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 mechanisms 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001299-03
Application #
3073739
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1984-07-01
Project End
1987-01-15
Budget Start
1986-09-01
Budget End
1987-01-15
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Lasley, R D; Mentzer Jr, R M (1993) Adenosine increases lactate release and delays onset of contracture during global low flow ischaemia. Cardiovasc Res 27:96-101
Lasley, R D; Mentzer Jr, R M (1992) Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism. Am J Physiol 263:H1460-5
Van Wylen, D G; Willis, J; Sodhi, J et al. (1990) Cardiac microdialysis to estimate interstitial adenosine and coronary blood flow. Am J Physiol 258:H1642-9
Dorheim, T A; Wang, T; Mentzer Jr, R M et al. (1990) Interstitial purine metabolites during regional myocardial ischemia. J Surg Res 48:491-7
Lasley, R D; Rhee, J W; Van Wylen, D G et al. (1990) Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J Mol Cell Cardiol 22:39-47
Wyatt, D A; Ely, S W; Lasley, R D et al. (1989) Purine-enriched asanguineous cardioplegia retards adenosine triphosphate degradation during ischemia and improves postischemic ventricular function. J Thorac Cardiovasc Surg 97:771-8
Mentzer Jr, R M; Van Wylen, D G; Sodhi, J et al. (1989) Effect of pyruvate on regional ventricular function in normal and stunned myocardium. Ann Surg 209:629-33;discussion 633-4
Mainwaring, R D; Ely, S W; Mentzer Jr, R M (1988) Myocardial reactive hyperemia in the newborn. J Surg Res 44:603-8
Mentzer Jr, R M; Ely, S W; Lasley, R D et al. (1988) The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function. J Thorac Cardiovasc Surg 95:286-93
Lasley, R D; Ely, S W; Berne, R M et al. (1988) Allopurinol enhanced adenine nucleotide repletion after myocardial ischemia in the isolated rat heart. J Clin Invest 81:16-20

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