The objective of this project is to determine the magnitude of the role of interstitial adenosine in producing the coronary vasodilation associated with catecholamine infusion, cardiac pacing and hypoperfusion. To do this we need to increase our understanding of the role of endothelial cells in capillary exchange of adenosine. Our hypothesis for capillary exchange of adenosine includes diffusion through water filled channels as well as endothelial cell uptake and release of adenosine. The tests of the hypothesis will consist of single pass indicator diffusion experiments on isolated guinea pig hearts involving the simultaneous injection of three tracers: 125I-albumin (RISA), 3H-arabinofuranosyl hypoxanthine (3H-araH) and 14C-adenosine (14C-ADO). A newly developed mathematical model will aid in the analysis of these data. RISA allows optimizationof model parameters associated with intravascular transit and volume. We will use H-araH, an analogue of adenosine which is not transported by the nucleoside carrier, to optimize model parameters related to extracellular diffusion of adenosine and interstitial volume. Finally, 14C-adenosine will be used to characterize its carrier mediated transport and subsequent metabolism by endothelial cells. Further information about the symmetry of the carrier on thelumenal and ablumenal surface of endothelial cells will be obtained in parallel experiments on C-5 feet-deoxyadenosine which is transported by the carrier, but not metabolized. Dipyridamole and competing concentrations of unlabelled adenosine will be used to further characterize the role of carrier mediated transport by endothelial cells. We will also selectively label the adenine nucleotide pool of endothelial cells in order to determine the conditions under which adenosine is released from in situ endothelium. Once a model of the capillary barrier has been established, we will use it to calculate [ADO]ISF in a variety of conditions including catecholamine infusion alone, and in the presence of theophylline or dipyridamole, pacing and hypoperfusion. These experiments are designed to further test the role of adenosine in the local regulation of coronary blood flow flow insituations in which there are observations which are inconsistent with the adenosine hypothesis. The experiments will also provide new information on the role of endothelial cells in nucleoside homeostasis in the heart as well as a new approach to the investigation of the metabolism of in vivo endothelial cells in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024232-09
Application #
3337554
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1978-12-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Osteopathy
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Gorman, M W; He, M X; Hall, C S et al. (1997) Inorganic phosphate as regulator of adenosine formation in isolated guinea pig hearts. Am J Physiol 272:H913-20
Gorman, M W; He, M X; Sparks, H V (1994) Adenosine formation during hypoxia in isolated hearts: effect of adrenergic blockade. J Mol Cell Cardiol 26:1613-23
Gorman, M W; Ning, X H; He, M X et al. (1992) Adenosine release and high energy phosphates in intact dog hearts during norepinephrine infusion. Circ Res 70:1146-51
He, M X; Gorman, M W; Romig, G D et al. (1991) Adenosine formation and energy status during hypoperfusion and 2-deoxyglucose infusion. Am J Physiol 260:H917-26
Gorman, M W; Wangler, R D; Bassingthwaighte, J B et al. (1991) Interstitial adenosine concentration during norepinephrine infusion in isolated guinea pig hearts. Am J Physiol 261:H901-9
Gorman, M W; Wangler, R D; Sparks, H V (1989) Distribution of perfusate flow during vasodilation in isolated guinea pig heart. Am J Physiol 256:H297-301
Wangler, R D; Gorman, M W; Wang, C Y et al. (1989) Transcapillary adenosine transport and interstitial adenosine concentration in guinea pig hearts. Am J Physiol 257:H89-106
Wangler, R D; Peterson, W P; Sparks, H V (1989) d-Propranolol prevents adenosine formation associated with myocardial hypoperfusion. Am J Physiol 256:H772-8
Toma, B S; Wangler, R D; Sparks, H V (1988) Metabolic hyperemia is reduced in adult vs. immature guinea pig hearts. Am J Physiol 255:H1460-7
Otero, H O; Wangler, R D; Sparks, H V et al. (1988) Alpha-human atrial natriuretic peptide is a coronary vasodilator in the Langendorff-perfused guinea pig heart. Life Sci 42:695-700

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