Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation.
We tested whether hypoxia-induced coronary artery dilatation could be mediated by an increase in adenosine concentration within the coronary artery wall or by an increase in adenosine sensitivity. Porcine left anterior descendent coronary arteries, precontracted with prostaglandin F(2alpha) (10(-5) M), were mounted in a pressure myograph and microdialysis catheters were inserted into the tunica media. Dialysate adenosine concentrations were analysed by HPLC. Glucose, lactate and pyruvate were measured by an automated spectrophotometric kinetic enzymatic analyser. The exchange fraction of [(14)C]adenosine over the microdialysis membrane increased from 0.32 +/- 0.02 to 0.46 +/- 0.02 (n = 4, P < 0.01) during the study period. At baseline, interstitial adenosine was in the region of 10 nM which is significantly less than previously found myocardial concentrations. Hypoxia (P(O(2)) 30 mmHg for 60 min, n = 5) increased coronary diameters by 20.0 +/- 2.6% (versus continuous oxygenation -3.1 +/- 2.4%, n = 6, P < 0.001) but interstitial adenosine concentration fell. Blockade of adenosine deaminase (with erythro-9-(2-hydroxy-3-nonyl-)-adenine, 5 microM), adenosine kinase (with iodotubericidine, 10 microM) and adenosine transport (with n-nitrobenzylthioinosine, 1 microM) increased interstitial adenosine but the increase was unrelated to hypoxia or diameter. A coronary dilatation similar to that during hypoxia could be obtained with 30 microM of adenosine in the organ bath and the resulting interstitial adenosine concentrations (n = 5) were 20 times higher than the adenosine concentration measured during hypoxia. Adenosine concentration-response experiments showed vasodilatation to be more pronounced during hypoxia (n = 9) than during normoxia (n = 9, P < 0.001) and the A(2A) receptor antagonist ZM241385 (20 nM, n = 5), attenuated hypoxia-induced vasodilatation while the selective A(2B) receptor antagonist MRS1754 (20 nM, n = 4), had no effect. The lactate/pyruvate ratio was significantly increased in hypoxic arteries but did not correlate with adenosine concentration. We conclude that hypoxia-induced coronary artery dilatation is not mediated by increased adenosine produced within the artery wall but might be facilitated by increased adenosine sensitivity at the A(2A) receptor level.
Frøbert
Ole
O
Department of Cardiology, Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Denmark. frobert@dadlnet.dk
Haink
Gesine
G
Simonsen
Ulf
U
Gravholt
Claus H
CH
Levin
Max
M
Deussen
Andreas
A
D000081:Acetamides / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000243:Adenosine Deaminase / Q000502:physiology; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D003331:Coronary Vessels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000032:analysis / Q000502:physiology*; D043704:Receptor, Adenosine A2B / Q000032:analysis / Q000502:physiology; D013552:Swine; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation
D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D058892:Adenosine Deaminase Inhibitors; D007773:Lactates; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D011687:Purines; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D019289:Pyruvic Acid; D000248:Adenosine Kinase; D000243:Adenosine Deaminase; D005947:Glucose; D000241:Adenosine