Yuan Kuichang, Bai Guang Yi, Park Woo Hyun, Kim Sung Zoo, Kim Suhn Hee
Department of Physiology, Diabtes Research Center, Chonbuk National University Medical School, 2-20 Keum-Am-Dong-San, Jeonju 561-180, Republic of Korea.
Peptides. 2008 Dec;29(12):2216-24. doi: 10.1016/j.peptides.2008.09.003. Epub 2008 Sep 16.
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.
腺苷是通过A(1)或A(3)受体对心肌肥厚起保护作用的强效介质，这可能部分与心房利钠肽（ANP）释放有关。然而，关于A(3)受体在ANP释放中可能的作用知之甚少。我们研究了A(3)受体对心房功能的影响及其在肥厚心房中的改变。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）灌注到有或没有受体调节剂的离体搏动大鼠心房中。2-CI-IB-MECA剂量依赖性地增加ANP分泌，这被A(3)受体拮抗剂阻断，但30μM 2-CI-IB-MECA诱导的心房收缩力增加和cAMP水平降低不受影响。100μM 2-(1-己炔基)-N-甲基腺苷（HEMADO）和A(3)受体激动剂N(6)-(3-碘苄基)腺苷-5'-N-甲基脲酰胺（IB-MECA）也刺激ANP分泌而无正性肌力作用。刺激ANP分泌的效力为2-CI-IB-MECA>>IB-MECA=HEMADO。抑制兰尼碱受体或钙/钙调蛋白依赖性激酶II（CaMKII）减弱了2-CI-IB-MECA诱导的ANP释放、正性肌力作用和细胞外液转运。然而，抑制L型钙通道、肌浆网钙再摄取、磷脂酶C或肌醇1,4,5-三磷酸受体并不影响这些参数。2-CI-IB-MECA降低cAMP水平，这仅被CaMKII抑制剂或腺苷酸环化酶抑制剂阻断。这些结果表明，2-CI-IB-MECA主要通过A(3)受体激活增加ANP分泌，并通过兰尼碱受体和CaMKII对细胞内钙进行调节从而产生正性肌力作用。
