Galindo-Tovar Alejandro, Vargas Maria Luisa, Kaumann Alberto J
Department of Pharmacology, University of Murcia, University Hospital Virgen de la Arrixaca, Murcia, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):379-84. doi: 10.1007/s00210-008-0367-7. Epub 2008 Nov 14.
Acting through a low-affinity site of the beta(1)-adrenoceptor (beta(1L)AR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 microM) on the (-)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 +/- 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (-)-CGP12177 (-logEC(50)M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 +/- 9% of the effect of 200 microM (-)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (-)-CGP12177 (-logEC(50)M = 7.4) but concurrent rolipram + cilostamide caused potentiation (-logEC(50)M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the beta(1L)AR-induced cAMP compartment through which (-)-CGP12177 causes tachycardia. In contrast to the (-)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (-)-CGP12177-evoked increases of left atrial contractility through beta(1L)AR.
CGP12177 通过 β1 -肾上腺素能受体（β1L AR）的低亲和力位点起作用，可引起大鼠窦房性心动过速和左心房正性肌力作用，但对心室无此作用。然而，抑制磷酸二酯酶 3（PDE3）或磷酸二酯酶 4（PDE4）也可揭示 CGP12177 在心室中的正性肌力作用，但这些磷酸二酯酶是否也控制 CGP12177 的心房激动剂作用尚不清楚。因此，我们研究了 PDE3 选择性抑制剂西洛他唑（300 nM）和 PDE4 抑制剂咯利普兰（1 μM）对（-）-CGP12177 诱发的大鼠窦房率增加和起搏左心房力的影响。咯利普兰（n = 8）使基础窦房率增加 27±5 次/分钟，但西洛他唑（n = 8）无此作用。咯利普兰和西洛他唑或其组合未改变（-）-CGP12177 的变时效力（-logEC50M = 7.5）。与（-）-异丙肾上腺素相比，（-）-CGP12177 使左心房力增加，内在活性为 0.25。咯利普兰（n = 8）和西洛他唑（n = 8）未改变左心房基础力，但咯利普兰 + 西洛他唑联合使用（n = 8）使力增加了 200 μM（-）-异丙肾上腺素作用的 52±9%。咯利普兰和西洛他唑均未影响（-）-CGP12177 的正性肌力效力（-logEC50M = 7.4），但咯利普兰 + 西洛他唑联合使用引起增强作用（-logEC50M = 8.2），并使（-）-CGP12177 相对于（-）-异丙肾上腺素转变为完全激动剂。环磷酸腺苷（cAMP）似乎维持窦房率，PDE4 通过在与 β1L AR 诱导的 cAMP 区室不同的区室中水解 cAMP 引发心动过缓，（-）-CGP12177 通过该 β1L AR 诱导的 cAMP 区室引起心动过速。与不受 PDE3 和 PDE4 控制的（-）-CGP12177 诱发的心动过速相反，这些同工酶通过 β1L AR 共同降低（-）-CGP12177 诱发的左心房收缩力增加。
