Contribution of Adenosine A2A and A2B Receptors to Ischemic Coronary Dilation: Role of KV and KATP Channels

Abstract

This study was designed to elucidate the contribution of adenosine A 2A and A 2B receptors to coronary reactive hyperemia and downstream K + channels involved. Coronary blood flow was measured in open-chest anesthetized dogs. Adenosine dose-dependently increased coronary flow from 0.72 ± 0.1 to 2.6 ± 0.5 ml/min/g under control conditions. Inhibition of A 2A receptors with SCH58261 (1 μM) attenuated adenosine-induced dilation by ~50%, while combined administration with the A 2B receptor antagonist alloxazine (3 μM) produced no additional effect. SCH58261 significantly reduced reactive hyperemia in response to a transient 15 sec occlusion; debt/repayment ratio decreased from 343 ± 63 to 232 ± 44%. Alloxazine alone attenuated adenosine-induced increases in coronary blood flow ~30% but failed to alter reactive hyperemia. A 2A receptor agonist CGS21680 (10 μg bolus) increased coronary blood flow by 3.08 ± 0.31 ml/ min/g. This dilator response was attenuated to 0.76 ± 0.14 ml/min/g by inhibition of K v channels with 4-aminopyridine (0.3 mM) and to 0.11 ± 0.31 ml/min/g by inhibition of K ATP channels with glibenclamide (3 mg/kg). Combined administration abolished vasodilation to CGS21680. These data indicate that A 2A receptors contribute to coronary vasodilation in response to cardiac ischemia via activation of K V and K ATP channels.

Contributions of A2Aand A2Badenosine receptors in coronary flow responses in relation to the KATPchannel using A2Band A2A/2Bdouble-knockout mice

“…Adenosine is well known to play a vasoregulatory role in human coronary arteries (16,17,62,63). We and others (5,63,67,69) have also previously demonstrated the pivotal role of A 2A ARs in CF regulation. We also have preliminary data showing the involvement of A 2 ARs in coronary reactive hyperemia that indirectly supports a physiological role for adenosine in CF regulation (data not shown), which is in support of previous in vivo and ex vivo reactive hyperemia studies (5,12,77).…”

“…We and others (5,63,67,69) have also previously demonstrated the pivotal role of A 2A ARs in CF regulation. We also have preliminary data showing the involvement of A 2 ARs in coronary reactive hyperemia that indirectly supports a physiological role for adenosine in CF regulation (data not shown), which is in support of previous in vivo and ex vivo reactive hyperemia studies (5,12,77). Additionally, it has been suggested that A 2A AR activation contributes to basal tone in the coronary circulation through the release of nitric oxide (69).…”

“…It is well established that the activation of A 2A ARs induces positive inotropic effects and that A 2A ARs play a major role in the regulation of CF in ex vivo models (67,69). Additionally, in vivo studies in dogs have shown the involvement of A 2A ARs in CF (reactive hyperemia) regulation (5,77) and, thus, support a physiological role for adenosine. Adenosine-induced effects are species dependent (20,23).…”

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

“…However, the application of exogenous adenosine to increase coronary flow for the investigation of adenosine receptor-mediated signaling pathways has been well established [37,44]. Thus, in agreement with previous studies from our laboratory [37,44,49] and others [14], adenosine produced a large increase in coronary flow in isolated mouse hearts, supporting the overall effect of vasodilation by adenosine in the coronary circulation [14,15,37,50,51].…”

Electrical Neuromodulation and the Heart with Special Emphasis on Myocardial Ischemia

“…113,114 Adenosine plays a role in myocardial ischemia as well, which effect is thought to take place through activation of the A2 adenosine receptor, generating in its turn, under ischemic conditions, redistribution of local blood flow from sub-epicardial towards epicardial tissues. 115 So, the moment the critical balance between myocardial oxygen supply and demand is deferred, by either improving supply, or through a reduction in demand, a cascade of chemical reactions take place. It is conceivable that electrical neuromodulation employs its effect through interference with local adenosine handling.…”