Korean J Physiol Pharmacol.
2001 Oct;5(5):423-431.
Differential modulation of exogenous and endogenous adenosine-induced
coronary vasodilation by dipyridamole
- Affiliations
-
- 1Department of Pharmacology, Seoul National University
College of Medicine, 28 Yongon-dong Chongno-gu, Seoul, 110-799, South
Korea. kimmsu@snu.ac.kr
Abstract
- Some recent investigations revealed that vasodilatory action of
adenosine is mainly not mediated by surface A2 receptor and suggested the
existence of an intracellular action site. In the present study, we tried
to differentiate intracellular from extracellular site of adenosine
action in the regulation of coronary flow. In perfused rabbit hearts,
concentration-response curve of coronary flow to exogenous adenosine was
constructed in the presence or absence of dipyridamole, an inhibitor of
transmembrane purine transport. Inhibition of cellular adenosine uptake
by dipyridamole suppressed the increase of flow rate while enhancing the
decrease in heart rate induced by exogenous adenosine. In another series
of experiments, perfused rabbit hearts were subjected to energy
deprivation in order to increase the production of endogenous adenosine.
Energy deprivation along with dipyridamole administration resulted in
higher coronary flow rate. Lower perfusate adenosine concentration was
observed along with higher tissue adenosine content in this group. These
results
implied that coronary flow rate is determined not by interstitial
adenosine concentration but by intracellular activity of adenosine. To
confirm the effects of dypiridamole in vivo, direct measurement of
interstitial adenosine concentration by mycrodialysis along with the
assay of intracellular adenosine content was performed after intranenous
dipyridamole administration. After dipyridamole infusion, intracellular
adenosine content was markedly increased while interstitial adenosine
concentration was not altered. In another series of experiments, the
right shift of concentration-response curve of adenosine-induced
vasodilation by 8-phenyltheophilline, a representative adenosine receptor
antagonist, was mostly abolished by prior administration of prazosin,
indicating that the influence of 8-PT on the adenosine action is not
attributed to the inhibition of A2 receptor but related to the
suppression of alpha-adrenoceptor activation. From these results, we
concluded that adenosine acts intracellularly to regulate the coronary
blood flow.