MINIREVIEW Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation Iain L. O. Buxton Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada Received October 13, 2003; accepted February 18, 2004 This article is available online at http://molpharm.aspetjournals.org ABSTRACT Premature birth accounts for the majority of fetal morbidity and mortality in the developed world and is disproportionately rep- resented in some populations, such as African Americans in the United States. The costs associated with prematurity are stag- gering in both monetary and human terms. Present therapeutic approaches for the treatment of labor leading to preterm deliv- ery are inadequate and our understanding of the regulation of myometrial smooth muscle contraction-relaxation is incom- plete. The ability of nitric oxide to relax smooth muscle has led to an interest in employing nitric oxide-donors in the treatment of preterm labor. Fundamental differences exist, however, in the regulation of uterine smooth muscle relaxation and that of other smooth muscles and constitute a conundrum in our un- derstanding. We review the evidence that nitric oxide-mediated relaxation of myometrial smooth muscle, unlike vascular or gastrointestinal smooth muscle, is independent of global ele- vation of cyclic guanosine 5'-monophosphate. Applying our current understanding of microdomain signaling and taking clues from genomic studies of pregnancy, we offer a framework in which to view the apparent conundrum and suggest testable hypotheses of uterine relaxation signaling that can explain the mechanistic distinctions. We propose that understanding these mechanistic distinctions in myometrium will reveal molecular targets that are unique and thus may be explored as therapeu- tic targets in the development of new uterine smooth muscle- specific tocolytics. The precise physiological processes leading to birth are mysterious and the physiology of preterm labor (PTL) is unknown (Buxton et al., 2000). The majority of PTL becomes preterm delivery (PTD), accounting for 9 to 11% of births in the United States (ACOG Bulletin, 2003). If a test were available to predict PTL as well as its onset, we would fail to prevent the delivery of a preterm fetus, because there is no safe and effective means of halting labor and maintaining pregnancy until term. Although various tocolytics are in rou- tine use, their efficacy and safety are questionable. Thus, a basic understanding of the mechanisms regulating the contractile state of uterine smooth muscle will have imme- diate and important clinical utility. For several years now, we have been focused on studies of myometrial function with the goal of improving our understanding of the regulation of relax- ation. Working first in guinea pig, then monkey, and now with an emphasis in human tissues, we have concluded that uterine smooth muscle is neither vascular nor gastrointestinal smooth muscle. Beyond the obvious absurdity of this statement lies a biochemical conundrum. That is, studies of receptor signal- transduction in these other muscles does not teach us what we need to know about myometrium; therefore, if the critical prob- lem of treating PTL and PTD is to be solved, we must focus on basic studies in myometrium, preferably human myometrium. The following pages describe a conundrum in cyclic nucleotide signaling that grew out of these observations of the capacity of nitric oxide to relax myometrium. Nitric Oxide and Uterine Function Interest in the ability of NO donors to relax myometrium (Kuenzli et al., 1996, 1998; Bradley et al., 1998; Buxton et al., This work was supported by grants from the Clayton Foundation for Re- search, the Robert Z. Hawkins Foundation, and the National Institutes of Health. ABBREVIATIONS: PTL, preterm labor; PTD, preterm delivery; sGC, soluble guanylate cyclase; BK, large conductance potassium channel; SK, small conductance potassium channel; PKG, protein kinase G; rMLC 20 , 20-kDa regulatory myosin light chain; MLCK, myosin light chain kinase; MP, myosin phosphatase holoenzyme; MBS, myosin-binding subunit; PP1, myosin phosphatase; ROK, Rho kinase; SIN-1, 3-morpholinosyd- nonimine; SNAP, S-nitroso N-acetyl penicillamine; PGC, particulate guanylyl cyclase; NAADP, nicotinic acid adenine dinucleotide phosphate. 0026-895X/04/6505-1051–1059$20.00 MOLECULAR PHARMACOLOGY Vol. 65, No. 5 Copyright © 2004 The American Society for Pharmacology and Experimental Therapeutics 3026/1149361 Mol Pharmacol 65:1051–1059, 2004 Printed in U.S.A. 1051 at ASPET Journals on October 13, 2017 molpharm.aspetjournals.org Downloaded from