Kehler C H, Hebl J R, Soule C L, Gallagher W J, Houlton A J
Department of Anesthesiology, University of Minnesota, Minneapolis 55455, USA.
J Heart Lung Transplant. 1997 Jun;16(6):636-42.
Cardiac beta receptor down-regulation is associated with a reduction of tissue cyclic adenosine monophosphate (AMP) content. Milrinone exerts its effects by inhibiting the metabolism of existing cyclic AMP. The purpose of this study was to evaluate the effect of reduced myocardial cyclic AMP content on the pharmacologic action of milrinone.
A reduction of myocardial cyclic AMP content was produced by creating catecholamine depletion in the hearts of adult guinea pigs with intraperitoneal reserpine. Control animals received the reserpine vehicle. Isolated heart perfusion was maintained with modified Krebs buffer, and hearts were paced at 270 beats/min. A latex balloon and transducer-tipped catheter were inserted into the left ventricle. Isovolemic work was maintained at a constant balloon volume. Hearts from control and reserpine treated animals were perfused for 20 minutes with buffer containing either no milrinone, 1.7 x 10(-6), or 1.0 x 10(-4) mol/L milrinone (n = 12 for each dose). Maximal positive and negative dP/dt were assessed. The hearts were then frozen and cyclic AMP was measured.
Cyclic AMP content was significantly lower in the reserpine-treated hearts at each milrinone concentration (0.33 +/- 0.01 vs 0.46 +/- 0.01; 0.33 +/- 0.01 vs 0.53 +/- 0.01; 0.30 +/- 0.01 vs 0.61 +/- 0.02 pmol/mg wet weight, p < 0.05). Milrinone significantly increased positive and negative dP/dtmax (p < 0.05), but no difference was observed between control and reserpine-treated hearts.
Endogenous catecholamine depletion reduces myocardial cyclic AMP content but does not attenuate the response to milrinone in the isolated heart.
心脏β受体下调与组织环磷酸腺苷（AMP）含量降低有关。米力农通过抑制现有环磷酸腺苷的代谢发挥作用。本研究的目的是评估心肌环磷酸腺苷含量降低对米力农药理作用的影响。
通过腹腔注射利血平使成年豚鼠心脏儿茶酚胺耗竭，从而降低心肌环磷酸腺苷含量。对照动物接受利血平溶媒。用改良的 Krebs 缓冲液维持离体心脏灌注，心脏以每分钟 270 次的频率起搏。将乳胶气球和带有换能器尖端的导管插入左心室。在恒定的气球体积下维持等容功。用不含米力农、1.7×10⁻⁶或 1.0×10⁻⁴mol/L 米力农的缓冲液对来自对照和利血平处理动物的心脏进行 20 分钟灌注（每种剂量 n = 12）。评估最大正负 dP/dt。然后将心脏冷冻并测量环磷酸腺苷。
在每个米力农浓度下，利血平处理的心脏中环磷酸腺苷含量均显著降低（0.33±0.01 对 0.46±0.01；0.33±0.01 对 0.53±0.01；0.30±0.01 对 0.61±0.02 pmol/mg 湿重，p < 0.05）。米力农显著增加正负 dP/dtmax（p < 0.05），但对照和利血平处理的心脏之间未观察到差异。
内源性儿茶酚胺耗竭降低心肌环磷酸腺苷含量，但不减弱离体心脏对米力农的反应。
