting tone, significantly inhibited gallbladder contractions evoked by cumulative additions of the G-protein-coupled agonists, carbachol (1 nM-100 microM; P<0.05) and cholecystokinin (10 nM-1 microM; P<0.005). Y-27632 also inhibited the contractions evoked by a single addition of the sarcoplasmic reticulum ATPase inhibitor, thapsigargin (1 microM; P<0.0005) and cumulative additions of KCl (10-85 mM; P<0.0005). The contractile response to Ca2+ entry through store-operated Ca2+ channels was significantly inhibited by Y-27632 (P<0.05) as were the contractile responses evoked by electrical field stimulation (2-25 Hz; P<0.0005). In contrast, Y-27632 had no significant effect on contractions evoked by phorbol 12,13-dibutyrate (0.1 nM-1 microM; a protein kinase C activator) or by the phosphatase inhibitor, cantharidin (100 microM). In conclusion, Rho-kinase contributes to the contractile response in guinea-pig gallbladder smooth muscle evoked by both G-protein-coupled and non-G-protein-coupled mechanisms in addition to contributing to the maintenance of basal tone. It also contributes to the contractile responses resulting from electrical field stimulation and store-operated Ca2+ channel entry.
Quinn
Teresa
T
School of Agriculture, Food Science and Veterinary Medicine, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
Feighery
Ronan
R
Baird
Alan William
AW
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects / Q000201:enzymology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology*; D009543:Nifedipine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D054460:rho-Associated Kinases
D000577:Amides; D002121:Calcium Channel Blockers; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D011189:Potassium Chloride; D019284:Thapsigargin; D002217:Carbachol; D002766:Cholecystokinin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D009543:Nifedipine; D002118:Calcium