Adenosine and adenosine receptor-mediated action in coronary microcirculation

Abstract

Adenosine is an ubiquitous extracellular signaling molecule and plays a fundamental role in the regulation of coronary microcirculation through activation of adenosine receptors (ARs). Adenosine is regulated by various enzymes and nucleoside transporters for its balance between intra- and extracellular compartments. Adenosine-mediated coronary microvascular tone and reactive hyperemia are through receptors mainly involving A_2AR activation on both endothelial and smooth muscle cells, but also involving interaction among other ARs. Activation of ARs further stimulates downstream targets of H₂O₂, K_ATP, K_V and K_Ca2+ channels leading to coronary vasodilation. An altered adenosine-ARs signaling in coronary microcirculation has been observed in several cardiovascular diseases including hypertension, diabetes, atherosclerosis and ischemic heart disease. Adenosine as a metabolite and its receptors have been studied for its both therapeutic and diagnostic abilities. The present review summarizes important aspects of adenosine metabolism and AR-mediated actions in the coronary microcirculation.

Keywords: Adenosine; Coronary microcirculation; Diabetes; Extracellular nucleotides; Ischemic heart disease; Purinergic receptor.

Fig. 1

Adenosine generation and metabolism. Adenosine can be formed intracellularly from ATP, ADP or adenosine monophosphate (AMP) by cytoplasmic 5′-nucleosidase activity. The conversion of cAMP to AMP by phosphodiesterase is responsible for adenosine production referring as the cAMP-adenosine pathway. In addition, adenosine can be produced from S-adenosylhomocysteine (SAH) via SAH hydrolase. Once ATP is released extracellularly through pannexin 1 channels or ATP binding cassette transporter, ATP is degraded to ADP and AMP mainly through the continuous action of CD39. Adenosine is then generated from AMP derived from both ATP and cAMP pathways via CD73. Extracellular adenosine is rapidly taken up by the cells via nucleoside transporters for subsequent metabolism. Adenosine is then phosphorylated in the cells by adenosine kinase to form AMP or degraded to inosine by adenosine deaminase

Fig. 2

Adenosine and adenosine receptor (AR)-mediated action in coronary microcirculation in physiology. a Adenosine is generated via extracellular breakdown of ATP released from various cells upon stimulation like hypoxia or ischemia. Adenosine-mediated coronary microvascular tone is mainly through activation of A_2AR and A_2BR. A_2AR and A_2BR can compensate for each other, while A₁R and A₃R negatively modulate the A_2AR- and A_2BR-mediated coronary vasodilation. A_2AR plays a role in coronary reactive hyperemia. A₁R negatively modulates coronary reactive hyperemia mediated by A_2AR. b There are endothelium-dependent and -independent regulations of adenosine-mediated coronary microvascular function. Nitric oxide (NO) is involved in A_2AR-mediated basal tone control and reactive hyperemia, as well as adenosine-mediated A_2AR activation. NO is also involved in A_2AR-K_ATP axis for reactive hyperemia. Activation of A_2AR can stimulate NADPH oxidase 2 (NOX₂) resulting in H₂O₂ production, which leads to smooth muscle cell (SMC) K_ATP opening and coronary vasodilation. Activation of A_2AR by reactive hyperemia also involves downstream H₂O₂-K_ATP axis accounting for coronary vasodilation. Hypoxia can directly activate K_ATP channels. Involvement of SMC Kv and K_Ca2+ is coupled to activation of A_2AR. EC endothelial cells