Previous research from our laboratory has shown that myometrial contractility is reduced in pregnant sheep exposed to long-term hypoxia (LTH). The studies in this dissertation examined the effect of LTH on various aspects of Ca2 regulation, large-conductance, Ca2+ activated (BK) channels activity and protein expression, and cGMP-depended protein kinase (PKG) activity. Myometrium was collected from near-term pregnant sheep exposed to high altitude-associated LTH and from normoxic pregnant controls. After pretreatment with 10-8 M oxytocin (OT), circular and longitudinal myometrial strips were treated with nifedipine (L-type Ca2+ channel blocker), ruthenium red, ryanodine (blockers of IPssensitive stores), 2-Nitro-4-carboxyphenyI-N,N-diphenyIcarbamate (NCDC; phospholipase C inhibitor), tetraethylammonium (TEA; nonspecific K+channel inhibitor), iberiotoxin (IbTX; specific blocker of BK channels), or KT-5823 (PKG inhibitor). Western blots were also conducted for BKa and BKp subunit protein. LTH increased the maximum relaxation response to nifedipine whereas no significant differences were observed in response to ruthenium red or lyanodine. The maximum relaxation response to NCDC was lower in the LTH circular layer. No significant differences in response to TEA were found; however, the maximum tension response to IbTX in the LTH group was significantly increased. Western blot analysis revealed two P1 subunit bands (38 and 48 kDa), but did not show any significant differences between treatment groups or layers. However, the BK P:a subunit ratio (using either the 48 kDa P band only or combined with the 38 kDa P band) showed a significant decrease in the circular layer after exposure to LTH. After treatment with KT-5823, the contractility of LTH tissue significantly decreased in both layers. We conclude that LTH decreases reliance on IPs-associated Ca2+ stores and increases dependence upon Ca2+ entry through L-type Ca2+ channels. The contribution of SR Ca2+ is negligible. In addition, BK channel activity is enhanced following LTH, possibly mediated by a decreased P:a subunit ratio. Finally, PKG inhibitory activity may be suppressed in LTH myometrium with a possible switch to stimulatory in the circular muscle.
Doctor of Philosophy (PhD)
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Library of Congress/MESH Subject Headings
Fetal Hypoxia -- physiology; Myometrium -- physiology; Parturition -- physiology; Uterine Contraction; Labor -- physiology; Pregnancy, Animal Sheep
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This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Arakawa, Timothy Kimo, "Effect of Long-term Hypoxia on Myometrial Contractility in the Pregnant Sheep" (2008). Loma Linda University Electronic Theses, Dissertations & Projects. 1133.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives