Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
Department of Internal Medicine (Building C), Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
Molecules. 2018 Aug 30;23(9):2186. doi: 10.3390/molecules23092186.
Based on results, recently we have assumed that FSCPX, an irreversible A₁ adenosine receptor antagonist, inhibits the action of NBTI that is apparent on / curves of adenosine receptor agonists. As a mechanism for this unexpected effect, we hypothesized that FSCPX might modify the equilibrative and NBTI-sensitive nucleoside transporter (ENT1) in a way that allows ENT1 to transport adenosine but impedes NBTI to inhibit this transport. This assumption implies that our method developed to estimate receptor reserve for agonists with short half-life such as adenosine, in its original form, overestimates the receptor reserve. In this study, therefore, our goals were to experimentally test our assumption on this effect of FSCPX, to improve our receptor reserve-estimating method and then to compare the original and improved forms of this method. Thus, we improved our method and assessed the receptor reserve for the direct negative inotropic effect of adenosine with both forms of this method in guinea pig atria. We have found that FSCPX inhibits the effects of NBTI that are mediated by increasing the interstitial concentration of adenosine of endogenous (but not exogenous) origin. As a mechanism for this action of FSCPX, inhibition of enzymes participating in the interstitial adenosine production can be hypothesized, while modification of ENT1 can be excluded. Furthermore, we have shown that, in comparison with the improved form, the original version of our method overestimates receptor reserve but only to a small extent. Nevertheless, use of the improved form is recommended in the future.
基于结果，我们最近假设，FSCPX（一种不可逆的 A₁ 腺苷受体拮抗剂）抑制了 NBTI 的作用，这种作用在腺苷受体激动剂的 / 曲线中表现明显。作为这种意外效应的一种机制，我们假设 FSCPX 可能以某种方式改变平衡和 NBTI 敏感核苷转运体（ENT1），使 ENT1 能够转运腺苷，但阻碍 NBTI 抑制这种转运。这个假设意味着，我们开发的用于估计具有短半衰期的激动剂（如腺苷）受体储备的方法，在其原始形式下，会高估受体储备。因此，在这项研究中，我们的目标是实验性地检验 FSCPX 对这种效应的假设，改进我们的受体储备估计方法，然后比较这种方法的原始形式和改进形式。因此，我们改进了我们的方法，并使用这两种方法评估了在豚鼠心房中腺苷直接负性变力作用的受体储备。我们发现，FSCPX 通过增加内源性（而非外源性）来源的腺苷的细胞间隙浓度来抑制 NBTI 介导的作用。FSCPX 这种作用的一种机制可以假设是抑制参与细胞间隙腺苷产生的酶，而排除 ENT1 的修饰。此外，我们已经表明，与改进后的形式相比，我们方法的原始版本高估了受体储备，但只是在很小的程度上。尽管如此，在未来仍推荐使用改进后的形式。
