Verrijk R, Vleeming W, van Rooij H H, Wemer J, Porsius A J
Department of Biomedical Pharmacy, Faculty of Pharmacy, University of Utrecht, The Netherlands.
Arch Int Pharmacodyn Ther. 1989 Jan-Feb;297:7-17.
The recent development of new positive inotropic agents, such as milrinone, sulmazole and AR-L100 might provide new insights for the treatment of congestive heart failure. Although it has been reported that milrinone and sulmazole have cardiac phosphodiesterase III inhibiting properties, the pharmacological action of these drugs cannot be explained by these mechanisms alone. Despite the presence of cardiac phosphodiesterase III in the rat, the effect of milrinone on the rat heart has been reported to be small or even absent. In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction. A perfused heart preparation was used to assess the direct positive inotropic effect of milrinone, sulmazole and AR-L100 as well as their effect on isoprenaline-evoked increase of contractile force. The increase in left ventricular systolic pressure (LVP) in hearts of control animals amounted to 42.0 +/- 3.9 mm Hg, 18.2 +/- 2.4 mm Hg and 8.0 +/- 1.7 mm Hg for AR-L100, milrinone and sulmazole, respectively. The average initial LVP was 70.4 +/- 5.3 mm Hg. In infarcted hearts, the increase in LVP was 25.5 +/- 5.9 mm Hg, 12.6 +/- 2.3 mm Hg and 6.7 +/- 1.2 mm Hg for AR-L100, milrinone and sulmazole, respectively. In infarcted hearts, the average initial LVP was 38.6 +/- 1.6 mm Hg. These data show that these drugs have positive inotropic effects on rat hearts, although the effects of milrinone and AR-L100 on hearts from myocardial infarcted rats are smaller. However, interaction studies with isoprenaline showed a stronger potentiating effect of milrinone and sulmazole in infarcted hearts than in control hearts. Only in this respect sulmazole was more active than milrinone, while AR-L100 had no potentiating effect at all. These results suggest that milrinone and sulmazole are effective agents in conditions where higher levels of circulating catecholamines exist. Therefore, they might be particularly effective in the treatment of congestive heart failure.
新型正性肌力药物如米力农、舒马唑和AR-L100的最新进展可能为充血性心力衰竭的治疗提供新的思路。尽管已有报道称米力农和舒马唑具有抑制心脏磷酸二酯酶III的特性，但这些药物的药理作用不能仅用这些机制来解释。尽管大鼠心脏中存在心脏磷酸二酯酶III，但据报道米力农对大鼠心脏的作用很小甚至没有作用。在本研究中，我们比较了米力农、舒马唑和AR-L100对正常大鼠和实验性诱导心肌梗死大鼠离体心脏的作用。采用灌注心脏标本评估米力农、舒马唑和AR-L100的直接正性肌力作用以及它们对异丙肾上腺素诱发的收缩力增加的影响。对照组动物心脏左心室收缩压（LVP）的增加，AR-L100、米力农和舒马唑分别为42.0±3.9 mmHg、18.2±2.4 mmHg和8.0±1.7 mmHg。平均初始LVP为70.4±5.3 mmHg。在梗死心脏中，AR-L100、米力农和舒马唑的LVP增加分别为25.5±5.9 mmHg、12.6±2.3 mmHg和6.7±1.2 mmHg。在梗死心脏中，平均初始LVP为38.6±1.6 mmHg。这些数据表明这些药物对大鼠心脏有正性肌力作用，尽管米力农和AR-L100对心肌梗死大鼠心脏的作用较小。然而，与异丙肾上腺素的相互作用研究表明，米力农和舒马唑在梗死心脏中的增强作用比在对照心脏中更强。仅在这方面，舒马唑比米力农更具活性，而AR-L100根本没有增强作用。这些结果表明，米力农和舒马唑在循环儿茶酚胺水平较高的情况下是有效的药物。因此，它们可能在充血性心力衰竭的治疗中特别有效。
