RhoA kinase and protein kinase C participate in regulation of rabbit stomach fundus smooth muscle contraction.
1. The degree to which the RhoA kinase (ROK) blockers, Y-27632 (1 micro M) and HA-1077 (10 micro M), and the PKC blocker, GF-109203X (1 micro M), reduced force produced by carbachol, a muscarinic receptor agonist, and phenylephrine, an alpha-adrenoceptor agonist, was examined in rabbit stomach fundus smooth muscle. 2. When examining the effect on cumulative carbachol concentration-response curves (CRCs), ROK and PKC blockers shifted the potency EC50 to the right but did not reduce the maximum response. 3. In a single-dose carbachol protocol using moderate ( approximately EC50 and maximum carbachol concentrations, Y-27632 and HA-1077 reduced peak force, but GF-109203X had no effect. By contrast, all three agents inhibited the carbachol contractions of rabbit bladder (detrusor) smooth muscle. 4. Compared to carbachol, phenylephrine produced a weaker maximum response that was not inhibited by phentolamine, atropine nor capsaicin but was inhibited by Y-27632, HA-1077 and GF-109203X. 5. In detrusor, classical down-regulation occurred, but in fundus, up-regulation of responsiveness occurred. This up-regulation in fundus may have been a post-receptor event, because a KCl-induced contraction produced after a carbachol CRC was stronger than one produced before the carbachol stimulus. 6. In conclusion, these data suggest that ROK plays a critical role in the regulation of rabbit fundus smooth muscle contraction, which is distinct from chicken gizzard smooth muscle, where ROK is reported to exist but to not play a role in muscarinic receptor-induced contraction. Additional unique findings are that PKC participates in phenylephrine- but not carbachol-induced contraction in fundus, that carbachol does not activate identical subcellular signalling systems in fundus and detrusor, and that fundus, unlike detrusor, responds to carbachol stimulation with post-receptor up-regulation of contraction.
Ratz
Paul H
PH
Department of Physiological Sciences, Eastern Virginia Medical School, PO Box 1980, Norfolk, Virginia, VA 23501, USA.
Meehl
Joel T
JT
Eddinger
Thomas J
TJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013270:Stomach / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
D000316:Adrenergic alpha-Agonists; D000577:Amides; D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008301:Maleimides; D009125:Muscle Relaxants, Central; D011725:Pyridines; C108830:Y 27632; D010656:Phenylephrine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; C049347:fasudil