Uterine Stimulants and Relaxants
The physiological processes involved in parturition (i.e., labor, delivery, and birth) require a complex inter-play of hormonal action, neuronal activity, and uterine smooth muscle contraction. During the first two trimesters of pregnancy, the uterus remains in a rela-tively quiescent state, demonstrating little or no con-traction of the myometrium. This inactivity is largely the result of the inhibitory action of high circulating levels of progesterone on the uterine musculature . During the final trimester, however, uter-ine smooth muscle becomes increasingly excitable, such that mild muscle contractions are seen (Braxton-Hicks contractions); these gradually increase in both strength and frequency, occasionally to the extent that they may even be thought to signal the onset of labor, a phenom-enon termed false labor. Parturition requires in part the integration of processes that involve cervical canal dila-tion and uterine smooth muscle contractions that are strong enough to expel the fetus.
Other physiological events must occur at the end of pregnancy to facilitate birth. The cervix begins to soften (cervical ripening) as a direct result of connective tissue dissociation; this process may involve the actions of the peptide hormone relaxin, which is produced both in the corpus luteum and in the placenta. Relaxin also aids in the dissociation of the connective tissue between the pelvic bones, a process that also aids in the facilitation of birth. At the true onset of labor, coordinated, rhyth-mic contractions of the uterus begin, and as labor pro-gresses, the myometrial contractions increase in inten-sity and strength. These contractions force the fetus against the cervix, further dilating the cervix. Once the cervix has dilated sufficiently, the uterine contractions push the fetus through the birth canal.
A variety of endocrine hormones play a role in ini-tiating the changes in uterine contractility, especially during the final trimester. It is probable that the con-centration of receptors responsive to the hypothalamic peptide hormone oxytocin increases in the uterine musculature in response to the increasing levels of estrogen during pregnancy. Although circulat-ing blood levels of oxytocin do not change markedly throughout pregnancy, it is likely that the augmented number of oxytocin receptors in the uterus makes the muscle increasingly responsive to plasma oxytocin. There also is speculation that the uterus itself may be capable of synthesizing oxytocin. If such a synthesis does indeed occur, much higher local concentrations of the peptide will be found than would be predicted strictly on the basis of circulating amounts of the hor-mone. Increases in the number of myometrial α-adren-ergic and angiotensin receptors also will increase the sensitivity of these muscle cells to contractile stimuli. Finally, the possibility of fetal factors playing a role in the initiation of parturition should be considered.
Although, like other smooth muscle, the myo-metrium is capable of contraction at any time, it is generally quiescent throughout most of pregnancy. As pregnancy progresses, spontaneous repetitive action po-tentials can be seen, but muscle tension will develop only once these action potentials become synchronized electrical discharges. Contractions do become evident, however, several weeks before labor begins. The con-tractions of the myometrium progressively increase during the onset of labor, in part through the action of a positive neuroendocrine feedback system that in-volves both synthesis and release of oxytocin and
prostaglandins. The stretching of the softened cervix in-duced by increasing fetal pressure results in local recep-tor stimulation and the initiating of a spinal reflex that eventually results in the release of oxytocin from the posterior pituitary. This additional oxytocin will further promote uterine contractions.
Release of oxytocin at this stage of parturition pro-motes prostaglandin production, particularly of the E and F series, within the decidua; these prostaglandins are powerful myometrial stimulants and thus further enhance uterine contractions. The prostaglandin con-centration in maternal serum and amniotic fluid in-creases with the progression of labor.
Many of the biochemical and molecular events that are responsible for uterine smooth muscle contraction are the same as those that control other smooth muscle tissues (Fig. 62.1). Once uterine smooth muscle sensitiv-ity has been augmented, actin and myosin must interact for contraction to occur. This interaction depends on the phosphorylation of the contractile proteins by the en-zyme myosin light chain kinase (MLCK). This enzyme requires Ca++ and is active only when associated with calmodulin. Activation of the entire muscle contraction process involves the receptor binding of estrogen, oxy-tocin, α1α-adrenergic agonists, and prostaglandins (PGE1 and PGE2).
A decrease in the progesterone–estrogen ra-tio in the myometrium is also an important factor in the timing and initiation of labor; this altered ratio may in-volve increased fetal estrogen production, particularly in the latter weeks of pregnancy. Cytokines produced by the fetus are also thought to be responsible for stimulating uterine contraction.
Uterine relaxation is mediated in part through inhi-bition of MLCK. This inhibition results from the phos-phorylation of MLCK that follows the stimulation of myometrial β-adrenoceptors; relaxation involves the activity of a cyclic adenosine monophosphate (cAMP) mediated protein kinase, accumulation of Ca++ in the sarcoplasmic reticulum, and a decrease in cytoplasmic Ca++ . Other circulating substances that favor quies-cence of uterine smooth muscle include progesterone, which increases throughout pregnancy, and possibly prostacyclin. Progesterone’s action probably involves hyperpolarization of the muscle cell membrane, reduc-tion of impulse conduction in muscle cells, and in-creased calcium binding to the sarcoplasmic reticulum.
Drugs and hormones used clinically to enhance uter-ine contractions are primarily employed either to induce or to augment contractions during labor and delivery. They have particular value in limiting an extended preg-nancy, preventing the early rupture of membranes, or aiding placental insufficiency. Many of these com-pounds also are useful in limiting postpartum hemor-rhage. The primary use of uterine relaxants (tocolytic agents) is in the prevention of premature labor. These drugs act either directly to suppress myometrial smooth muscle contraction or indirectly to inhibit synthesis or release of the prostaglandins and/or other endogenous uterine stimulants.
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