The relationship between nitric oxide synthase (NOS) and cyclooxygenase (COX) in the control of cervical ripening and parturition



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Stephen G. Marx\r\nThe University of Texas Medical Branch at Galveston, April 2005\r\n\r\nSupervisor: Robert E. Garfield\r\n\r\nThe purpose of these studies is to examine if there is relationship between iNOS and COX-2 in the control of cervical ripening and parturition. Cervices were obtained from estrus and timed pregnant Sprague-Dawley rats (n = 4-10 per group) under normal conditions; or after treating with LPS (100ƒÝg i.p.), Onapristone (3mg/rat), progesterone (2.5 mg, twice daily), L-NAME (50mg/day), or SNP (0.3mg/rat). Collagen changes were measured and visualized with the picrosirius polarization method. Expression of iNOS and COX-2 mRNA was determined using RT-PCR. Immunohistochemistry (IHS) was performed for localization of the iNOS and COX-2 enzymes (significance: P<0.05). Picrosirius polarization showed a decrease in the organization and birefringence of the cervical collagen from the non-pregnant state through pregnancy and is supported by changes in the luminosity (P<0.001). The iNOS and COX-2 enzymes were mainly localized in the cervical muscle with labeling also in the vascular smooth muscle and epithelium. Under normal term pregnant conditions, iNOS mRNA levels decrease as COX-2 mRNA levels increased demonstrating an inverse correlation (Spearman r = -0.497; P = 0.00295). Onapristone stimulated preterm labor and/or birth causing a parallel increase in iNOS and COX-2 mRNA demonstrating a positive correlation (Spearman r = 0.456; P = 0.03). Progesterone prolonged pregnancy stimulating a decrease in the iNOS and COX-2 (P=0.036) mRNA. In comparing term to preterm laboring conditions, there is a significant increase in the iNOS mRNA (P=0.004) but not the COX-2 mRNA. LPS enhanced the iNOS mRNA (P<0.001) but had no effect on the COX-2 mRNA. L-NAME had no effect on the COX-2 or iNOS mRNA. SNP decreased the COX-2 and iNOS with the decrease in the iNOS being significant (P=0.007). In conclusion, under normal term pregnant conditions iNOS and COX-2 play an important role in regulating cervical ripening and parturition but the pathways appear to act independently of one another in regulating iNOS and COX-2 expression at the mRNA level. Under preterm laboring conditions, when NO is up regulated and/or over expressed, there may be an interaction between the NO and PG pathways in the control of cervical ripening and parturition. \r\n\r\n



prostagladins, prolongation of pregnancy, preterm labor, nitric oxide, iNOS, COX2, cervix