Preterm labor occurs due to various causes, such as multiple gestation, infection, polyhydramnios, and uterine anomalies. However, often its etiology is unknown (""""""""idiopathic""""""""). Management of preterm labor depends on inhibition of contraction of uterine smooth muscle. The ion channel (e.g., voltage-dependent Ca2+ channels, various K+ channels, stretch-activated channels, and Cl-channels) of myometrial cell membrane play an important role in excitation-contraction coupling. The ion channels control the cytosolic Ca2+ level, and hence the contractile sate of the myometrial cells. During pregnancy, these ion channels are modified by chronic exposure to various hormones, such as estrogen, progesterone or hCG. Resting membrane potential and spike formation of myometrium change during pregnancy. We will first investigate the change in the properties of ion channels of rat uterine smooth muscle cells during pregnancy and during chronic treatment with estrogen and/or progesterone. Then we will examine the effects of various substances and conditions, which are considered to be related to the etiology of preterm labor (e.g., leukotrienes, platelet activating factor, ischemia, mechanical stretch), on the ion channels. These studies will facilitate our understanding of the prevention and treatment of preterm labor. Further, they may provide a clue as to the cause of idiopathic preterm labor. We will also examine the effects of tocolytic agents on the activity of the myometrial ion channels. In management of preterm labor, beta-adrenergic agonists (such as ritodrine and terbutaline) have been widely used for uterine tocolytic therapy. The resulting increase in cAMP within the myometrial cell is believed to mediate the inhibition of uterine contraction, by decreasing the availability of free Ca2+. However, the mechanism of the tocolytic action of beta-agonists is still unknown at the subcellular and membrane level. It has been suggested that cAMP; (a) activates the Ca2+ pump, (b) inhibits the myosin-light chain kinase by phosphorylation, (c) inhibit Ca2+ channels, and/or (d) enhances K+ channel activity. The tocolytic agent, Mg2+,, is thought to act on the Ca2+ channel to prevent Ca2+ entry into the cell. Some of these proposed mechanisms will be clarified in our electrophysiological experiments on isolated single myometrial cells. Although the beta-adrenergic tocolytic agents are selected for beta 2 specificity, they do possess some beta 1 activity, which give rise to cardiovascular side effects. therefore, we will also test the effects of the beta-adrenergic tocolytic agents on cardiac muscle, to provide comprehensive information about their cardiovascular side effects. Finally, studies will also be done on isolated human myometrial tissue, to compare with the results on animal tissue, in order to provide new information for better management of preterm labor in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026170-03
Application #
3327550
Study Section
Special Emphasis Panel (SRC (17))
Project Start
1989-09-01
Project End
1993-06-30
Budget Start
1991-12-01
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Inoue, Y; Shimamura, K; Sperelakis, N (1993) Forskolin inhibition of K+ current in pregnant rat uterine smooth muscle cells. Eur J Pharmacol 240:169-76
Sperelakis, N; Inoue, Y; Ohya, Y (1992) Fast Na+ channels and slow Ca2+ current in smooth muscle from pregnant rat uterus. Mol Cell Biochem 114:79-89
Inoue, Y; Shimamura, K; Sperelakis, N (1992) Oxytocin actions on voltage-dependent ionic channels in pregnant rat uterine smooth muscle cells. Can J Physiol Pharmacol 70:1597-603
Sperelakis, N; Inoue, Y; Ohya, Y (1992) Fast Na+ channels in smooth muscle from pregnant rat uterus. Can J Physiol Pharmacol 70:491-500
Inoue, Y; Sperelakis, N (1991) Gestational change in Na+ and Ca2+ channel current densities in rat myometrial smooth muscle cells. Am J Physiol 260:C658-63
Ohya, Y; Sperelakis, N (1991) Involvement of a GTP-binding protein in stimulating action of angiotensin II on calcium channels in vascular smooth muscle cells. Circ Res 68:763-71