The effect of lactate on myometrial contractility

Hanley, Jacqui-Ann The effect of lactate on myometrial contractility. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Strong coordinated uterine contractions are needed in labour and the mechanisms that govern this are well understood. However when these contractions are weak or uncoordinated, labour cannot progress normally. This is termed dysfunctional labour and it accounts for ~20% of all caesarean sections (CS) in the UK. Currently the only treatment available is oxytocin, however this does not reduce the incidence of CS. Lactate is significantly increased in myometrial capillary blood during dystocia suggesting it may be impairing force production, but there are no functional data on the effect of lactate on myometrial contractility. The aims of this work were to a) investigate the effect of lactate and its mechanism of action on myometrial contractility using both human myometrium and an animal model. The effect on spontaneous and oxytocin-stimulated contractions was also examined and b) investigate the presence of lactate transporters MCT-1 and MCT-4 in rat myometrium throughout gestation and in human myometrium was looked at. Lactate, dose-dependently and significantly, decreased spontaneous contractility in rat and human myometrium. Weak acids butyrate, propionate, and pyruvate also significantly reduced contractions in a dose-dependent manner. The effects of lactate were reduced in the presence of oxytocin but not abolished. The effect on pregnant myometrium was greater than in non-pregnant, and was shown to increase towards term in the animal model. In labouring myometrium, there was little effect of lactate on contractility. Using the animal model to investigate lactate’s mechanism in the myometrium, tissue strips were loaded with either Indo-1 AM (a Ca2+ sensitive indicator) or Carboxy SNARF-AM (a pH sensitive indicator). Lactate inhibited Ca2+ transients and had little effect on force when a Ca2+ channel agonist was present. Lactate decreased pHi in a dose dependent manner and this drop in pHi was reduced when the tissue was stimulated by oxytocin or in labour. Both MCT-1 and MCT-4 were found to be present in rat and human myometrium, with MCT-1 at a higher amount in pregnant myometrium. From this work I have shown that lactate in the physiological range potently decreases spontaneous contractility in both rat and human myometrium. The effects of lactate were reduced in the presence of oxytocin or labour but still produced significant decreases and this may be due the difference in alteration of pHi. Other weak acids produce similar effects to lactate suggesting its mechanism of action is not via lactate’s role in metabolism. Lactate inhibited Ca2+ transients, which could be due to a fall of pHi, as it has previously been demonstrated that intracellular acidification decreases Ca2+ current through L-type Ca2+ channels. The difference in MCT-1 and MCT-4 expression between non-pregnant and pregnant tissue may indicate a role in labour. I suggest that differences in myometrial lactate in women can lead to accumulation of extracellular lactate, which as we have shown, will reduce myometrial contractions and could therefore contribute to dysfunctional labour.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2013-09 (completed)
Uncontrolled Keywords:	Uterus, myometrium, lactate
Subjects:	?? QP ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	11 Feb 2014 16:17
Last Modified:	16 Dec 2022 04:40
DOI:	10.17638/00014253
Supervisors:	Wray, Susan ORCID: 0000-0002-0086-1359 Weeks, Andrew Alfirevic, Zarko
URI:	https://livrepository.liverpool.ac.uk/id/eprint/14253