Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure.
Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure.
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患有心力衰竭的清醒犬对 PDE 抑制剂（米力农）的脱敏机制。
DOI：
10.1152/ajpheart.1999.276.5.h1699
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Vatner,DE
中科院分区：
文献类型：
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作者：
Sato,N;Asai,K;Okumura,S;Takagi,G;Shannon,RP;Fujita-Yamaguchi,Y;Ishikawa,Y;Vatner,SF;Vatner,DE
本研究的目的是确定米力农在心力衰竭 (HF) 中的作用脱敏程度，并确定其机制，即这些作用是否可归因于 HF 中 cAMP 或磷酸二酯酶 (PDE) 活性的变化。因此，我们在 240 次/分钟的快速心室起搏诱发心力衰竭之前和之后，检查了七只清醒的狗中米力农的作用。长期用仪器测量狗的左心室（LV）压力和左心室压力的一阶导数（dP/dt）、动脉压、左心室内径和壁厚度。米力农 (10 μg·kg−1·min−1iv) 使 HF 前的 LV dP/dt 从 2,701 ± 105 mmHg/s 增加了 1,854 ± 157 (P< 0.05)。心力衰竭后，左心室 dP/dtin 对米力农反应的增加显着减弱（P<0.05）；它从 1,550 ± 107 mmHg/s 增加了 615 ± 67，表明明显脱敏。在存在神经节阻滞的情况下，米力农对 LV dP/dt (+445 ± 65 mmHg/s) 的增加明显较少 (P< 0.01)，而米力农对 HF 的 LV dP/dt 增加甚至更小 (+240 ± 65 mmHg/s)。测量正常和衰竭心肌的心内膜和心外膜层的 cAMP 和 PDE 活性。左心室心内膜 (-26%) 中 cAMP 显着降低 (P< 0.05)，但左心外膜 (-14%) 中 cAMP 不显着降低。左心室心内膜 (-18%) 的 PDE 活性也显着降低 (P< 0.05)，但左心室心外膜 (-4%) 没有显着降低。因此，在清醒的心衰犬中观察到对米力农的显着脱敏。主要作用是自主调节的。生化机制似乎部分归因于衰竭心肌中 PDE 活性的适度降低，这反过来可能是维持 HF 中 cAMP 水平的补偿机制。 cAMP 和 PDE 水平的降低仅限于心内膜下，表明壁应力增加和冠状动脉储备减少在介导这些变化中发挥了作用。
The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/dt), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 μg ⋅ kg−1⋅ min−1iv) increased LV dP/dtby 1,854 ± 157 from 2,701 ± 105 mmHg/s (P< 0.05) before HF. After HF the increase in LV dP/dtin response to milrinone was attenuated significantly (P< 0.05); it increased by 615 ± 67 from 1,550 ± 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/dt(+445 ± 65 mmHg/s) in response to milrinone were markedly less (P< 0.01), and milrinone increased LV dP/dteven less in HF (+240 ± 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly (P< 0.05) in LV endocardium (−26%) but not significantly in LV epicardium (−14%). PDE activity was also decreased significantly (P< 0.05) in LV endocardium (−18%) but not in LV epicardium (−4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.