Adenosine is a potent mediator of myocardial protection against hypertrophy via A(1) or A(3) receptors that may be partly related to atrial natriuretic peptide (ANP) release. However, little is known about the possible involvement of the A(3) receptor on ANP release. We studied the effects of the A(3) receptor on atrial functions and its modification in hypertrophied atria. A selective A(3) receptor agonist, 2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide (2-CI-IB-MECA), was perfused into isolated, beating rat atria with and without receptor modifiers. 2-CI-IB-MECA dose-dependently increased the ANP secretion, which was blocked by the A(3) receptor antagonist, but the increased atrial contractility and decreased cAMP levels induced by 30muM 2-CI-IB-MECA were not affected. The 100muM 2-(1-hexylnyl)-N-methyladenosine (HEMADO) and N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide (IB-MECA), A(3) receptor agonist, also stimulated the ANP secretion without positive inotropy. The potency for the stimulation of ANP secretion was 2-CI-IB-MECA>IB-MECA=HEMADO. The inhibition of the ryanodine receptor or calcium/calmodulin-dependent kinase II (CaMKII) attenuated 2-CI-IB-MECA-induced ANP release, positive inotropy, and translocation of extracellular fluid. However, the inhibition of L-type Ca(2+) channels, sarcoplasmic reticulum Ca(2+)-reuptake, phospholipase C or inositol 1,4,5-triphosphate receptors did not affect these parameters. 2-CI-IB-MECA decreased cAMP level, which was blocked only with an inhibitor of CaMKII or adenylyl cyclase. These results suggest that 2-CI-IB-MECA increases the ANP secretion mainly via A(3) receptor activation and positive inotropy by intracellular Ca(2+) regulation via the ryanodine receptor and CaMKII.

译文

:腺苷是心肌通过A(1)或A(3)受体对抗肥大的有效保护介质,而A(1)或A(3)受体可能与心钠素的释放有关。但是,关于A(3)受体可能参与ANP释放的消息鲜为人知。我们研究了A(3)受体对心房功能及其在肥大心房中的修饰的影响。将选择性A(3)受体激动剂2-氯-N(6)-(3-碘苄基)腺苷5'-N-甲基脲酰胺(2-CI-IB-MECA)灌注到孤立的,搏动的大鼠心房中而且没有受体修饰剂。 2-CI-IB-MECA剂量依赖性地增加了ANP的分泌,ANP的分泌被A(3)受体拮抗剂所阻断,但由30μM2-CI-IB-MECA诱导的心房收缩力的增加和cAMP水平的降低均未受到影响。也刺激了100μM的2-(1-己基)-N-甲基腺苷(HEMADO)和N(6)-(3-碘苄基)腺苷-5'-N-甲基脲酰胺(IB-MECA),A(3)受体激动剂。 ANP分泌无正性变质现象。刺激ANP分泌的效力为2-CI-IB-MECA> IB-MECA = HEMADO。 ryanodine受体或钙/钙调蛋白依赖性激酶II(CaMKII)的抑制作用减弱了2-CI-IB-MECA诱导的ANP释放,正性肌力和细胞外液易位。但是,L型Ca(2)通道,肌质网Ca(2)重新摄取,磷脂酶C或肌醇1,4,5-三磷酸受体的抑制不影响这些参数。 2-CI-IB-MECA降低了cAMP水平,仅被CaMKII或腺苷酸环化酶抑制剂所阻断。这些结果表明,2-CI-IB-MECA主要通过A(3)受体激活和通过胞内Ca(2)调控通过利安诺定受体和CaMKII来增加ANP分泌。

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