COX-1 vs. COX-2 as a determinant of basal tone in the internal anal sphincter.
Prostanoids, produced endogenously via cyclooxygenases (COXs), have been implicated in the sustained contraction of different smooth muscles. The two major types of COXs are COX-1 and COX-2. The COX subtype involved in the basal state of the internal anal sphincter (IAS) smooth muscle tone is not known. To identify the COX subtype, we examined the effect of COX-1- and COX-2-selective inhibitors, SC-560 and rofecoxib, respectively, on basal tone in the rat IAS. We also determined the effect of selective deletion of COX-1 and COX-2 genes (COX-1(-/-) and COX-2(-/-) mice) on basal tone in murine IAS. Our data show that SC-560 causes significantly more efficacious and potent concentration-dependent decreases in IAS tone than rofecoxib. In support of these data, significantly higher levels of COX-1 than COX-2 mRNA were found in the IAS. In addition, higher levels of COX-1 mRNA and protein were expressed in rat IAS than rectal smooth muscle. In wild-type mice, IAS tone was decreased 41.4 +/- 3.4% (mean +/- SE) by SC-560 (1 x 10(-5) M) and 5.4 +/- 2.2% by rofecoxib (P < 0.05, n = 5). Basal tone was 0.172 +/- 0.021 mN//mg in the IAS from wild-type mice and significantly less (0.080 +/- 0.015 mN/mg) in the IAS from COX-1(-/-) mice (P < 0.05, n = 5). However, basal tone in COX-2(-/-) mice was not significantly different from that in wild-type mice. We conclude that COX-1-related products contribute significantly to IAS tone.
de Godoy
Márcio A F
MA
Division of Gastroenterology & Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Rattan
Neeru
N
Rattan
Satish
S
D001003:Anal Canal / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D015153:Blotting, Western; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C115461:SC 560; D013450:Sulfones; C034671:prostaglandin F2alpha receptor; C116926:rofecoxib; C121227:AL 8810; D015237:Dinoprost; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D007213:Indomethacin