Adenosine-mediated relaxation and activation of cyclic AMP-dependent protein kinase in coronary arterial smooth muscle

Abstract

Conflicting evidence exists regarding the participation of cyclic AMP (cAMP) in adenosine-induced relaxation of the coronary vasculature. Because the mechanism of action of cAMP is thought to involve activation of its dependent protein kinase, the purpose of this study was to determine if cytosolic cAMP protein kinase was activated in response to adenosine stimulation and to determine if such activation was correlated to the extent of relaxation in intact coronary arterial strips. Adenosine produced increases in cAMP protein kinase activity in both main trunk and branch circumflex bovine arterial strips. However, both the relaxant and kinase effects were greater in branch strips. Concentration and time-dependent increases in adenosine-induced relaxation of contracted branch strips were tightly coupled to concomitant increases in cAMP protein kinase activity (r = 0.93). Moreover, this increase in kinase activity was ascribable to the cAMP-dependent kinase, as the specific inhibitor of the cAMP protein kinase attenuated these increases. In contrast, relaxation produced by sodium nitroprusside was associated with an increase in a cAMP-independent kinase. In additional experiments, cumulative dose-response curves (10(-7) to 10(-3) M) for relaxation by adenosine and nine of its analogs showed that all agents were more effective in branch strips. Adenine-9-beta-D-arabinofuranoside, the least potent analog, did not produce relaxation or increase kinase activity. In contrast, 2-chloroadenosine, the most effective relaxant analog, also increased cAMP protein kinase activity. These findings suggest that adenosine-induced relaxation may involve cAMP and activation of cAMP protein kinase in coronary arterial smooth muscle.