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This review presents evolving concepts of how the human uterus contracts in pregnancy, with emphasis on the mechanisms of long-distance signaling. Action potential propagation has historically been assumed to be the sole mechanism for signaling and tissue recruitment over both short and long distances. However, data in animals and humans indicate that a single action potential does not travel distances greater than a few centimeters. To address this enigma, a long-distance signaling mechanism based on hydraulic signaling and mechanotransduction is developed. By combining this mechanism for long-distance signaling with the action potential propagation mechanism for signaling over short distances, a comprehensive dual mechanism model (or 'dual model') of uterine function is formulated. Mechanotransduction is an accepted phenomenon of myometrium, but the dual model identifies mechanotransduction as relevant to normal labor. For hydraulic signaling, a local contraction slightly increases intrauterine pressure, which globally increases wall tension. Increased wall tension then mechanically induces additional local contractions that further raise pressure. This leads to robust, positive feedback recruitment that explains the emergence of consistently strong contractions of human labor. Three key components of the dual model - rapid long-distance signaling, mechanical triggering, and electrical activity - converge with the concept of mechanically sensitive electrogenic pacemakers distributed throughout the wall. The dual model retains excitation-contraction coupling and action potential propagation for signaling over short distances (<10 cm) and hence is an extension of the action potential model rather than a replacement. [ABSTRACT FROM AUTHOR]

The mechanisms used to coordinate uterine contractions are not known. We develop a new model based on the proposal that there is a maximum distance to which action potentials can propagate in the uterine wall. This establishes “regions”, where one action potential burst can rapidly recruit all the tissue. Regions are recruited into an organ-level contraction via a stretch-initiated contraction mechanism (myometrial myogenic response). Each uterine contraction begins with a regional contraction, which slightly increases intrauterine pressure. Higher pressure raises tension throughout the uterine wall, which initiates contractions of more regions and further increases pressure. The positive feedback synchronizes regional contractions into an organ-level contraction. Cellular automaton (CA) simulations are performed with Mathematica. Each “cell” is a region that is assigned an action potential threshold. An anatomy sensitivity factor converts intrauterine pressure to regional tension through the Law of Laplace. A regional contraction occurs when regional tension exceeds regional threshold. Other input variables are: starting and minimum pressure, burst and refractory period durations, enhanced contractile activity during an electrical burst, and reduced activity during the refractory period. Complex patterns of pressure development are seen that mimic the contraction patterns observed in laboring women. Emergent behavior is observed, including global synchronization, multiple pace making regions, and system memory of prior conditions. The complex effects of nifedipine and oxytocin exposure are simulated. The force produced can vary as a nonlinear function of the number of regions. The simulation directly links tissue-level physiology to human labor. The concept of a uterine pacemaker is re-evaluated because pace making activity may occur well before expression of a contraction. We propose a new classification system for biological CAs that parallels the 4-class system of Wolfram. However, instead of classifying the rules, biological CAs should classify the set of input values for the rules that describe the relevant biology. [ABSTRACT FROM AUTHOR]

To investigate the relationship between tissue-level bioelectrical signals and tension development during oxytocin-stimulated contractions of human myometrium.We performed in vitro muscle bath experiments on human myometrial tissue strips while simultaneously monitoring bioelectrical activity with two loose-contact electrodes. Tissue was obtained by myometrial biopsy from term pregnant women at the time of cesarean delivery. Tissue strips (1 × 1 × 10 mm) were hung vertically and maintained in culture in media while suspending a 400-mg weight. The tissue exhibited strong isometric contractions in response to 5-nM oxytocin even after 10 to 14 days in culture. The electrodes were separated by 4 mm, and allowed us to distinguish between local and tissue-level bioelectrical signals. Electrical activity was monitored using two, independent AC-coupled amplifiers.Following exposure to oxytocin, the tissue contracted periodically every 3.5 to 6 minutes, with each contraction lasting 50 to 60 seconds. Near the beginning of each contraction, synchronized spike-like bioelectrical signals were observed in both channels. These bioelectrical signals from each electrode lasted approximately 2 seconds and demonstrated unique fingerprints that were repetitive and remarkably similar over 18 contractions. In each of the contractions, the onset of rapid force increases was synchronized with the bioelectrical signals. Cell recruitment continued during the plateau phase of each contraction even though other tissue-level bioelectrical signals were not observed.These findings suggest that the trigger for the initiation of each contraction is a tissue-level bioelectrical event, and some cells are initially recruited to participate in each contraction by excitation-contraction coupling. After the initial phase of the contraction, cells are recruited by a nonelectrical mechanism. [Copyright &y& Elsevier]

Investigates differing mechanisms of inhibition of calcium increases in human uterine myocytes by indomethacin and nimesulide. Acquisition of human uterine myometrium during cesarean deliveries; Comparison between nimesulide and indomethacin pretreatments to prostaglandin; Reduction of the fraction of responding cells.

An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor. [ABSTRACT FROM AUTHOR]