Metabolism of cAMP to adenosine: role in vasodilation of rat pial artery in response to hypotension

Abstract

The purpose of this experiment was to examine whether the cAMP-adenosine pathway is implicated in the autoregulatory vasodilation in response to hypotension. Suffusion with cAMP (1–100 μmol/l) or adenosine (0.01–10 μmol/l) caused a sustained vasodilation of the resting pial arteries in a concentration-dependent manner. In contrast, N 6,2′- O-dibutyryl-cAMP and 8-bromo-cAMP exerted a weak dilation at high concentration (100 μmol/l). The vasodilation to cAMP (1–100 μmol/l), adenosine (0.01–10 μmol/l), and hypotension was significantly reduced by pretreatment with 3,7-dimethyl-1-propargylxanthine (1 μmol/l), an A2 receptor antagonist, as well as 3-isobutyl-1-methylxanthine (3 μmol/l), an inhibitor of endo- and ectophosphodiesterase, 1,3-dipropyl-8- p-sulfophenylxanthine (100 μmol/l), an inhibitor of ecto-5′-phosphodiesterase, or α,β-methylene-adenosine 5′-diphosphate (100 μmol/l), an inhibitor of ecto-5′-nucleotidase. However, 8-cyclopentyltheophylline (1 μmol/l), an A1 antagonist, did not elicit a similar response. The increased release of adenosine when the cortical surface was suffused with cAMP (100 μmol/l) was significantly reduced by 3-isobutyl-1-methylxanthine, 1,3-dipropyl-8- p-sulfophenylxanthine, and α,β-methylene-adenosine 5′-diphosphate (each 100 μmol/l). These results indicate that the cAMP-adenosine pathway as a viable metabolic mechanism is implicated in the production of adenosine in the rat pial artery and contributes to the regulation of vasodilation in response to hypotension.

ATP inhibits pump activity of lymph vessels via adenosine A1 receptor-mediated involvement of NO- and ATP-sensitive K+ channels

“…The myocyte-derived adenosine is a key substance in autoregulation of the coronary arterial system (11,12,19,43). Adenosine may play similar crucial roles in the autoregulatory function of the aortic (5), cerebral (14), and renal vasculature (17). Recently, it was reported that cultured pulmonary arterial endothelial cells endogenously produce ATP in response to shear stress and that endogenous release of ATP plays a significant role in the regulation of functions of cultured endothelial cells (47).…”

Overexpression of adenosine kinase in cortical astrocytes and focal neocortical epilepsy in mice

“…50 Further it has been shown that inhibition of ADK increases cerebral blood flow (CBF) by augmenting interstitial adenosine levels. 56 In addition, chronically increased levels of adenosine have been shown to stimulate angiogenesis 1,29,49 Consequently, chronic overexpression of ADK, as seen in epilepsy, may result in reduced CBF and reduction of local vasculature. Therefore, ADK-dependent changes in vasculature might provide a diagnostic opportunity for the detection of an epileptogenic focus that is characterized by overexpression of ADK.…”

The Extracellular cAMP-Adenosine Pathway Significantly Contributes to the in Vivo Production of Adenosine

“…Significant increases in extracellular adenosine levels occur with concentrations of cAMP in the medium as low as 1 M, and steady-state levels of adenosine are achieved in the culture medium within 5 min after adding exogenous cAMP. In addition to aortic vascular smooth muscle cells and cardiac fibroblasts, the extracellular cAMPadenosine pathway is present in hepatocytes (Gorin and Brenner, 1976;Smoake et al, 1981), neurons (Rosenberg and Dichter, 1989;Rosenberg et al, 1994;Li, 1995, 1996;Brundege et al, 1997), adipocytes (Kather, 1990;Zacher and Carey, 1999), isolated perfused kidneys Jackson, 1995, 1998), cerebral blood vessels (Hong et al, 1999), renal microvessels , collecting ducts , and proximal tubules (Jackson et al, 2006). However, whether the extracellular cAMP-adenosine pathway accounts for a significant portion of adenosine biosynthesis in vivo is unknown and is the focus of the present investigation.…”