Proceedings of The Physiological Society
University of Manchester (2010) Proc Physiol Soc 19, C26
Investigating the effects of acidic pH on placental resistance arteries
T. Ali1, F. Broughton Pipkin2, R. N. Khan1
1. Obstetrics and Gynaecology, University of Nottingham, Derby, United Kingdom. 2. Perinatal Physiology, University of Nottingham, Nottingham, United Kingdom.
Blood vessels from the placenta need to respond to stimuli including hypoxia and acidic pH which can be the result of an intermittent blood supply from the myometrial vascular bed. Unlike other vascular tissue the placenta lacks nervous control so any response to such stimuli will be autoregulated by ion channels expressed in vascular tissue. We have recently detected expression of the TWIK related potassium channel TREK-1, and the TWIK related acid sensitive potassium channels TASK-3 in human placental resistance arteries. We hypothesise that extracellular acidification activates TASK-3 and TREK-1 channels to modulate the vasoactive responses of placental arteries. Placentae (N=25) were collected with written informed consent from healthy patients undergoing elective Caesarean section at term (≥37 wks). Arteries (≤500µm) taken from the stem villi (SVA) and the chorionic plate (CPA) were studied using wire myography. Vessels were contracted with the thromboxane-mimetic U46619 (1pM-1µM) and following stabilisation the pH of the bathing saline was lowered using 1M lactic acid to give falls of 0.2 pH units over a range of pH 7.4-6.4. In parallel experiments CPA vessels were also preincubated either the TREK-1 antagonist L-methionine (1mM) or the TASK-3 antagonist ZnCl2 (1mM) prior to the pH stimulation. A change from pH 7.4-7.2 produced a 39% (n=20) relaxation of CPA which increased to 69% at the lowest pH of 6.4. Similarly altering the pH of preconstricted SVA vessels caused a 21% (n=8) fall at pH 7.2 with a maximum relaxation of 71% at pH 6.4. The response to acidic pH stimulation was biphasic with a rapid loss in vessel tone (phase 1) followed by gradual recovery to maximum constriction (phase 2) and was repeated with each subsequent pH insult. We then examined the response in CPA vessels in the presence L-methionine or ZnCl2. Surprisingly, both antagonists inhibited the recovery seen in phase 2 of the pH response and as a result enhanced the loss in tone seen with each acidic pH treatment. L-methionine increased the relaxation to 95% (n=4 p= 0.001) at pH 6.4 while ZnCl2 gave a maximum relaxation of 82% (n=3 p= 0.006). Our data shows that extracellular pH within the physiological range has an important role in controlling vasodilatation in the placenta. Protons are readily transported across the cell membrane and can activate a range of targets including the K2P channels. However we find that when TREK-1 and TASK-3 channels are blocked the response by CPAs to low pH is elevated which was unexpected and reflects the multiple effects of pH on vascular function. This also suggests that K2P channel activity can be compensated for by other pH sensitive channels and work is currently underway to identify the role of other ion channels that may be involved in this pathway.
Where applicable, experiments conform with Society ethical requirements