Effects of xanthine amine congener on hypoxic coronary resistance and venous and epicardial adenosine concentrations.
OBJECTIVE
The aim was to define the contributions of interstitial and vascular adenosine in regulating coronary vascular resistance during hypoxia. To help in the assessment of adenosine in the vasodilator response, a potent adenosine receptor antagonist, xanthine amine congener (XAC), was used to block adenosine receptors.


METHODS
Seven isolated guinea pig hearts were perfused at constant flow with Krebs buffer. Coronary vascular resistance was determined during normoxia (95% O2) and mild hypoxia (60% O2) in the absence or presence of 200 or 400 nM XAC. Interstitial fluid was sampled by the epicardial disc technique and the interstitial concentration of XAC (ISF[XAC]) was determined directly by a radioreceptor assay or as tritiated XAC. Venous and epicardial concentrations of adenosine were determined by high performance liquid chromatography. In six additional experiments, the vasodilator effect of 1 microM intracoronary adenosine was measured in the absence or presence of 100 or 200 nM XAC.


RESULTS
Mild hypoxia decreased coronary resistance by 37 (SEM 4)% in the absence of XAC and 26(5)% or 17(4)% in the presence of 200 or 400 nM XAC, respectively. ISF[XAC] rapidly equilibrated with [XAC] in the arterial perfusate or venous effluent. XAC 400 nM markedly increased (p < 0.05) the hypoxic levels of venous and epicardial fluid adenosine from 49(19) and 251(42) nM to 75(11) and 495(48) nM, respectively. XAC 100-200 nM almost completely prevented the vasodilatation induced by 1 microM intracoronary adenosine.


CONCLUSIONS
Adenosine mediates at least 54% of hypoxic vasodilatation. XAC rapidly equilibrates within the myocardial interstitial space and, as a result of blocking adenosine receptors, increases interstitial and venous adenosine concentrations. Increases in interstitial adenosine may partially overcome the adenosine receptor blockade by XAC, thereby reducing the effectiveness of XAC in attenuating the hypoxic vasodilatation. XAC attenuates intracoronary adenosine induced vasodilatation (mediated by endothelial adenosine receptors) much more effectively than it attenuates hypoxic vasodilatation, underscoring the minimal role played by the endothelial receptors in hypoxic vasodilatation.
Sawmiller
D R
DR
Department of Molecular Physiology and Biological Physics, University of Virginia Health Science Center, Charlottesville 22908.
Linden
J
J
Berne
R M
RM
D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006168:Guinea Pigs; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D010477:Perfusion; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism*; D011869:Radioligand Assay; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology*
D014970:Xanthines; C051869:8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine; D000241:Adenosine