Chronic dual inhibition of angiotensin-converting enzyme and neutral endopeptidase during the development of left ventricular dysfunction in dogs

Angiotensin-converting enzyme (ACE) inhibition as well as neutral endopepti dase (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 functi on 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 dysfu nction (216 +/- 2 beats/min, 28 days, n = 7), and in dogs with DMPI treatme nt during rapid pacing (10 mg/kg p.o., b.i.d., n = 6). With chronic rapid p acing, LV end-diastolic volume increased (84 +/- 4 vs. 49 +/- 3 ml), and LV ejection fraction decreased (38 +/- 3% vs. 68 +/- 3%) compared with contro l (p < 0.05). DMPI concomitantly administered during long-term rapid pacing did not change LV ejection fraction (35 +/- 3%), but LV end-diastolic volu me was reduced (70 +/- 5 vs. 84 +/- 4 ml: p < 0.05) when compared with rapi d pacing only. With long-term rapid pacing, myocyte cross-sectional area wa s decreased (278 +/- 5 vs. 325 +/- 5 mu m(2)), and resting length increased (178 +/- 2 vs. 152 +/- 1 mu m) when compared with control (p < 0.05). With DMPI concomitantly administered during rapid pacing, myocyte cross-section al area (251 +/- 5 mu m(2)) and resting length (159 +/- 4 mu m) were reduce d when compared with rapid pacing only (p < 0.05), Myocyte velocity of shor tening decreased from control values with long-term rapid pacing (39.3 +/- 3.9 vs. 73.2 +/- 5.9 mu m/s; p < 0.05) but improved with DMPI treatment dur ing rapid pacing when compared with rapid pacing only (58.9 +/- 6.7 mu m/s; p < 0.05). Myocyte velocity of shortening with beta-adrenergic-receptor st imulation (25 nM isoproterenol) was reduced from controls with rapid pacing (125 +/- 12 vs. 214 +/- 30 mu m/s; p < 0.05) but was improved with DMPI tr eatment during rapid pacing when compared with rapid pacing only (178 +/- 1 2 mu m/s: p < 0.05). In a model of rapid pacing-induced LV failure, concomi tant 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 P-ad renergic response. Thus the improvement in isolated myocyte contractile fun ction was not translated into improved global LV-pump performance. The mech anisms by which improved myocyte contractility was not translated into a be neficial effect on LV-pump function with DMPI treatment during rapid pacing remain speculative, but likely include significant changes in LV remodelin g and loading conditions.