Abstract
The organic anion transporter SLCO2A1 constitutes an essential core component of the ATP-conductive large-conductance anion (Maxi-Cl) channel. Our previous experiments using Langendorff-perfused mouse hearts showed that the Maxi-Cl channel contributes largely to the release of ATP into the coronary effluent observed during 10-min reperfusion following a short period (6 min) of oxygen-glucose deprivation. The present study examined the effect of endogenous ATP released via Maxi-Cl channels on the left ventricular contractile function of Langendorff-perfused mouse hearts, using a fluid-filled balloon connected to a pressure transducer. After the initial 30-min stabilization period, the heart was then perfused with oxygen-glucose-deprived Tyrode solution for 6 min, which was followed by a 10-min perfusion with oxygenated normal Tyrode solution in the absence and presence of an ATP-hydrolyzing enzyme, apyrase, and/or an adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the absence of apyrase and DPCPX, the left ventricular developed pressure (LVDP) decreased from a baseline value of 72.3 ± 7.1 to 57.5 ± 5.5 mmHg (n = 4) at the end of 6-min perfusion with oxygen-glucose-deprived Tyrode solution, which was followed by a transient increase to 108.5 ± 16.5 mmHg during subsequent perfusion with oxygenated normal Tyrode solution. However, in the presence of apyrase and DPCPX, the LVDP decreased to the same degree during 6-min perfusion with oxygen-glucose-deprived Tyrode solution, but failed to exhibit a transient increase during a subsequent perfusion with oxygenated normal Tyrode solution. These results strongly suggest that endogenous ATP released through Maxi-Cl channels contributes to the development of transient positive inotropy observed during reperfusion after short-period hypoxia/ischemia in the heart.
Highlights
We examined the effect of apyrase and DPCPX added separately to the perfusion medium during the same time period, and found that a transient increase in left ventricular (LV) pressure upon reperfusion following oxygenglucose deprivation (OGD) appeared in the presence of DPCPX alone but was abolished in the presence of apyrase alone
We previously showed that the amount of ATP release, which is largely mediated by the Maxi-Cl channel, is markedly enhanced during 10-min reperfusion following a short period (6 min) of perfusion with OGD in the Langendorff-perfused mouse heart model (Sabirov et al, 2017)
The left ventricular developed pressure (LVDP) gradually decreased during 6-min OGD, which was followed by a transient increase in LVDP during 10-min reperfusion with oxygenated medium (Figure 2A)
Summary
ATP is known to be released from the heart (Paddle and Burnstock, 1974; Forrester and Williams, 1977; Clemens and Forrester, 1981; Williams and Forrester, 1983; Vial et al, 1987; Borst and Schrader, 1991) and cardiomyocytes (Borst and Schrader, 1991; Kuzmin et al, 1998, 2000; Dutta et al, 2004; Kunugi et al, 2011). Our experiments using the Langendorff-perfused mouse heart model showed (i) that the release of ATP into the coronary effluent is markedly enhanced during 10-min reperfusion after a short period (6 min) of the oxygen-glucose deprivation, and (ii) that treatment of the mouse with Slco2a1-targeting siRNA significantly reduces the release of ATP (Sabirov et al, 2017). These observations support the view that ATP is released through the ATP-conductive large-conductance anion (Maxi-Cl) channel during reperfusion following a short period of hypoxia in the Langendorff-perfused mouse heart model. The present study was designed to investigate the effect of endogenous ATP released during hypoxia/reperfusion on the left ventricular contractile function of Langendorff-perfused mouse heart model
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