Species-dependent hemodynamic effects of adenosine A₃-receptor agonists IB-MECA and Cl-IB-MECA

Abstract

The purpose of this study was to compare the hemodynamic effects of the adenosine A3-receptor agonists N 6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-d-ribofuranosyl]adenine (IB-MECA) and 2-chloro- N 6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-d-ribofuranosyl]adenine (Cl-IB-MECA) in isolated rat and rabbit hearts and in the intact, open-chest pig. Isolated hearts perfused with Krebs-Henseleit buffer at a constant pressure (70 mmHg) were treated with 50 nM of either IB-MECA or Cl-IB-MECA. Neither IB-MECA nor Cl-IB-MECA altered ventricular function or heart rate in the isolated rat and rabbit hearts, and neither agent altered coronary flow in the rabbit. However, 2 min of IB-MECA treatment in the isolated rat heart increased coronary flow by 25%, an effect that did not exhibit tachyphylaxis. The IB-MECA-induced coronary dilation was only partially attenuated by the adenosine A3-receptor antagonist MRS-1191 (50 nM). IB-MECA-induced coronary dilation was completely blocked by the adenosine A2a-receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (Sch-58261, 50 nM). Cl-IB-MECA (50 nM) did not increase coronary flow in the rat, but 100 nM did increase flow by 18%. In pentobarbital sodium-anesthetized pigs IB-MECA (5 μg/kg iv) decreased systemic blood pressure and increased pulmonary artery pressure, effects that did exhibit tachyphylaxis. These results illustrate that adenosine A3-receptor agonists produce species-dependent effects, which in the rat heart appear to be caused by adenosine A2a-receptor activation.

Targeted deletion of adenosine A3 receptors augments adenosine-induced coronary flow in isolated mouse heart

“…3A), and were significantly different from vehicle controls (P Ͻ 0.05). Thus Cl-IB-MECA-induced coronary vascular responses in mouse hearts did not exhibit tachyphylaxis with successive dosing as has been reported in isolated rat hearts (16).…”

“…4) resulted in similar inhibition of Cl-IB-MECA-induced coronary vasodilation. This suggests that Cl-IB-MECA-induced increases in coronary flow in murine hearts (at higher concentrations) are mediated primarily by activation of A 2A receptors, as has been reported in isolated rat hearts (16).…”

“…1C). These findings suggest that selective activation of A 3 receptors with Cl-IB-MECA (nanomolar range) has no effect on coronary flow of isolated mouse hearts as has been reported in isolated rabbit and rat hearts (16). Rather, it indicates that at higher concentrations, Cl-IB-MECA elicits coronary vasodilation by nonselective activation of a receptor subtype other than A 3 , possibly the A 2A and/or A 2B receptor subtype.…”

“…The K i values for CGS-21680 at A 1 , A 2A , and A 2B receptors are Ͼ350 nM, 15 nM, and Ͼ100 M, respectively (6). The reproducibility of responses induced by CGS-21680 (100 nM) on the coronary flow has been previously demonstrated in mice (34) and rats (16). A 5 nM concentration of MRS-1220 was chosen for A 3 antagonist experiments to favor A 3 selectivity.…”

“…Recently, it has been reported (4, 7) that A 3 receptors play an injurious role during myocardial ischemia-reperfusion, because targeted deletion of the A 3 receptor confers resistance to myocardial ischemic injury. In isolated rat and rabbit hearts, selective activation of A 3 receptors did not change coronary flow (16), yet infusion of adenosine in A 3 KO mice has been shown to cause a significant decrease in blood pressure compared with wild-type (WT) mice (36), suggesting that A 3 receptors affect vascular tone in this species. However, there are no reports demonstrating whether and to what extent A 3 receptors are involved in the modulation of coronary flow in mice.…”