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Cardioprotective effects of a selective B(2) receptor agonist of bradykinin post-acute myocardial infarct.

AbstractBACKGROUND:
The cardioprotective benefits of bradykinin are attributable to activation of its B(2) receptor (B(2)R)-mediated actions and abolished by B(2)R antagonists. The current experiments evaluated the cardioprotective potential of a potent, long-acting B(2)R-selective agonist peptide analogue of bradykinin, the compound NG291.
METHODS:
We compared the extent of cardiac tissue damage and remodeling and expression pattern of selected genes in mice submitted to acute myocardial infarct (MI) and treated for 1 week with either NG291 [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin or with saline delivered via osmotic minipump.
RESULTS:
Active treatment resulted in better ejection fraction (EF) 69 +/- 1% vs. 61 +/- 3.1% (P = 0.01), (vs. 85 +/- 1.3% in sham-operated controls), fractional shortening (FS) 38 +/- 4% vs. 32 +/- 8% (NS) (vs. 53 +/- 1.2 in sham-operated controls), and fewer markers of myocyte apoptosis (TUNEL-positive nuclei 4.9 +/- 1.1% vs. 9.7 +/- 0.03%, P = 0.03). Systolic blood pressure (SBP) at end point was normal at 110 +/- 4.2 in actively treated mice, but tended to be lower at 104 +/- 4.7 mm Hg in saline controls with decreased cardiac systolic capacity. Expression patterns of selected genes to factors related to tissue injury, inflammation, and metabolism (i.e., the B(1)R, B(2)R, endothelial nitric oxide synthase (eNOS), TNF-alpha, cardiomyopathy-associated 3 (Cmya3), and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4)) showed that acute MI induced significant upregulation of these genes, and active treatment prevented or attenuated this upregulation, whereas the B(2)R agonist itself produced no difference in the myocardium of sham-operated mice.
CONCLUSIONS:
Treatment with a selective B(2)R agonist initiated at the time of induction of acute MI in mice had a beneficial effect on cardiac function, tissue remodeling, and inflammation-related tissue gene expression, which may explain its structural and functional benefits.
AuthorsMaria Marketou, Ekaterina Kintsurashvili, Kyriakos N Papanicolaou, Hector A Lucero, Irene Gavras, Haralambos Gavras
JournalAmerican journal of hypertension (Am J Hypertens) Vol. 23 Issue 5 Pg. 562-8 (May 2010) ISSN: 1941-7225 [Electronic] United States
PMID20186129 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cardiotonic Agents
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • Nuclear Proteins
  • Receptor, Bradykinin B2
  • Tumor Necrosis Factor-alpha
  • XIRP2 protein, mouse
  • Nitric Oxide Synthase Type III
  • Bradykinin
Topics
  • Animals
  • Apoptosis (drug effects)
  • Blood Pressure (drug effects, physiology)
  • Bradykinin (analogs & derivatives)
  • Cardiotonic Agents (pharmacology, therapeutic use)
  • Cytoskeletal Proteins
  • DNA-Binding Proteins (metabolism)
  • Disease Models, Animal
  • LIM Domain Proteins
  • Male
  • Mice
  • Mice, Inbred Strains
  • Myocardial Infarction (drug therapy, pathology, physiopathology)
  • Myocardium (metabolism, pathology)
  • Nitric Oxide Synthase Type III (metabolism)
  • Nuclear Proteins (metabolism)
  • Receptor, Bradykinin B2 (agonists)
  • Stroke Volume (drug effects, physiology)
  • Tumor Necrosis Factor-alpha (metabolism)

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