Intravascular ATP and coronary vasodilation in the isolated working rat heart.
1. Adenosine-5'-triphosphate (ATP) is a potent coronary vasodilator. Because of the efficient hydrolysis of ATP, adenosine-5'-diphosphate (ADP) and adenosine-5'-monophosphate (AMP) by ectonucleotidases located in the coronary endothelium ATP-induced vasodilation may be mediated via both P1 (AMP and adenosine) and P2Y (ATP and ADP) receptors. We have used the change in total coronary resistance (TCR) induced by intravascular ATP in the isolated working rat heart to determine both the component of the vasodilation mediated via P2Y receptors and the identity of the subclass of receptor involved. 2. The dose response for ATP revealed a half maximal effect at an apparent ATP concentration of 0.08 +/- 0.009 microM. The response was saturated at apparent ATP concentrations greater than 0.23 microM. Contrary to much of the current literature, the perfusion of a 0.25 microM concentration of adenosine resulted in the identical response to an equimolar concentration of ATP suggesting a significant role for adenosine in coronary vasodilation. 3. The non-selective P1 receptor antagonist 8-(p-Sulfophenyl)theophylline (8-SPT) was used to show that the response to ATP was mediated via both P1 and P2Y receptors. Whilst 8-SPT abolished the effect of adenosine it reduced the effect of ATP by only 50%. Thus, at a saturating concentration of ATP, P1 and P2Y receptors were shown to contribute equally to the observed vasodilation. 4. Uridine-5'-triphosphate (UTP), ADP and adenosine-5'-O-thiotriphosphate (ATP gamma S) were used to characterize the component of coronary vasodilation that was mediated via P2Y receptors. UTP at 0.25 microM was ineffective and did not induce vasodilation. Perfusion with 0.25 microM ADP resulted in a vasodilation that was identical to 0.25 microM ATP. In the absence of 8-SPT the perfusion of 0.25 microM ATP gamma S produced a vasodilation that was significantly (P < 0.05) less than ATP. However, the vasodilation due to ATP gamma S, like that of adenosine, but unlike that of both ATP and ADP, was abolished in the presence of 8-SPT. The ability of ADP to induce vasodilation combined with both the lack of response to UTP and the ability of 8-SPT to abolish the vasodilation induced by ATP gamma S suggested very strongly that the component of ATP-induced coronary vasodilation in the isolated working rat heart that was mediated via P2Y receptors was achieved by the action of ADP (and not ATP) at P2Y1 receptors. 5. These results suggest that the vasodilatory action of intravascular ATP in the coronary circulation should be attributed to the dual and equal activities of adenosine and ADP acting at P1 and P2Y1 receptors respectively.
Birchall Centre for Inorganic Chemistry and Materials Science, Department of Chemistry, Keele University, Staffordshire.
O
O
Korchazhkina
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G
Wright
C
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Exley
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D002317:Cardiovascular Agents; D058915:Purinergic P1 Receptor Antagonists; D018048:Receptors, Purinergic P2; D014665:Vasodilator Agents; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate