Ion channels in the cell membrane of uterine smooth muscle play a crucial role in propagation and excitation-contraction coupling during pregnancy. The activity of these ion channels is regulated by intrinsic factors (such as ATP level, pH, and cyclic nucleotides) and by extrinsic factors (such as neurotransmitters, hormones, and drugs). One very important ion channel is the fast sodium channel and the accompanying fast Na+ current. This current is important to excitability, the rate of rise of the action potential, and therefore to propagation velocity through the myometrium. Faster and more complete propagation will allow more forceful contractions to occur within the pregnant uterus in an effort to expel the fetus. In addition, Na+-influx, coupled with the Na/Ca exchange system, will cause a higher [Ca]i, and thereby a more forceful contraction. Although smooth muscle cells generally do not possess functional fast Na+ channels, we have discovered that a substantial number of these channels are present in uterine smooth muscle cells isolated from 18-day pregnant rats (Ohya and Sperelakis 1989). The amount of fast Na+ current (INa(f)), measured by whole-cell voltage clamp, was almost as great as the slow Ca2+ current (ICa(s)). The INa(f) had the typical properties of fast Na+ channels in nerve, skeletal muscle, and cardiac muscle, including high sensitivity to tetrodotoxin (TTX) and half-inactivation at -64 mV. Mironneau and colleagues recently reported at a workshop on uterine contractility in St. Louis (March, 1990) that they were able to confirm our findings, namely that a substantial fast INa(f), sensitive to TTX, exists in 18-day pregnant rat myometrium. In addition, they found high-affinity binding of saxitoxin (STX), in confirmation of the electrophysiological data. Therefore, we have continued to examine this INa(f) in pregnant rat incorporated into the cell membrane during the course of pregnancy, and that the associated current plays an important role in normal delivery at term. To this end, we have made preliminary measurements of INa(f) (and compared it with the magnitude of ICa(s)) in 5-, 9-, 14-, 18-, and 21- day pregnant rat myometrial cells. These pilot experiments suggest that cells containing fast Na+ channels are fewer in number during early pregnancy compared to late pregnancy. In the present application, we propose to do a thorough investigation of INa(f) during the entire course of pregnancy, including post-partum and non-pregnant stages in order to elucidate the role played by this current in normal delivery at term. Consequently, corresponding studies will also be performed on human myometrial cells. The information learned will be very important to our understanding of the factors that bring about normal labor, and may have important implications for the causes of preterm labor.
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