Adenosine relaxation in isolated rat aortic rings and possible roles of smooth muscle K v channels, K ATP channels and A 2a receptors

Adenosine is a ubiquitous endogenous mediator that is activated in response to cellular ischemic/hypoxic/shear stress [1–5]. Adenosine exerts it cellular effects by binding to four major subtypes of the G-protein-coupled receptors; A₁, A_2a, A_2b, and A₃ which activate intracellular survival kinase pathways in a cell- and tissue-specific manner [2, 3, 5, 6]. Through receptor-modulation and downstream signaling pathways adenosine alters coronary and peripheral vascular tone, cardiac function, brain and central nervous system signalling, sleep, the state of natural hibernation, ischemic preconditioning, post-conditioning, inflammation, coagulation, angiogenesis and cell proliferation and remodelling [4–7].

An area of ongoing controversy is the role adenosine to regulate vascular tone in the arterial tree, and the receptor subtypes involved. The subtype A_2a appears to be the predominate receptor in arterial vasodilation in mouse, rat, guinea pig, pigs and humans, however, the A_2b receptor has also been reported to dilate human coronary arteries [8], and possibly rat coronary arteries [6]. In the guinea pig, A_2b appears to predominate in the thoracic aorta to induce relaxation [9] and both A_2a and A_2b in the rat [10–12]. In addition, there is ongoing debate on the relative importance of an intact endothelium to adenosine relaxation in these vessels, and the role of nitric oxide (NO) and interplay between voltage-dependent transmembrane Na⁺, K⁺ and Ca²⁺ fluxes and signalling pathways. In the thoracic aorta, adenosine relaxation has been reported to be fully dependent [10, 13], partially dependent [14–17] or not dependent on the presence of an intact endothelium [10, 18–20]. Adenosine vasodilation has also been linked to A₁ and A_2a receptor activation of endothelial production of NO and prostanoids [21], hyperpolarising factors [4], and a complex interplay between endothelial and smooth muscle mitochondrial and sarcolemmal K_ATP channels [16, 22, 23], and Na⁺/K⁺ ATPase activation [4, 24].

The aim of the present study was to investigate adenosine relaxation in intact versus denuded rat thoracic aortic rings, and examine the effect of inhibitors of nitric oxide (NO), prostanoids, K_v channels, K_ATP channels, and adenosine A_2a and A_2b receptors. The rat thoracic aorta was chosen because of the ongoing debates about the mechanisms of adenosine relaxation, and its in vivo significance.