Congenital heart disease represents a wide spectrum of altered hemodynamics which affect pulmonary and cardiac function. In certain forms of congenital heart disease, survival of infants is dependent upon patency of the ductus arteriosus as this represents the only source of blood flow to the lungs. The long-term goals of this are to determine what role, if any, adenosine (an endogenously released vasoactive adenine nucleoside) plays in the maintenance of patent ductus arteriosus before and after birth. Specifically, the objectives of this proposal are to determine: (1) if endogenous adenosine plays a role in modulating ductal resistance by evaluating in vivo the effects of aminophylline and dipyridamole (agents known to attenuate and potentiate the adenosine response) in the fetal lamb in which pre- and post-ductal pressures and ductal flow are monitored under conditions of (a) nonventilation, (b) ventilation with 100% N2, and (c) ventilation with 100% O2; (2) the relationship between blood PO2, circulating adenosine arterial and venous blood concentrations, and ductal resistance under the same conditions as above; (3) whether ductal tissue adenosine plays a role independent of circulating plasma adenosine by evaluating the response of the isolated perfused ductus to O2 in the presence and absence of aminophylline and dipyridamole; (4) ductal tissue adenosine content in the isolated perfused ductus when the perfusate is bubbled with (a) 100% N2, (b) 10% O2, and (c) 100% O2; (5) the histochemical localization of 5 feet-nucleotidase and nucleoside phosphorylase by fixing the ductus arteriosus in situ with glutaraldehyde, incubating the tissue with specific monophosphate nucleotides, and trapping the released phosphate with lead at the site of reaction, which can be detected by electron microscopy. The information to be gained from this project will not only provide basic data on the mechanims involved in the closure of the ductus arteriosus, but may well lead to new rational approaches for the treatment of certain forms of congenital heart disease.
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