Predominant role of A 1 adenosine receptors in mediating adenosine induced vasodilatation of rat diaphragmatic arterioles: involvement of nitric oxide and the ATP‐dependent K + channels

We investigated, by intravital microscopy in rats, the role of the subtypes of adenosine receptors A 1 (A 1 /AR) and A 2 (A 2 AR) in mediating adenosine‐induced vasodilatation of second and third order arterioles of the diaphragm. Adenosine, and the A 1 AR selective agonists R (−)‐N 6 ‐(2‐phenylisopropyl)‐adenosine ( R ‐PIA) and N 6 ‐cyclo‐pentyl‐adenosine (CPA) induced a similar concentration‐dependent dilatation of diaphragmatic arterioles. The non selective A 2 AR subtype agonist N 6 ‐[2‐(3,5‐dimethoxyphenyl)‐2‐(2‐methylphenyl) ethyl]adenosine (DPMA) also dilated diaphragmatic arterioles but induced a significantly smaller dilatation than adenosine. By contrast the selective A 2a AR subtype agonist 2‐[p‐(2‐carboxyethyl)phenyl amino]‐5′‐N‐ethyl carboxamido adenosine (CGS 21680) did not modify diaphragmatic arteriolar diameter. The non selective adenosine receptor antagonist 1,3‐dipropyl‐8‐ p ‐sulphophenylxanthine (SPX, 100 μ M ) and the selective A 1 AR antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (CPX, 50 n M ) significantly attenuated adenosine‐induced dilatation of diaphragmatic arterioles. By contrast, adenosine significantly dilated diaphragmatic arterioles in the presence of A 2 AR antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX, 10 μ M ). The dilatation induced by adenosine was unchanged by the mast cell stabilizing agent sodium cromoglycate (cromolyn, 10 μ M ). The nitric oxide (NO) synthase inhibitor N ω ‐nitro‐ L ‐arginine ( L ‐NOARG, 300 μ M ) attenuated the dilatation induced by adenosine, and by the A 1 AR and A 2 AR agonists. The ATP‐dependent K + channel blocker glibenclamide (3 μ M ) significantly attenuated diaphragmatic arteriolar dilatation induced by adenosine and by the A 1 AR agonists R ‐PIA and CPA. By contrast, glibenclamide did not significantly modify arteriolar dilatation induced by the A 2 AR agonist DPMA. These findings suggest that adenosine‐induced dilatation of diaphragmatic arterioles in the rat is predominantly mediated by the A 1 AR, via the release of NO and activation of the ATP‐dependent K + channels.