Juan-Fita María Jesús, Vargas María Luisa, Hernández Jesús
Departmento de Farmacologia, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain.
Eur J Pharmacol. 2005 Apr 11;512(2-3):207-13. doi: 10.1016/j.ejphar.2005.01.056.
The effects of phosphodiesterase (PDE) inhibitors (1-3) on tissue cAMP concentrations and the inotropic responses to dobutamine and glucagon were investigated in electrically driven right ventricular strips of the rat heart. Dobutamine (0.3-100 microM) produced a concentration-dependent positive inotropic effect which was not affected by 50 nM (+/-)-1-(2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy)-3-((1-methylethyl)amino)-2-butanol hydrochloride (ICI 118551), a beta2-receptor antagonist, but was virtually abolished by 0.3 microM (+/-)-2-hydroxy-5-(2-((2-hydroxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-l)phenoxy)propyl)amino)ethoxy)-benzamide methanesulfonate (CGP 20712A), a beta1-receptor antagonist. Glucagon (0.01-1 microM) also enhanced the contractility of the preparation in a concentration-dependent way. Selective inhibitors of PDE 1 8-methoxymethyl-3-isobutyl-1-methylxantine (MIMX, 1 muM), PDE 2 erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA, 1 microM) and PDE 3 cilostamide (0.1 microM) did not affect basal contractility. Cilostamide increased the positive inotropic effects of glucagon but not those of dobutamine. MIMX and EHNA did not alter the effects of either dobutamine or glucagon. Dobutamine (3 microM), but not glucagon (0.1 microM), increased tissue levels of cAMP. 1 microM of MIMX or EHNA were devoid of effects and failed to alter the effects of dobutamine and glucagon on cAMP. Cilostamide (0.1 microM) did not increase the effects of dobutamine but caused glucagon to enhance cAMP. The pharmacological and biochemical data presented in this study can be explained quantitatively by a cell compartment model in which PDE 3 appears to be colocalized with the contractile machinery responsible for the effects of glucagon but not those of dobutamine. Neither PDE 1 nor PDE 2 appears to regulate the inotropic effects of dobutamine and glucagon in rat ventricular myocardium.
在大鼠心脏的电驱动右心室条带上，研究了磷酸二酯酶（PDE）抑制剂（1 - 3）对组织环磷酸腺苷（cAMP）浓度以及对多巴酚丁胺和胰高血糖素的变力反应的影响。多巴酚丁胺（0.3 - 100微摩尔）产生浓度依赖性正性变力作用，该作用不受50纳摩尔（±）-1 -（2,3 -（二氢-7 - 甲基-1H - 茚-4 - 基）氧基）-3 -（（1 - 甲基乙基）氨基）-2 - 丁醇盐酸盐（ICI 118551，一种β2受体拮抗剂）影响，但几乎完全被0.3微摩尔（±）-2 - 羟基-5 -（2 -（（2 - 羟基-3 -（4 -（1 - 甲基-4 -（三氟甲基）-1H - 咪唑-2 - l）苯氧基）丙基）氨基）乙氧基）-苯甲酰胺甲磺酸盐（CGP 20712A，一种β1受体拮抗剂）消除。胰高血糖素（0.01 - 1微摩尔）也以浓度依赖性方式增强制剂的收缩性。PDE 1的选择性抑制剂8 - 甲氧基甲基-3 - 异丁基-1 - 甲基黄嘌呤（MIMX，1微摩尔）、PDE 2的赤藓醇-9 - [2 - 羟基-3 - 壬基]腺嘌呤（EHNA，1微摩尔）和PDE 3的西洛他唑（0.1微摩尔）不影响基础收缩性。西洛他唑增加了胰高血糖素的正性变力作用，但不增加多巴酚丁胺的正性变力作用。MIMX和EHNA不改变多巴酚丁胺或胰高血糖素的作用。多巴酚丁胺（3微摩尔）增加组织cAMP水平，但胰高血糖素（0.
