Uterine Contractility in the Nonpregnant Mouse: Changes During the Estrous Cycle and Effects of Chloride Channel Blockade1

Abstract

Mechanisms involved in the generation of spontaneous uterine contractions are not fully understood. Kit-expressing interstitial cells of Cajal are pacemakers of contractile rhythm in other visceral organs, and recent studies describe a role for Ca(2+)-activated Cl(-) currents as the initiating conductance in these cells. The existence and role of similar specialized pacemaker cells in the nonpregnant uterus remains undetermined. Spontaneous contractility patterns were characterized throughout the estrous cycle in isolated, nonpregnant mouse uteri using spatiotemporal mapping and tension recordings. During proestrus, estrus, and diestrus, contraction origin predominated in the oviduct end of the uterus, suggesting the existence of a dominant pacemaker site. Propagation speed of contractions during estrus and diestrus were significantly slower than in proestrus and metestrus. Five major patterns of activity were predominantly exhibited in particular stages: quiescent (diestrus), high-frequency phasic (proestrus), low-frequency phasic (estrus), multivariant (metestrus), and complex. Kit-immunopositive cells reminiscent of pacemaking ICCs were not consistently observed within the uterus. Niflumic acid (10 μM), anthracene-9-carboxylic acid (0.1-1 mM), and 5-nitro-2-(3-phenylpropylamino)benzoic acid (10 μM) each reduced the frequency of spontaneous contractions, suggesting involvement of Cl(-) channels in generating spontaneous uterine motor activity. It is unlikely that this conductance is generated by the Ca(2+)-activated Cl(-) channels, anoctamin-1 and CLCA4, as immunohistochemical labeling did not reveal protein expression within muscle or pacemaker cell networks. In summary, these results suggest that spontaneous uterine contractions may be generated by a Kit-negative pacemaker cell type or uterine myocytes, likely involving the activity of a yet-unidentified Cl(-) channel.

Reproductive disorders in female rats after prenatal exposure to betamethasone

“…Uterine rhythmic contractions are essential for the reproductive functions in all phases of the cycle (Dodds et al, 2015). The transport of eggs and sperm, proper placement of the embryo for implantation, maintenance of the fetus during its development and expulsion of the fetus or debris are organized by these contractions and, any increase in this contractility rhythmus can promote uterine abnormal function and be related to infertility and implantation failure (Dodds et al, 2015). Thus, in the present work, the increased post-implantation losses by the number of resorptions observed in the BM group could be correlated to the increased contractility activity of the uterus to muscarinic neurotransmitters.…”

Research in Reproduction: Challenges, Needs, and Opportunities

“…Early attempts to assess the influence of steroids and oxytocin were without significant result (Kunz et al, 1998 ). In the gut, such directionality is co-regulated by resident Cajal-like cells; there is still little information at all about the presence or function of similar cells (also called telocytes) in the uterus of any species (Hutchings et al, 2009 ; Dodds et al, 2015 ). There is a very obvious need here for intensive research into the basic biology of the system and about appropriate methods of early diagnosis and treatment.…”

Biomathematical pattern of EMG signal propagation in smooth muscle of the non-pregnant porcine uterus

“…However, the specific mechanism by which the non-pregnant uterus autonomously initiates myometrial contractions remains poorly described. In spite of their clinical significance, contractile properties of the uterus during the entire estrous cycle have not been examined [4]. A better understanding of the complex myometrial activity would help to develop effective therapies for an array of reproductive disorders associated with the flawed rhythmicity of uterine contractions.…”

“…In both cases, uterine contractions were induced “from cellular level to the organ level” due to electrophysiological properties of the pacemaker cells and ensuing propagation of electrical discharges via gap junctions within the myometrium. Most of earlier studies on uterine activity deal primarily with the electrophysiology of the SMC membrane [4, 10]. In all in vitro investigations, at the level of single myometrial myocyte, equations describing various ionic membrane currents were established from their respective activation curves.…”

“…In contrast to skeletal muscle, in which the propagation of action potentials that progresses in muscle fibers is highly predictable, the direction and speed of electrical activation in myometrial cells remain to be elucidated [17]. Most of previously published studies were devoted to the analysis of entire bursts or single spikes in pregnant uterus [8, 18, 19, 20], and only few studies dealt with non-pregnant state [4, 21]. Hence, the main goal of the present study was to determine the biomathematical pattern describing EMG signal propagation in the non-gravid porcine uterus in vivo .…”