Sato N, Asai K, Okumura S, Takagi G, Shannon R P, Fujita-Yamaguchi Y, Ishikawa Y, Vatner S F, Vatner D E
Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
Am J Physiol. 1999 May;276(5):H1699-705. doi: 10.1152/ajpheart.1999.276.5.H1699.
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 micrograms . kg-1. min-1 iv) increased LV dP/dt by 1,854 +/- 157 from 2,701 +/- 105 mmHg/s (P < 0.05) before HF. After HF the increase in LV dP/dt in 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/dt even 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.
本研究的目的是确定米力农在心力衰竭（HF）中的效应脱敏程度，并确定其机制，即这些效应是否可归因于HF中cAMP或磷酸二酯酶（PDE）活性的变化。因此，我们在240次/分钟快速心室起搏诱导HF前后，对7只清醒犬进行了米力农效应的研究。这些犬被长期植入仪器，用于测量左心室（LV）压力、LV压力的一阶导数（dP/dt）、动脉压、LV内径和壁厚。在HF之前，米力农（10微克·千克-1·分钟-1静脉注射）使LV dP/dt从2701±105 mmHg/s增加了1854±157（P<0.05）。HF后，米力农引起的LV dP/dt增加显著减弱（P<0.05）；从1550±107 mmHg/s增加了615±67，表明明显脱敏。在存在神经节阻断的情况下，米力农引起的LV dP/dt增加（+445±65 mmHg/s）明显较小（P<0.01），而在HF中米力农使LV dP/dt增加更少（+240±65 mmHg/s）。在正常和衰竭心肌的心内膜和心外膜层中测量了cAMP和PDE活性。LV心内膜中的cAMP显著降低（P<0.05）（-26%）但LV心外膜中无显著降低（-14%）。LV心内膜中的PDE活性也显著降低（P<0.05）（-18%）但LV心外膜中无降低（-4%）。因此，在清醒的HF犬中观察到对米力农的明显脱敏。主要效应由自主神经介导。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水平的一种代偿机制。cAMP和PDE水平的降低仅限于心内膜下，提示增加的壁应力和降低的冠脉储备在介导这些变化中起作用。
