CHAPTER 7Uterine Contractility
The best known task of uterine contractions is the expulsion of the fetus at the term of pregnancy, but the contractile ability of the nonpregnant uterus is also important. Uterine contractions are necessary for sperm transport and, on the other hand, in the elimination of excessive semen, bacteria, and inflammatory by-products after breeding. Probably the susceptibility of some mares to uterine infections is determined by their ability to evacuate uterine contents, which depends on uterine contractions and on the degree of cervical opening. The contractility of the myometrium is controlled by steroid and ecbolic hormones. Also, some clinically used drugs affect uterine contractions. This overview focuses on the nonpregnant uterus only.
PHYSIOLOGICAL BASIS OF MYOMETRIAL CONTRACTILITY
The myometrium consists of two layers of smooth muscle with a vascular zone in between. The muscle fibers of the outer longitudinal layer are arranged parallel and those of the inner circular layers concentrically around the long axis of the uterus. The spindle-shaped, membrane-bound muscle cells are arranged into bundles of 10 to 50 cells. Neighboring cells come in close apposition in certain specialized regions of their plasma membranes forming cell-to-cell contacts, which are termed gap junctions. They are modifications of the apposing plasma membranes of the adjacent cells and couple them electrically and metabolically. The gap is a narrow space of about 2 to 3 nm, and it is composed of a few thousand channels.1
The contractile activity in the uterus is a direct consequence of the electrical activity in the smooth muscle cells. This activity is characterized by cyclic depolarization and repolarization of the plasma membrane and termed action potentials. Depolarization is mainly due to an increased permeability to Ca2+and, to a lesser extent, to Na+. Both ions have higher concentrations in the extracellular space and hence easily move into the intracellular space, making the membrane potential more positive. The membrane repolarizes by increasing the permeability to K+(high concentration in intracellular fluid), which results in outward movement of K+.1
Some muscle cells are specialized for pacesetting uterine contractions. Pacemaker regions are 2 to 4 mm in size and contain one or more specialized pacemaker cells. Any myometrial cell is capable of assuming the role of a pacemaker. Therefore pacemaker regions can shift from one site to another. The individual muscle cell is the unit for excitation of the myometrium, but a bundle of muscle cells is the unit of propagation of the electrical stimulus. Gap junctions are the sites of intercellular propagation of action potentials. The gap junction channels exhibit rapid transformations between open and closed states.1
The magnitude of uterine contractions is dependent on the total number of simultaneously and synchronously active smooth muscle cells. A single action potential can generate a twitch contraction. A synchronized contraction of many uterine smooth muscle cells (estimated to be billions) decreases the diameter of uterine lumen. At an action potential discharge rate around 1 cycle per second, a tetanic type of contraction is produced.1
MEASURING UTERINE CONTRACTILE ACTIVITY IN MARES
Electromyography
Electromyography (EMG) measures electrical changes in the membrane potential of the myometrium,2,3 but neither the direction of contractions nor movement of intraluminal fluids can be studied using this technique. The method is sensitive to environmental stimuli (e.g., entry to the mare’s stall, feeding, and human voices induced temporary changes in electrical activity).4 Four pairs of electrodes are surgically implanted in the myometrium (tip, middle, and base of a horn and uterine body) under general anesthesia, which makes the technique unsuitable for routine use. Troedsson and his co-workers2,3 have used the following system for quantification of the data for statistical analysis. A burst is defined as activity consisting of at least 10 peaks per minute and separated from other bursts by at least 1 minute. Frequency is the number of activity bursts per hour. Intensity is the number of spikes per minute. Amplitude is the highest recorded amplitude of spikes in a burst for each minute. All registered electrical activity is classified as total uterine activity. The presence of synchronous activity is expressed as the number of implantation sites that are active simultaneously.
Intrauterine Pressure Transducers
Intrauterine pressure (IUP) transducers record intraluminal pressure changes by responding to increases and decreases in the diameter of uterine lumen. Nowadays the transducers are electronic catheter–tipped and have one or two ultraminiature pressure sensors at the distal end coupled by a cable to a computer.5,6 Also, IUPs are sensitive to various environmental stimuli. Respiration, resting a hind leg, stretching, urination, snorting, and whinnying induced transient variations in uterine pressure.5 Jones et al7 compared EMG and IUP in mares and found very little correlation between the two methods. They questioned the validity of IUP recordings, because intestinal motility and intraabdominal pressure changes can influence IUP responses.
Ultrasonography
The noninvasive technique of transrectal ultrasonography allows visualization of uterine contractions both in nonpregnant and pregnant animals. Active bowel movements near the uterus can confound uterine examination, and therefore it has been recommended that the uterus is examined only when the ventral limits of the uterus can be delineated above a full urinary bladder.8 However, this would mean visualizing mostly the uterine body, and the body displays much less uterine contractile activity (UCA) than the horns.9 Another concern has been the effect of rectal palpation itself, because it has been known to increase briefly the electrical activity of the myometrium.4 It was shown that mean oxytocin (OT) and prostaglandin F2metabolite (PGFM) levels and mean UCA scores did not change significantly at any time throughout a 10-minute scanning procedure. It was concluded that transrectal ultrasonography is a useful tool for monitoring and evaluating UCA and does not appear to stimulate ecbolic hormone release.10 B-mode (brightness mode) ultrasonography has been used most commonly, but Campbell and England9 applied M-mode (motion mode) ultrasonography in the imaging of contractions in the equine uterus. This technique produces a graph of motion, contractions being positive deviations from the horizontal axis. The amplitude, duration, and frequency of contractions are recorded.
Scintigraphy
Scintigraphy is a technique where radioactive material is imaged in the body of an animal or a human being using a gamma-camera. Static scintigrams have been used to study uterine clearance in mares.11 Dynamic scintigrams (one to two pictures per second) allow the visualization of uterine contractions, their direction, and the movement of intraluminal fluid.12 The radioactive material infused into the uterus, as well as the possible use of sedatives, may cause uterine contractions. It is obvious that none of the techniques presented above is fully reliable in distinguishing natural uterine contractions from the ones induced by the use of the method itself or by environmental stimuli.13 In practice conditions, the only method available is ultrasonography, preferably equipped with the M-mode technique.
HORMONAL CONTROL OF UTERINE CONTRACTILITY
Steroid hormones regulate uterine contractility. High progesterone levels maintain the quiescence of the uterus, whereas a decrease in progesterone and an increase in estrogens stimulate contractility. Progesterone suppresses the formation of gap junctions, thereby decreasing the coupling between the cells. Estrogens induce the formation of gap junctions, depolarize the muscle plasma membrane, increase prostaglandin (PG) production, and enhance the expression of OT receptors (OT-Rs) in the smooth muscle. OT stimulates uterine contractions and release of arachidonic acid and thus formation of PGs. Prostaglandins enhance uterine contractions by causing membrane depolarization and by increasing the number of gap junctions.1
Cyclicity and Stage of the Estrous Cycle
Anestrous mares showed significantly less uterine contractions than steroid-treated mares14 when examined by ultrasonography. EMG recordings of anestrous mares were variable, but transitional mares resembled estrous mares.7
In transrectal M-mode ultrasonography, the number of contractions was lowest on the day of ovulation, but no significant differences were found between the other days of the cycle.9 Transrectal B-mode ultrasonography of cyclic mares demonstrated a postovulatory decrease in UCA followed by a progressive increase between days 2 and 4. Another increase was detected on days 11 and 12, reaching the maximum on days 13 to 14, at the onset of luteolysis, and was followed again by a decrease on days 14 to 16.15 In EMG, frequent phases of high-amplitude, low-density spikes alternated with short periods of inactivity during spontaneous luteolysis.4 Estrus was characterized in EMG by well-defined but short phases of activity, closely grouped high-amplitude spikes, or high-intensity bursts separated by periods of relative inactivity.2,4 During diestrus, more diffuse phases of activity with low-amplitude spikes were separated by variable periods of relative inactivity.2,4 Because of the prolonged duration of activity bursts, the total time of electrical activity was higher during diestrus than during estrus.2 This correlates well with the increased tone and tubularity that is characteristic of the equine uterus at diestrus upon rectal palpation.2,16 Synchronization of electrical activity at different sites of the uterus was more marked during estrus than in diestrus.2 A wave of synchronized activity is a prerequisite for a contraction to occur. It can be concluded that lowest UCA occurs on the day of ovulation and in the postovulatory period and highest during the time of luteolysis and that the type of activity during estrus is most likely to result in effective contractions.
Effects of Ecbolic Hormones
Oxytocin Receptors
The action of OT is mediated via oxytocin receptors (OT-Rs), which are located on the plasma membrane of smooth muscle cells. The number of binding sites was threefold greater in the myometrium than in the endometrial layer.17 Lowest concentrations of OT-Rs were found during estrus and on days 1 to 13 of diestrus, whereas highest concentrations were detected on day 1418 or on days 14 to 17 of the cycle.17 Increasing amounts of estradiol induce estrogen and OT binding sites.
It is assumed that the release of PGF2αis induced by OT and mediated by occupied OT-Rs. Therefore the increase in OT-Rs during days 14 to 17 may enhance PGF2α-production.17,18
Endogenous Oxytocin and Prostaglandin Release
Because OT and PGF2αare known to induce uterine contractions, it is of interest to know the pattern of endogenous OT release and the stimulants of release. OT has been shown to be secreted in a pulsatile manner throughout the estrous cycle of the mare, but no differences in pulse frequencies were observed during the cycle.19 Mean plasma OT concentrations were greater on day 15 after ovulation compared with days 0, 3, and 7.19
The release of PGF2αin response to OT injection has been shown to change throughout the estrous cycle, being maximal at the time of luteolysis.20 When only two periovulatory days were compared, PGFM response after OT administration was higher on the day of ovulation than 2 days after ovulation.21 Taking of an endometrial biopsy transcervically elicited prompt OT release in all mares, followed by a PGFM increase after 15 minutes, and highest OT and PG releases were detected on days 12 and 14 of the cycle, respectively.18
Sexual stimulation, stallion’s call, teasing, and artificial insemination (AI), induce pituitary OT secretion in estrous mares, and therefore it has been suggested that it could increase reproductive tract motility.22 Madill et al23 measured OT in pituitary venous fluid after the mares were exposed to sexual stimulation (stallion call, visual contact with a stallion, active teasing, or AI). All treatments increased significantly electrical activity of the myometrium and OT release, but the onset of OT secretion was simultaneous with uterine contractility, rather than preceding it.
Another study investigated the effects of teasing, mating, and manual manipulation of the genital tract and intrauterine infusion of fluid on venous OT and PGFM concentrations. Mating and genital tract manipulation caused a significant increase in OT in all mares. Teasing provoked a significant OT response in 6 of 10 estrous mares and in 3 of 5 diestrous mares. Three mares of 5 responded to intrauterine infusion with OT release. No significant effects were detected on PGFM concentrations, with the exception of two mares, which showed significant PG responses after manual manipulation of clitoris, vagina, and cervix or intrauterine infusion.24 Vaginal distension appeared to be a potent stimulant for OT release associated with mating. Mating constantly induced an OT release, but PGFM was not detected.
Oxytocin Treatments
It has been demonstrated that OT injections increase UCA in mares3,6,7,25 and uterine clearance in mares.26 Anovulatory mares are an exception. Although they were primed with progesterone for 16 days, OT did not significantly alter contractility but did increase uterine tone.27 A better effect of OT on contractility has been demonstrated during estrus than in diestrus.3,7 Gutjahr et al28 compared three periovulatory days and found best uterine contractile response to exogenous OT 2 days before ovulation, followed by day of ovulation, and with the lowest response on day 2 after ovulation.
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