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Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease

¹Department of Medicine, Cardiovascular Center, and Veterans Administration Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin; ²Second Department of Internal Medicine, Akita University School of Medicine, Akita; and ³Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Submitted 14 June 2004 ; accepted in final form 13 December 2004

Adenosine is a key myocardial metabolite that elicits coronary vasodilation in a variety of pathophysiological conditions. We examined the mechanism of adenosine-induced vasodilation in coronary arterioles from patients with heart disease. Human coronary arterioles (HCAs) were dissected from pieces of the atrial appendage obtained at the time of cardiac surgery and cannulated for the measurement of internal diameter with videomicroscopy. Adenosine-induced vasodilation was not inhibited by endothelial denudation, but A₂ receptor antagonism with 3,7-dimethyl-1-propargylxanthine and adenylate cyclase (AC) inhibition with SQ22536 significantly attenuated the dilation. In contrast, A₁ receptor antagonism with 8-cyclopentyl-1,3-dipropylxanthine significantly augmented the sensitivity to adenosine. Moreover, dilation to A_2a receptor activation with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine hydrochloride was reduced by the A₁ receptor agonist (2S)-N⁶-(2-endo-norbornyl)adenosine. The nonspecific calcium-activated potassium (K_Ca) channel blocker tetrabutylammonium attenuated adenosine-induced dilation, as did the intermediate-conductance K_Ca blocker clotrimazole. Neither the large-conductance K_Ca blocker iberiotoxin nor small-conductance K_Ca blocker apamin altered the dilation. In conclusion, adenosine endothelium independently dilates HCAs from patients with heart disease through a receptor-mediated mechanism that involves the activation of intermediate-conductance K_Ca channels via an AC signaling pathway. The roles of A₁ and A₂ receptor subtypes are opposing, with the former being inhibitory to AC-mediated dilator actions of the latter. These observations identify unique fundamental physiological characteristics of the human coronary circulation and may help to target the use of novel adenosine analogs for vasodilation in perfusion imaging or suggest new strategies for myocardial preconditioning.

receptors; potassium channels; microcirculation

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