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Activity and Expression of Soluble and Particulate Guanylate Cyclases in Myometrium from Nonpregnant and Pregnant Women: Down-Regulation of Soluble Guanylate Cyclase at Term

Department of Obstetrics and Gynecology, University of Glasgow (J.F.T., A.J.T., J.E.N.), Glasgow, Scotland G31 2ER; Departments of Obstetrics and Gynecology, Pediatrics, and Animal Sciences, University of Wisconsin, Perinatal Research Laboratories (H.I., R.R.M.), Madison, Wisconsin 53715; Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (K.N.), Kyoto 606-01, Japan; and Maternal and Fetal Research Unit, Department of Obstetrics and Gynecology, GKT School of Medicine, St. Thomas’ Hospital (J.S.C., L.P., R.M.T.), London, United Kingdom SE1 7EH

Address all correspondence and requests for reprints to: Ronald R. Magness, Ph.D., Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin, 7E Meriter Hospital/Park, 202 South Park Street, Madison, Wisconsin 53715. E-mail: rmagness{at}facstaff.wisc.edu

Abstract

The role of cGMP in the regulation of human myometrial smooth muscle contractility is at present unclear. cGMP can be synthesized by a cytoplasmic, soluble guanylate cyclase (sGC), which is stimulated by nitric oxide and carbon monoxide, and by particulate membrane-bound GC, which are activated by natriuretic peptides. The aim of this study was to determine whether sGC or pGC are present in nonpregnant and pregnant human myometrium, and whether the activity and expression of these enzymes and the cGMP content change during pregnancy and with labor. Myometrium was obtained from nonpregnant women (n = 12) and pregnant women who were preterm (25–34 wk gestation; n = 12), term (>38 wk) not in labor (n = 14), or term in active labor (n = 12). The cGMP content in myometrium obtained from preterm deliveries was significantly higher than that in tissue obtained from nonpregnant women and decreased at term, especially in laboring groups. Protein and mRNA for sGC, particulate GC-A, GC-B, and the clearance receptor were detected in human myometrium. cGMP in pregnant human myometrium, however, appears to be produced predominately by sGC and possibly by GC-B, as GC-A was only weakly expressed. sGC activity was greater in myometrium from preterm (nonlabor) deliveries compared those taken at term (in labor), but was down-regulated compared with activity in nonpregnant myometrium. Neither atrial natriuretic peptide nor C-type natriuretic peptide (agonists for GC-A and GC-B, respectively) altered contractility in vitro of myometrium from women at term (not in labor). We conclude that the cGMP/guanylate cyclase system in human myometrium is gestationally regulated and potentially plays an important role in mediating quiescence during early pregnancy. A reduction in cGMP availability may contribute to the switch to contractile activity at term.

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