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

Abstract

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 A(2) receptor antagonism with 3,7-dimethyl-1-propargylxanthine and adenylate cyclase (AC) inhibition with SQ22536 significantly attenuated the dilation. In contrast, A(1) 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 A(1) receptor agonist (2S)-N(6)-(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 A(1) and A(2) 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.

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

“…However, the application of exogenous adenosine to increase coronary flow for the investigation of adenosine receptor-mediated signaling pathways has been well established [37,44]. Thus, in agreement with previous studies from our laboratory [37,44,49] and others [14], adenosine produced a large increase in coronary flow in isolated mouse hearts, supporting the overall effect of vasodilation by adenosine in the coronary circulation [14,15,37,50,51].…”

“…We [9,16] and others [14,15] have demonstrated that adenosine-mediated coronary vasodilation is predominantly attributed to A 2A AR as compared to vasodilator A 2B AR. In contrast, adenosine A 1 and A 3 ARs counteract the adenosine-mediated coronary vasodilation [15,17,18].…”

“…In contrast, adenosine A 1 and A 3 ARs counteract the adenosine-mediated coronary vasodilation [15,17,18]. Despite the findings that all four adenosine receptor subtypes are expressed and functional in the coronary vasculature [13], their roles in regulating coronary vascular tone through generation of ROS remain unclear.…”

“…The role of these receptors has been studied in various species [12]. With an overall coronary vasodilation, A 2A AR predominantly and A 2B AR minimally contribute to dilating coronary vasculature [14][15][16], whereas A 1 AR and A 3 AR counteract the effects of A 2A /A 2B ARs resulting in a diminished coronary vasodilation [15,17,18]. At post-receptor levels, several effector pathways of adenosine-mediated coronary flow have been reported, such as activation of nitric oxide (NO) pathway [19,20], cyclic adenosine 5′-monophosphate (cAMP)-dependent pathway [21], activation of potassium channels [9,21], and the involvement of H 2 O 2 [19].…”

Cardiac purinergic signalling in health and disease

“…Adenosine-mediated relaxation in human small coronary arteries via A2BR, which was independent of the endothelium and NO [436]. However, in a later paper, it was claimed that in human coronary arteriolar smooth muscle, the A2AR mediated vasodilation [437]. A2AR and A2BR mediate production of NO in cultured porcine coronary artery endothelial cells [438] and it was suggested that while A2AR are predominant, A2BR may also play a role in adenosineinduced vasodilation, possibly through the p38 MAPK pathway [439].…”