MECHANISMS OF B1 AND B2 ADRENERGIC ACTIONS IN CANINE HEART CELLS

β-肾上腺素能受体(β-AR)介导的心肌细胞调制 运动能力是心血管储备功能的重要组成部分。 虽然有几种不同类型的BetaAR，但 心肌主要是β受体。但现在强有力的证据表明 Beta1AR和Beta2AR亚型同时存在于不同的心脏 哺乳动物物种，这两种AAR亚型的刺激起到了 在心脏功能调节中的重要作用。因为 老年人和老年人对BetaAR刺激的收缩反应降低 心力衰竭伴随着大量的Beta1AR的损失，没有 β2AR的丢失，β2AR激活对改善的潜在作用 心脏功能已受到相当大的关注。最近，我们 演示了Beta1AR和Beta2AR在功能上共存于 心肌细胞及β2受体刺激对L钙离子的影响 电流(ICa)、胞浆钙(CaI)瞬变和收缩。然而， 刺激β_2AR对心肌钙代谢和心肌细胞功能的影响 收缩能力在很大程度上与cAMP的产生和 大鼠心肌细胞中磷蛋白的磷酸化。百日咳毒素 (PTX)预处理可特异性增强刺激的β-2AR CAI一过性、收缩和ICA增加。在本研究中，我们 研究发现，虽然zinterol对Beta2AR的刺激确实会产生积极的 变力作用和增加ICA和CAI的暂时性，它没有作用 对细胞内cAMP生成或磷蛋白磷酸化的影响 犬的肌细胞。这些结果强烈地表明，营地信号 该通路可能不参与犬心脏β2AR的刺激。 此外，在β1AR激动剂引起的ICA增大的同时， Ne，被一种特定的多肽抑制剂完全阻断 CAMP依赖的蛋白激酶(PKI，在吸管充注液中为50um)， β-2AR刺激的ICa升高持续存在 公钥基础设施的概念。此外，G蛋白抑制剂GDPbetaS(5 MM)包括在 吸管充注液完全取消了Beta2AR AS的作用 以及β-AR对ICA的刺激作用。综合来看，我们得出的结论是 而刺激Beta1AR对ICA的影响完全是由于 β2AR刺激对cAMP依赖的蛋白磷酸化的影响 ICA可能由非cAMP依赖的G蛋白(S)偶联介导 犬心室肌细胞的信号通路(S)。

The beta-adrenergic receptor (betaAR) mediated modulation of myocardial performance is a major component of cardiovascular reserve function. While there are several different types of betaAR, those in the myocardium are primarily beta1AR.However, now strong evidence suggests that both beta1AR and beta2AR subtypes coexist in the hearts of various mammalian species, and that stimulation of both aAR subtypes play a significant role in the regulation of cardiac performance. Because the reduced contractile response to betaAR stimulation in both aged and failing hearts is accompanied by a substantial loss of beta1AR, with no loss of beta2AR, the potential role of beta2AR activation for improving cardiac performance has received considerable attention. Recently, we demonstrated that both beta1AR and beta2AR functionally coexist in cardiac myocytes and that beta2AR stimulation augments L-type Ca2+ current (ICa), cytosolic Ca2+ (Cai) transient, and contraction. However, the actions of beta2AR stimulation on cardiac Ca2+ metabolism and contractility are largely dissociated from cAMP production and phospholamban phosphorylation in rat heart myocytes. Pertussis toxin (PTX) pretreatment specifically potentiates the beta2AR stimulated increases in Cai transient, contraction and ICa.In the present study,we found that while beta2AR stimulation by zinterol does induce an positive inotropic effect and increases in ICa and Cai transient, it has no effect on cellular cAMP production or on phospholamban phosphorylation in canine myocytes. These results strongly suggest that cAMP signalling pathway may not be involved in canine cardiac beta2AR stimulation. Furthermore, while the augmentation of ICa induced by beta1AR agonist, NE, is completely blocked by a specific peptide inhibitor of cAMP-dependent protein kinase (PKI, 50 muM in pipette filling solution), beta2AR stimulated increase in ICa by zinterol persists in the presence of PKI. In addition, a G protein inhibitor, GDPbetaS (5 mM), included in pipette filling solution completely abolished the actions of beta2AR as well as beta1AR stimulation on ICa. Taken together, we conclude that while the effect of beta1AR stimulation on ICa is due exclusively to cAMP-dependent protein phosphorylation, the effect of beta2AR stimulation on ICa may be mediated by non-cAMP-dependent G protein(s)-coupled signalling pathway(s) in canine ventricular myocytes.