Drugs in R & D

, Volume 3, Issue 4, pp 239–249 | Cite as

Effects of Angiotensin Receptor Blockade on Haemodynamics and Gene Expression after Myocardial Infarction

  • Andrey K. Gurevich
  • Sandor A. Falk
  • Raphael A. Nemenoff
  • Howard D. Weinberger
  • Sandra N. Summer
  • Mona Rizeq
  • Patricia E. Gengaro
  • Martin P. Bedigian
  • Robert W. Schrier
Original Research Article

Abstract

Introduction: Despite the fact that congestive heart failure (CHF) remains the most common disease in the developed world and has been extensively studied, there is little known about the molecular and cellular mechanisms of cardiac dysfunction. Angiotensin has been implicated as a mediator of cardiac injury; however, the mechanisms of its action have not been delineated. The objective of this study was to examine the relationship between the haemodynamic and molecular events during cardiac dysfunction and the role of the angiotensin system.

Study design: We examined the effects of the angiotensin receptor blocker, valsartan, on changes in the haemodynamic and gene expression patterns in a postmyocardial infarction model in the rat.

Methods: Myocardial infarction (MI) was induced in rats by coronary artery ligation. Cardiac haemodynamicswere monitored using echocardiography. Gene expression profiles after myocardial infarction were identified using Affymetrix Genechip® oligonucleotide arrays.

Results: Myocardial contractility, as assessed by cardiac output and left ventricle (LV) fraction of shortening, was reduced in untreated animals by week 3 after MI (p < 0.05 versus baseline), and preserved with valsartan treatment as observed by the nonsignificant changes versus baseline. LV dilatation, as demonstrated by increases in LVsystolic and diastolic diameters, developed by week 3 in untreated animals (p < 0.05 versus baseline) while valsartan-treated animals were protected and showed no significant increases in diameter size compared with baseline. LV hypertrophy, as shown by LV posterior wall thickness, was more profound in untreated animals (p < 0.05 versus baseline) than in those treated with valsartan at weeks 3 and 4. Changes in gene expression at 4 weeks after MI included those encoding muscle-specific genes, fibrous tissue proliferation, immune response and various others. Treatment with valsartan reversed these changes in 67% of overexpressed genes and 83% of underexpressed genes.

Conclusion: Angiotensin receptor blockade with valsartan was found to protect cardiac function, and this beneficial effect was accompanied by a reversal of changes in gene expression induced by MI.

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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Andrey K. Gurevich
    • 1
  • Sandor A. Falk
    • 1
  • Raphael A. Nemenoff
    • 1
  • Howard D. Weinberger
    • 2
  • Sandra N. Summer
    • 1
  • Mona Rizeq
    • 3
  • Patricia E. Gengaro
    • 1
  • Martin P. Bedigian
    • 4
  • Robert W. Schrier
    • 1
  1. 1.Department of Medicine, Division of Renal Diseases and HypertensionUniversity of Colorado Health Sciences CenterDenverUSA
  2. 2.Department of Medicine, Division of CardiologyUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.Department of PathologyVeterans Administration Medical CenterDenverUSA
  4. 4.Novartis Pharmaceutical CorporationEast HanoverUSA

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