Adenosine Receptor Regulation of Coronary Blood Flow in Ossabaw Miniature Swine

Abstract

Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A 1 , A 2A , A 2B , A 3 ) to CBF in swine have not been determined. ARs generally decrease (A 1 , A 3 ) or increase (A 2A , A 2B ) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A 1 antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A 1 /A 2A expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A 2 -nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A 1 -selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A 2 antagonist 3,7-dimethyl-1-propargylxanthine and A 2A -selective antagonist 4-(2-[7-amino-2-(2-furyl) [1,2,4] triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A 2B and A 3 antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ϳ70%, whereas A 1 , A 2A , and A 2B mRNA were up-regulated in dyslipidemic versus control Ͼ5-fold and there was no change in the ratio of A 1 /A 2A protein in microvessels distal to the stent. In control Ossabaw swine A 1 antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A 1 and A 2A signaling, not receptor expression.

Heart of the matter: Coronary dysfunction in metabolic syndrome

“…There is little change in baseline coronary blood flow in either animals [13–15;22;41–45] or humans [16–19;46] with MetS. While myocardial perfusion is equivalent, myocardial oxygen consumption (MVO 2 ) is elevated in proportion to increases in stroke volume, cardiac output, and blood pressure; i.e.…”

“…MetS attenuates coronary flow responses to pharmacologic vasodilator compounds such as acetylcholine, adenosine, papaverine, and dipyridamole [16–20;45;73]. Decreases in coronary flow reserve directly correlate with waist-to-hip ratio [74], body mass index [17], blood pressure [20], degree of insulin resistance [16;20], and the clinical diagnosis of MetS [18].…”

“…In contrast, decreased coronary flow reserve is evident in swine with later-stage MetS [41;73;75] and worsens with the onset of type 2 diabetes [16;17]. Exact mechanisms underlying impaired pharmacologic coronary vasodilation in MetS have not been clearly defined, but are likely related to altered functional expression of receptors and ion channels [41;44;45;73;76;77], endothelial and vascular smooth muscle function [36;56;77;78], paracrine and neuro-endocrine influences [32;48–50;54;79;80], structural remodeling of coronary arterioles [35;81;82], and/or microvascular rarefaction [83–85]. …”

Contribution of voltage-dependent K+ channels to metabolic control of coronary blood flow

“…Coronary microvascular dysfunction in the MetS is evidenced by reductions in coronary venous P o 2 [9;11;12], diminished vasodilatory responses to pharmacologic agonists (i.e. coronary flow reserve) [13–17], and alterations in functional and reactive coronary hyperemia [18]. Decreases in K + channel function contribute to this impairment as MetS depresses outward K + current in coronary artery smooth muscle cells [14;19–21] and diminishes the role of specific K + channels in coronary vasodilatory responses [6;18].…”

Low Coronary Microcirculatory Resistance Associated With Profound Hypotension During Intravenous Adenosine Infusion

“…Another possible explanation for this observation comes from recent insights on adenosine physiology because some pathological states have been associated with an heterogeneous impairment in adenosine receptor subtypes. 35 Specifically, it has been proposed that in conditions where A 2 receptor-mediated responses are preserved but A 1 receptor-mediated responses are impaired, an increase in adenosine-induced dilatation can be produced because of diminished A 1 constrictive effects. 20,21,36,37 Obesity is one of these conditions.…”