Mechanism of Relaxation Via TASK-2 Channels in Uterine Circular Muscle of Mouse

Abstract

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K+ channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K+ conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.

Regulation of myometrial contraction by ATP-sensitive potassium (K_ATP) channel via activation of SUR2B and Kir 6.2 in mouse

“…Tissue preparation for isometric contraction : All experiments were performed in accordance with the guidelines for animal care and use approved by Chungbuk National University and The Physiological Society of Shanghai Jiaotong University. Female non-pregnant ICR (age, 10–12 weeks) mice were anesthetized with fluoromethyl 2,2,2-trifluoro-1 (trifluoromethyl) ethyl ether (Sevoflurane; Maruishi Pharma., Osaka, Japan) and killed by cervical dislocation [ 10 ]. The uteri were cut open from the neck to the end of the uterine horns, rinsed in Krebs-Ringer bicarbonate (KRB) solution and pinned on a Sylgard plate [ 10 ].…”

“…Female non-pregnant ICR (age, 10–12 weeks) mice were anesthetized with fluoromethyl 2,2,2-trifluoro-1 (trifluoromethyl) ethyl ether (Sevoflurane; Maruishi Pharma., Osaka, Japan) and killed by cervical dislocation [ 10 ]. The uteri were cut open from the neck to the end of the uterine horns, rinsed in Krebs-Ringer bicarbonate (KRB) solution and pinned on a Sylgard plate [ 10 ]. Longitudinal muscle strips (1 × 5 mm) were mounted on vertical chambers in an isometric contractile measuring system.…”

“…The PowerLab-Data Acquisition System and a personal computer running Charter v5.5 software (ADinstruments, Colorado Springs, CO, U.S.A.) were used. Each strip was stretched passively to resting tension for 1–2 hr after a 1.5 hr equilibration [ 10 ]. Contractile responses of the strip to high K + (50 mM) were repeated two times.…”

“…ATP-sensitive potassium (K ATP ) channels were first identified in cardiac cell, and their physiological functions, such as hypoxic and ischemic conditions, are well characterized, even in smooth muscle and pancreatic cells [ 3 , 4 , 5 , 9 , 10 , 20 ]. Cellular metabolism is tightly linked to regulation of K ATP channel activity, as the channels open in response to lower ATP levels and close in response to higher ATP levels.…”

“…Basically, activation of K + channels opposes muscle excitability and relaxes the myometrium by regulating the resting membrane potential. Several types and/or different activities of K + channels, such as Ca 2+ -activated K + (K Ca ) channels and voltage-dependent K + (K V ) channels, are involved in the regulation of myometrial contractility in non-pregnant and pregnant myometria [ 10 , 13 , 14 , 15 , 23 ]. Recently, we also reported functional upregulation of TASK-2 channels in pregnant than that in non-pregnant mice [ 10 ].…”