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Effects of Long-Term, High-Altitude Hypoxia on Tension and Intracellular Calcium Responses in Coronary Arteries of Fetal and Adult Sheep

Virginia M. Stiffel, BS

Center for Perinatal Biology, Loma Linda University, Loma Linda, California, USA

Raymond D. Gilbert, PhD

Center for Perinatal Biology, Loma Linda University, Loma Linda, California, USA; rgilbert{at}somllu.edu

Objectives: We have previously shown that after exposure to long-term hypoxia, fetal coronary flow is maintained at control levels despite a 25% reduction in cardiac output. We also demonstrated that coronary vascular rings isolated from the long-term hypoxic fetuses and studied in well-oxygenated bath system displayed significantly reduced depolarization-induced contraction strength in response to KCl. To study the mechanism of reduced fetal coronary vascular responses to KCl-induced contractions following exposure to long-term hypoxia, we measured tension and intracellular calcium simultaneously, as well as L-type Ca²⁺ channel density and sensitivity.

Methods: Pregnant ewes were housed at altitude (3820 m) for approximately 110 days. At 138 to 141 days of gestation, long-term hypoxic and control animals were killed and fetal and adult left anterior descending coronary artery (LAD) was isolated and studied in a well-oxygenated bath system. Tension and intracellular calcium ([Ca²⁺]i) were measured simultaneously in response to increasing concentrations of KCl and, in addition, the sensitivity to the calcium channel blocker nifedipine was measured at a half maximal concentration of KCl. We also measured L-type Ca²⁺ channel density with (+)-[³H]PN200-110.

Results: L-type Ca²⁺ channel density was decreased by 31% in the long-term hypoxic fetal, but not adult, LAD. Tension in the long-term hypoxic fetal and adult LAD was significantly lower at all concentrations of KCl. [Ca²⁺]i was lower at rest in both fetal and adult LAD from long-term hypoxic animals and increased to lower levels at all concentrations of KCl. The ratio of tension to [Ca²⁺]i was also lower at all concentrations of KCl. Sensitivity to nifedipine was unchanged.

Conclusions: The reduced L-type Ca²⁺ channel density and the reduced [Ca²⁺]i response to KCl, as well as the reduced tension response to [Ca²⁺]i, could potentially be involved in the reduction in depolarization-induced contractions in LAD from long-term hypoxic fetuses. In hypoxic adults, reduced [Ca²⁺]i and reduced tension response to [Ca²⁺]i may be involved in the lower tension response to KCl-induced contractions.

Key Words: Fetus • blood flow • heart

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