Chronic Dual Inhibition of Angiotensin-Converting Enzyme and Neutral Endopeptidase During the Development of Left Ventricular Dysfunction in Dogs


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Abstract

Summary:Angiotensin-converting enzyme (ACE) inhibition as well as neutral endopeptidase (NEP) inhibition was demonstrated to influence hemodynamics in various cardiac disease states. However, specific effects of chronic combined ACE and NEP inhibition on left ventricular (LV) and myocyte geometry and function remain unclear. In this study, a dual-acting metalloprotease inhibitor (DMPI), which possesses both ACE and NEP inhibitory activity, was used in a rapid-pacing model of LV dysfunction. LV and myocyte geometry and function were examined in control dogs (n = 6), in dogs with pacing-induced LV dysfunction (216 ± 2 beats/min, 28 days, n = 7), and in dogs with DMPI treatment during rapid pacing (10 mg/kg p.o., b.i.d., n = 6). With chronic rapid pacing, LV end-diastolic volume increased (84 ± 4 vs. 49 ± 3 ml), and LV ejection fraction decreased (38 ± 3% vs. 68 ± 3%) compared with control (p < 0.05). DMPI concomitantly administered during long-term rapid pacing did not change LV ejection fraction (35 ± 3%), but LV end-diastolic volume was reduced (70 ± 5 vs. 84 ± 4 ml; p < 0.05) when compared with rapid pacing only. With long-term rapid pacing, myocyte cross-sectional area was decreased (278 ± 5 vs. 325 ± 5 μm2), and resting length increased (178 ± 2 vs. 152 ± 1 μm) when compared with control (p < 0.05). With DMPI concomitantly administered during rapid pacing, myocyte cross-sectional area (251 ± 5 μm2) and resting length (159 ± 4 μm) were reduced when compared with rapid pacing only (p < 0.05). Myocyte velocity of shortening decreased from control values with long-term rapid pacing (39.3 ± 3.9 vs. 73.2 ± 5.9 μm/s; p < 0.05) but improved with DMPI treatment during rapid pacing when compared with rapid pacing only (58.9 ± 6.7 μm/s; p < 0.05). Myocyte velocity of shortening with β-adrenergic-receptor stimulation (25 nM isoproterenol) was reduced from controls with rapid pacing (125 ± 12 vs. 214 ± 30 μm/s; p < 0.05) but was improved with DMPI treatment during rapid pacing when compared with rapid pacing only (178 ± 12 μm/s; p < 0.05). In a model of rapid pacing-induced LV failure, concomitant DMPI treatment significantly reduced the degree of LV dilation with no apparent effect on LV pump function. At the level of the LV myocyte, long-term DMPI treatment with rapid pacing improved myocyte performance and β-adrenergic response. Thus the improvement in isolated myocyte contractile function was not translated into improved global LV-pump performance. The mechanisms by which improved myocyte contractility was not translated into a beneficial effect on LV-pump function with DMPI treatment during rapid pacing remain speculative, but likely include significant changes in LV remodeling and loading conditions.

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