Mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation

The mechanism of adenosine-induced vasodilation in rat diaphragm microcirculation was investigated using laser Doppler flowmetry. Adenosine (10^-5, 3.2 x 10^-5, and 10^-4 M), the nonselective adenosine agonist 5'-N-ethylcarboxamido-adenosine (NECA) (10^-8-10^-7 M), the specific A(2A) agonist 2-p-(2-carboxyethyl)phenyl-amino-5'-N-ethyl carboxamidoadenosine (CGS-21680) (10^-8-10^-7 M), and the adenosine agonist with higher A₁-receptor affinity, R-N⁶-phenylisopropyladenosine (R-PIA) (10^-7, 3.2 x 10^-7, and 10^-6 M) elicited a similar degree of incremental increase of microcirculatory flow in a dose-dependent manner. The ATP-dependent potassium (K(ATP)) channel blocker glibenclamide (3.2 x 10^-6 M) significantly attenuated the vasodilation effects of these agonists. Adenosine-induced vasodilation could be significantly attenuated by the nonselective adenosine antagonist 8-(p-sulfophenyl)-theophylline (3 x 10^-5 M) or the selective A(2A) antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl ) phenol (ZM-241385, 10^-6 M), but not by the selective A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine (5 x 10^-8 M). Adenylate cyclase inhibitor N-(cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride (MDL-12330A, 10^-5M) effectively suppressed the vasodilator response of adenosine and forskolin. These results suggest that adenosine-induced vasodilation in rat diaphragm microcirculation is mediated through the stimulation of A(2A) receptors, which are coupled to adenylate cyclase activation and opening of the K(ATP) channel.