Abstract
The present study was designed to investigate the effect of O2 on intracellular Ca concentration ([Ca]i) in the ductus arteriosus and the mechanisms for O2-induced ductal contraction. The force of isometric contraction of the ring of the ductus arteriosus isolated from fetal rabbits at 30 days of gestation (term, 31 days) was measured. The ductus arteriosus was loaded with fura 2, a calcium-sensitive dye, and [Ca]i was determined from the ratio of fluorescence intensity at 340 and 380 nm excitation wavelengths. The ductus arteriosus was initially superfused with hypoxic control solutions and contraction was induced by application of oxygenated solutions. The O2-induced contraction of the ductus arteriosus was associated with increases in [Ca]i and was eliminated in the absence of extracellular calcium. An increase in [K]o from 5 to 50 mM, which causes membrane depolarization, induced ductal contraction. The calcium channel blockers verapamil, diltiazem, and nickel caused a similar inhibition of O2-induced contraction as well as KCl-induced contraction. The role of intracellular calcium stores in O2-induced ductal contraction was examined using ryanodine, an inhibitor of calcium uptake and release from the sarcoplasmic reticulum. The inhibition of O2-induced contraction by ryanodine was minimal. Infusion of glibenclamide, an inhibitor for opening the ATP-sensitive potassium channel, caused contraction of the ductus arteriosus in the hypoxic solution. Cromakalim, an opener of ATP-sensitive potassium channels, completely relaxed the contraction induced by O2. These data suggest that O2 increases [Ca]i and causes contraction in the ductus arteriosus. Application of O2 may change from anaerobic to aerobic metabolism and depolarize membrane potential by closing the ATP-sensitive potassium channel, which in turn increases calcium influx via the voltage-dependent calcium channel. Mechanisms other than the ATP-sensitive potassium channel may also be involved in the O2-induced contraction and remain to be studied.
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