| Chronic dual inhibition of angiotensin-converting enzyme and neutral endopeptidase during the development of left ventricular dysfunction in dogs. | |
| | |
MedLine Citation:
|
PMID: 9869495 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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 microm2), and resting length increased (178 +/- 2 vs. 152 +/- 1 microm) when compared with control (p < 0.05). With DMPI concomitantly administered during rapid pacing, myocyte cross-sectional area (251 +/- 5 microm2) and resting length (159 +/- 4 microm) 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 microm/s; p < 0.05) but improved with DMPI treatment during rapid pacing when compared with rapid pacing only (58.9 +/- 6.7 microm/s; p < 0.05). Myocyte velocity of shortening with beta-adrenergic-receptor stimulation (25 nM isoproterenol) was reduced from controls with rapid pacing (125 +/- 12 vs. 214 +/- 30 microm/s; p < 0.05) but was improved with DMPI treatment during rapid pacing when compared with rapid pacing only (178 +/- 12 microm/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 beta-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. |
| | |
Authors:
|
C V Thomas; G M McDaniel; H H Holzgrefe; R Mukherjee; R B Hird; J D Walker; L Hebbar; J R Powell; F G Spinale |
Related Documents
:
|
9843795 - Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced h... 7471375 - Atrial excitability and conduction during rapid atrial pacing. 3989125 - Dual carbon-labeled isotope experiments using d-[6-14c] glucose and l-[1,2,3-13c3] lact... 8945035 - Single lead ddd system: a comparative evaluation of unipolar, bipolar, and overlapping ... 21160705 - Percutaneous coronary intervention for acute myocardial infarction in a patient with de... 10868925 - Prognostic role of heart rate variability in patients with idiopathic dilated cardiomyo... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Journal of cardiovascular pharmacology Volume: 32 ISSN: 0160-2446 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 1998 Dec |
Date Detail:
|
Created Date: 1999-03-05 Completed Date: 1999-03-05 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 902-12 Citation Subset: IM |
Affiliation:
|
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Angiotensin-Converting Enzyme Inhibitors
/
pharmacology* Animals Cardiovascular Agents / pharmacology Dogs Enzyme Inhibitors / pharmacology* Female Hormones / blood Male Metalloendopeptidases / antagonists & inhibitors Myocardial Contraction / drug effects Myocardium / cytology Neprilysin / antagonists & inhibitors*, metabolism Peptidyl-Dipeptidase A / metabolism* Pyridines / pharmacology* Receptors, Adrenergic, beta / drug effects, metabolism Thiazepines / pharmacology* Ventricular Dysfunction, Left / chemically induced, drug therapy* |
| Grant Support | |
ID/Acronym/Agency:
|
R29-HL-45024/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Angiotensin-Converting Enzyme Inhibitors; 0/Cardiovascular Agents; 0/Enzyme Inhibitors; 0/Hormones; 0/Pyridines; 0/Receptors, Adrenergic, beta; 0/Thiazepines; 0/omapatrilat; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.11/Neprilysin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Influence of age and dietary restriction on norepinephrine uptake into cardiac synaptosomes.
Next Document: Long-term alpha1-adrenergic blockade attenuates diet-induced dyslipidemia and hyperinsulinemia in th...