Contractile effects of adenosine, coronary flow and perfusion pressure in murine myocardium

Abstract

There is mixed evidence adenosine receptors (ARs) may enhance myocardial contractility, although this remains contentious. We assessed inotropic actions of adenosine (50 muM) and selective AR activation with 100 nM N (6)-cyclohexyladenosine (CHA; A(1)AR agonist), 25 nM 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS-21680; A(2A)AR agonist) and 100 nM 2-chloro-N (6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; A(3)AR agonist) in mouse hearts perfused at constant pressure, constant flow, or conditions of stable flow and pressure (following maximal nitroprusside-mediated dilatation at constant flow). Adenosine and CGS-21680 significantly (although modestly) increased force in constant-pressure perfused hearts (</=10 mmHg elevations in systolic pressure), effects paralleled by coronary vasodilatation (</=10 ml min(-1) g(-1) elevations in flow). Neither CHA nor Cl-IB-MECA altered force or flow. With constant-flow perfusion, adenosine and CGS-21680 reduced systolic pressure in parallel with perfusion pressure. When changes in coronary flow and pressure were prevented, CGS-21680 failed to alter contractility. However, adenosine still enhanced systolic pressure up to 10 mmHg. Relations between flow, perfusion pressure and ventricular force evidence substantial Gregg effects in murine myocardium: systolic force increases transiently by approximately 1 mmHg ml(-1) min(-1) g(-1) rise in flow during the first minutes of hyperaemia and in a sustained manner (by approximately 1 mmHg mmHg(-1)) during altered perfusion pressure. These effects contribute to inotropism with AR agonism when flow/pressure is uncontrolled. In summary, we find no evidence of direct A(1) or A(3)AR-mediated inotropic responses in intact myocardium. Inotropic actions of A(2A)AR agonism appear entirely Gregg-related. Nonetheless, the endogenous agonist adenosine exerts a modest inotropic action independently of flow and perfusion pressure. The basis of this response remains to be identified.

Differential effects of adenosine A2aand A2breceptors on cardiac contractility

“…CF increased by 50%, but cardiac function did not change with increasing concentrations of the A 2a AR agonist (up to 1 M). These results are consistent with our previous reports as well as those of others (13,16,19,31) showing that A 2a AR stimulation does not alter cardiac function in isolated perfused rat hearts or isolated cardiac myocytes. In contrast, it has been reported that the A 2a AR agonist CGS-21680 (100 nM) increased LV developed pressure in isolated mouse hearts by ϳ80% (20).…”

“…Additional studies from our laboratory (14,16) have indicated that A 2a AR stimulation has no effects on contractility in isolated rat hearts and intact porcine myocardium. Our findings are consistent with those of a study by Headrick et al (31) in which it was also shown that A 2a AR activation has no contractile effects in isolated mouse hearts. In contrast, other reports (6,8,20,30,33) have indicated that A 2a AR stimulation increases contractility in isolated rat and mouse hearts and in isolated rat cardiomyocytes.…”

“…However, this same concentration also increased CF by 500%, and the A 2a AR dose-response curves for LV function and coronary vasodilation exhibited similar EC 50 values. Willems and Headrick (31) concluded that this significant increase in contractility was due to the Gregg phenomenon or the garden hose effect (flow-induced increases in ventricular function). In the only other study to date in mouse myocardium, Tikh et al (30) concluded that A 2a AR stimulation with CGS-21680 increased contractility by ϳ5-10%, but these authors did not present specific data to support this conclusion.…”

“…The contractile effects of A 2b AR have not been studied in detail, due to the lack of readily available selective agonists and antagonists. One study (31) using wild-type (WT) mice reported that A 2b AR may be responsible for a small, but sustained, positive inotropic effect after adenosine administration in isolated perfused mouse hearts. In the only study (28) conducted thus far with a selective A 2b AR-selective agonist, BAY 60-6583 exerted dose-dependent increases in ventricular function in parallel with coronary vasodilation.…”

Pharmacology of the Adenosine A3 Receptor in the Vasculature and Essential Hypertension

“…Cardiac contraction is achieved through an increase in intracellular Ca 2+ levels and protein kinase A and protein kinase C pathways [ 37 ]. There is, however, controversy over the ability of the adenosine A 2A receptor to have a positive inotropic effect due to a number of studies revealing otherwise, such as Willems and Headrick [ 39 ], who reported that the adenosine A 2A receptor caused no contractile effects in mouse hearts. Reports of the selective the adenosine A 2A receptor agonist, 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS-21680) causing increased LVDP and coronary flow were suggested to be instead due to the Gregg phenomenon in which increased flow increases ventricular function [ 40 ].…”