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

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