An investigation into the effect of hypoxia in the uterus: Does hypoxic preconditioning occur?

Alotaibi, Mohammed
An investigation into the effect of hypoxia in the uterus: Does hypoxic preconditioning occur? Doctor of Philosophy thesis, University of Liverpool.

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During labour, the uterus experiences transient and repeated hypoxic episodes as contractions occlude uterine blood vessels. Despite this, uterine contractions are maintained, their strength gradually increases and labour progresses. The effect of repeated episodes of transient hypoxia on uterine contractility has not been previously investigated and in my study I investigate the hypothesis that multiple transient hypoxic episodes can increase the contractile activity in a pregnant rat uterus near term. Uterine strips were dissected and mounted in organ baths, bubbled with Hepes-buffered, oxygenated physiological saline solution for isometric force recording. The effects of repeated episodes of transient hypoxia (2, 5 or 10min) were studied by replacing the O2 for N2. Hypoxia abolished or significantly reduced the force of uterine contractions in a term-pregnant rat. Upon re-oxygenation, contractile activity was gradually and significantly increased after repeated episodes of transient hypoxia (i.e. similar to “hypoxic preconditioning”), an effect that was most pronounced after 2mins hypoxia. The increased strength of uterine contractions during re-oxygenation periods required the PO2 to be below 10% in the tissue bath during hypoxia. The increase in contractile activity during re-oxygenation was not transient; I found it could be maintained for 11 hrs. During oxytocin stimulation, the response was larger than during spontaneous activity. Moreover, to determine if the response was confined to term-pregnant rats, I examined the effect on rat uteri from different gestations (non-pregnant, 18-day pregnant and labouring). The rebound increase in uterine contractility was not seen in non-pregnant and day 18 pregnant rats with repeated hypoxic episodes, but was present in the labouring rat uterus. Interestingly, data from human uterine biopsies showed the significant rebound increase in contractile activity after the first hypoxic episode in all labouring samples and in one non-labouring sample that was very close to term. These data suggest that hypoxic preconditioning is gestational dependent in both rats and human uteri. To investigate if changes in intracellular calcium were involved in the rebound increase in force, indo-1 loaded myometrial strips from term-pregnant rats were studied. My data showed that initial hypoxia increases the basal [Ca2+]i , but with repeated hypoxia the overall [Ca2+]i decreased gradually suggesting that the increase in contractility was not due to increased [Ca2+]i . In addition, no increase in Ca2+ transients was apparent. Together this may suggest increased sensitivity of contractile machinery to calcium. I found that other mechanisms are likely to be responsible for the increase in contractile activity during hypoxic preconditioning. Repeated episodes of external acidosis were found to partly increase the uterine activity. Hypoxia and no flow resulted in an even larger rebound contractile activity than hypoxia alone. I found, also, that blocking adenosine receptors, particularly A1, abolished the protective effect induced by hypoxic episodes. Repeated episodes of ATP agonist was also found to increase uterine activity in the term-pregnant uterus and blocking P2X7 receptors completely abolished ATP-increased uterine activity. I also found that blocking prostaglandin biosynthesis can block the beneficial effects induced by transient hypoxic episodes in a term-pregnant uterus. Together, these mechanisms which lead to adaptive responses during repeated episodes of transient hypoxia are brought about by multiple changes in the external and internal environment during hypoxic episodes and any defect in any of these mechanisms will prevent the adaptive response to the transient hypoxic episodes. This in turn may have consequences for the progress of human labour.

Item Type: Thesis (Doctor of Philosophy)
Additional Information: Date: 2013-03-01 (completed)
Uncontrolled Keywords: hypoxia, uterus, hypoxic preconditioning, contraction
Divisions: Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 09 Sep 2013 11:20
Last Modified: 17 Dec 2022 01:28
DOI: 10.17638/00010833