Comparison of vasopeptidase inhibitor omapatrilat and angiotensin receptor blocker candesartan on extracellular matrix, myeloperoxidase, cytokines, and ventricular remodeling during healing after reperfused myocardial infarction.
We determined effects of the vasopeptidase inhibitor (VPI) omapatrilat and angiotensin II type 1 receptor (AT(1)R) blocker (ARB) candesartan in rats during healing between day-2 and day-21 after reperfused myocardial infarction (RMI) on left ventricular (LV) remodeling and function, and regional matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-3, inducible-nitric-oxide-synthase (iNOS), oxidant-generating myeloperoxidase (MPO), and cytokines tumor-necrosis-factor (TNF)-alpha, interleukin (IL)-6 and IL-10, and transforming-growth-factor (TGF)-beta(1), and collagens. Compared to RMI-placebo, both agents reversed adverse LV remodeling and systolic and diastolic dysfunction, improved collagen remodeling, and normalized MMP-9 (activity, protein, and mRNA), TIMP-3 (protein and mRNA), and iNOS, MPO, TNF-alpha, IL-6, and TGF-beta(1) proteins, and improved MMP-9/TIMP-3 balance and IL-10 levels in previously ischemic zones. The results suggest that modulation of matrix proteases, oxidants, cytokines, and NOSs with omapatrilat and candesartan contribute to reversal of adverse collagen and LV remodeling and attenuation of LV dysfunction during healing after RMI.
Palaniyappan
Arivazhagan
A
Cardiovascular Research Group, Faculty of Medicine, University of Alberta, AB, Canada.
Uwiera
Richard R E
RR
Idikio
Halliday
H
Jugdutt
Bodh I
BI
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002317:Cardiovascular Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002317:Cardiovascular Agents; D016207:Cytokines; D007527:Isoenzymes; D011480:Protease Inhibitors; D011725:Pyridines; D013777:Tetrazoles; D013841:Thiazepines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; C106266:omapatrilat; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C081643:candesartan
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