Christ Torsten, Galindo-Tovar Alejandro, Thoms Marcus, Ravens Ursula, Kaumann Alberto J
Department of Pharmacology, Dresden University of Technology, Dresden, Germany.
Br J Pharmacol. 2009 Jan;156(1):62-83. doi: 10.1111/j.1476-5381.2008.00015.x.
beta(1)- and beta(2)-adrenoceptors coexist in rat heart but beta(2)-adrenoceptor-mediated inotropic effects are hardly detectable, possibly due to phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide (300 nmol x L(-1)) and the PDE4 inhibitor rolipram (1 micromol x L(-1)) on the effects of (-)-catecholamines.
Cardiostimulation evoked by (-)-noradrenaline (ICI118551 present) and (-)-adrenaline (CGP20712A present) through beta(1)- and beta(2)-adrenoceptors, respectively, was compared on sinoatrial beating rate, left atrial and ventricular contractile force in isolated tissues from Wistar rats. L-type Ca(2+)-current (I(Ca-L)) was assessed with whole-cell patch clamp.
Rolipram caused sinoatrial tachycardia. Cilostamide and rolipram did not enhance chronotropic potencies of (-)-noradrenaline and (-)-adrenaline. Rolipram but not cilostamide potentiated atrial and ventricular inotropic effects of (-)-noradrenaline. Cilostamide potentiated the ventricular effects of (-)-adrenaline but not of (-)-noradrenaline. Concurrent cilostamide + rolipram uncovered left atrial effects of (-)-adrenaline. Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). (-)-Adrenaline (10 micromol x L(-1)) increased I(Ca-L) only in the presence of cilostamide but not rolipram.
PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. PDE4 reduces basal sinoatrial rate in a compartment distinct from compartments controlled by beta(1)- and beta(2)-adrenoceptors. PDE3 and PDE4 jointly prevent left atrial beta(2)-adrenoceptor-mediated inotropy. Both PDE3 and PDE4 reduce I(Ca-L) responses through beta(1)-adrenoceptors but the PDE3 component is unrelated to inotropy. PDE3 blunts both ventricular inotropic and I(Ca-L) responses through beta(2)-adrenoceptors.
β1 - 和β2 - 肾上腺素受体共存于大鼠心脏中，但β2 - 肾上腺素受体介导的变力作用几乎无法检测到，这可能是由于磷酸二酯酶（PDE）的活性所致。我们研究了PDE3抑制剂西洛酰胺（300 nmol·L-1）和PDE4抑制剂咯利普兰（1 μmol·L-1）对（-）-儿茶酚胺作用的影响。
分别比较了在Wistar大鼠离体组织中，（-）-去甲肾上腺素（存在ICI118551）和（-）-肾上腺素（存在CGP20712A）通过β1 - 和β2 - 肾上腺素受体诱发的心脏刺激对窦房结搏动率、左心房和心室收缩力的影响。采用全细胞膜片钳技术评估L型钙电流（I（Ca-L））。
咯利普兰引起窦房性心动过速。西洛酰胺和咯利普兰并未增强（-）-去甲肾上腺素和（-）-肾上腺素的变时作用强度。咯利普兰而非西洛酰胺增强了（-）-去甲肾上腺素的心房和心室变力作用。西洛酰胺增强了（-）-肾上腺素的心室作用，但未增强（-）-去甲肾上腺素的心室作用。西洛酰胺 + 咯利普兰同时使用时发现了（-）-肾上腺素对左心房的作用。咯利普兰和西洛酰胺均增强了（-）-去甲肾上腺素（1 μmol·L-1）诱发的I（Ca-L）增加。（-）-肾上腺素（10 μmol·L-1）仅在存在西洛酰胺而非咯利普兰时增加I（Ca-L）。
PDE4减弱β1 - 肾上腺素受体介导的变力作用。PDE4在与β1 - 和β2 - 肾上腺素受体控制的区室不同的区室中降低基础窦房结率。PDE3和PDE4共同阻止左心房β2 - 肾上腺素受体介导的变力作用。PDE3和PDE4均通过β1 - 肾上腺素受体降低I（Ca-L）反应，但PDE3成分与变力作用无关。PDE3减弱通过β2 - 肾上腺素受体介导的心室变力作用和I（Ca-L）反应。
