Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon


Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

Adenosine Actions at the Cellular Level: Arterial Endothelium and Smooth Muscle

Adenosine is able to regulate vascular tone in the arterial tree by relaxing arterial smooth muscle.[56,57] This relaxation decreases vascular resistance thereby facilitating blood flow and oxygen delivery.[58] The effects of adenosine on coronary blood flow are thought to be mediated primarily by activation of A2A receptors.[59] Adenosine activates A2A receptors, triggering the opening of Kv and KATP channels on smooth muscle cells. This leads to membrane hyperpolarization, and relaxation.[60,61] Other adenosine receptors and mechanisms may also contribute, particularly in pathological conditions such as diabetes and cardiovascular disease.[62] It has also been suggested that adenosine acts on endothelium to cause nitric oxide (NO) release which, in turn, dilates coronary arteries.[63]

Although an exercise stress test is the preferred stimulus to detect ischemic heart disease, pharmacological vasodilators are the next best option for those who cannot exercise adequately.[64] Adenosine, dipyridamole, or regadenoson (an A2A receptor agonist) can be used in myocardial perfusion imaging studies for pharmacological stress testing.[65] Dipyridamole increases levels of intrinsic adenosine because it inhibits ADA, the enzyme that breaks down adenosine. During myocardial perfusion imaging, adenosine increases coronary blood flow, partly through cAMP production, and with increased blood flow comes enhanced radionuclide uptake in myocardium.[66] In myocardium with an impaired coronary flow reserve, which can occur as a result of coronary artery narrowing, adenosine-mediated increases in blood flow and radionuclide uptake are blunted compared to the normal physiological response.[67]

Vascular tone is modulated by activation of adenosine receptors primarily on endothelial cells and, to a lesser extent, on vascular smooth muscle.[11] Endothelial cells that line the luminal surface of blood vessels function as a complex metabolically active organ system involved in regulation of blood flow, exchange of nutrients, passage of waste products and control of thrombosis/thrombolysis.[68] The endothelial monolayer resting upon a basement membrane comprises the intima. The endothelium is actively involved in maintaining vascular homeostasis, and adenosine A2A receptors expressed on these cells participate in the process by inducing vasodilation and vascular relaxation. In both human and porcine arterial endothelial cells, adenosine A2A receptors increase while adenosine A1 receptors decrease production of the vasodilator NO. NO is produced by endothelial cells lining the vasculature in a reaction catalyzed by NO synthase via a five-electron oxidation of the guanidine nitrogen terminal of the amino acid L-arginine. Stimulation of A2A receptors triggers the activation of endothelial nitric oxide synthase (eNOS), leading to increased synthesis of NO in human endothelium.[69] In rat aortic endothelium, A2A- mediated release of NO requires extracellular Ca2+ and Ca2+- activated K+ channels.[70] NO released by endothelium can diffuse to adjacent smooth muscle cells, where it binds to and activates the enzyme soluble guanylate cyclase by removing the histidine residue on its axial position. Soluble guanylate cyclase catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP, which relaxes smooth muscle.[71]

Further rodent studies confirm the importance of the A2A receptor in vasorelaxation. Ponnoth et al. compared aortic vasorelaxation in wild-type mice versus A2A knockout mice and found reduced relaxation in response to adenosine analogs in the knockout mice.[72] Mouse studies show that A2A receptor ligation induced relaxation of the aorta via KATP channels, and this response is blunted to a similar extent by removal of the endothelial layer or in A2A Knockout mice.[73]

In order to determine the effect of A2A receptors on vasorelaxation in mice, aortic rings prepared from wild-type and A2A receptor knockout mice fed a high (4%) or normal salt diet were exposed to adenosine agonists and antagonists in their water bath.[74,75] This approach showed that the A2A receptor protein was upregulated by about 30% in the high salt diet-derived wild-type aortas compared to the normal salt diet aortas. Under both dietary conditions, a non-specific adenosine agonist enhanced relaxation, and the effect was blocked by an A2A receptor-specific antagonist. An A2A receptor agonist caused relaxation of aortic rings from either high or normal salt diet mice as long as they were wild type. High salt diet-fed wild-type mouse aortae exhibited exaggerated vascular relaxation to the selective adenosine A2A receptor agonist, and this response is lost in A2A receptor null mice, indicating that the A2A receptor is important for adaptive relaxation under high salt conditions.

A2B receptors have a low affinity for adenosine and are thus activated only under pathological conditions in which high concentrations at the micromolar level are achieved, such as ischemia.[76] A2B receptors are upregulated by hypoxia inducible factor-1α (HIF-1α), a transcription factor that is stabilized by inflammatory/hypoxic conditions.[77–79] In humans, examination of adenosine receptor transcript levels in cardiac tissue from persons with ischemic heart disease showed a selective induction of A2B receptors in comparison with healthy controls and this may be a myocardial adaptation to ischemia.[80] Although there is some controversy over the cardioprotective value of A2B receptors, mice lacking these receptors display increased vulnerability to myocardial ischemia,[81] and the anti-inflammatory effect of A2B receptors present specifically on polymorphonuclear leukocytes is crucial to limiting injury.[82] A2B receptors may also mediate coronary artery dilation in humans, but the contribution of the A2B receptor may be minimal under normal conditions and more prominent in disease states such as metabolic syndrome.[83–85]

Endothelial cells produce adenosine when injured.[86] Adenosine has direct effects on endothelial barrier function, which is critically important in maintaining the arterial lumen and preventing inciting events in development of the fatty streak. Inflammation-induced increases in vascular permeability are blunted by adenosine, thus maintaining cell-to-cell adhesion and vascular integrity.[87,88] Which specific adenosine receptors are involved in these effects on the endothelial barrier is unclear, and either both A2A and A2B receptor activation or A2A activation alone is required.[89–91]

Adenosine stimulates proliferation of endothelial cells, and the A2B receptor is involved in this effect.[92,93] A2B receptor ligation promotes production of angiogenic factors, including vascular endothelial growth factor (VEGF).[94,95]

In vitro studies of cultured human coronary artery smooth muscle cells have shown that these cells express predominantly A1 and A2B adenosine receptors and, combined with A2B receptor silencing experiments, further demonstrate that anti-proliferative effects of adenosine on coronary artery smooth muscle proliferation are A2B mediated, likely via the adenylyl cyclase/cAMP/protein kinase A (PKA) axis.[96] The limiting of proliferation of smooth muscle through A2B activation may protect against luminal narrowing and stenosis post-injury.[97]