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Involvement of angiotensin II in cardiovascular and renal injury: effects of an AT1-receptor antagonist on gene expression and the cellular phenotype.

AbstractOBJECTIVES:
We investigated the effects of an angiotensin II type 1 (AT1)-receptor antagonist on experimental cardiac hypertrophy, vascular thickening and nephrosclerosis, in order to determine the involvement of this receptor in the development of cardiovascular and renal damage.
DESIGN:
Accumulating evidence indicates that various growth-related genes, growth factors and extracellular matrix components play a central part in the pathogenesis and development of cardiovascular and renal diseases, either by regulating cell growth and migration or by promoting tissue fibrosis.
MATERIALS AND METHODS:
Stroke-prone spontaneously hypertensive rats were given candesartan cilexetil, a specific non-peptide AT1-receptor antagonist, for 10 weeks, and cardiac phenotypic and fibrosis-related gene expression and aortic and mesenteric arterial gene expressions were determined. Balloon-injured carotid arteries and deoxycorticosterone acetate (DOCA)-salt hypertensive rats were also similarly examined.
RESULTS:
Treatment of hypertensive rats with an AT1-receptor antagonist led to the regression of cardiac hypertrophy, suppression of cardiac phenotypic changes to a fetal phenotype and an increase in fibrosis-related gene expression in the hypertrophied heart. Balloon injury-induced neointima formation in the rat carotid artery was prevented by the AT1-receptor antagonist, which was associated with the inhibition of the induction of proto-oncogenes such as c-fos, c-jun and Egr-1 and of increased fibronectin gene expression. Furthermore, the AT1-receptor antagonist prevented either the phenotypic modulation of glomerular cells or an increase in transforming growth factor-beta 1 expression in an experimental model of nephrosclerosis.
CONCLUSIONS:
AT1-receptor antagonists in vivo potently inhibit the expression of the growth-related and extracellular matrix genes, as well as cellular phenotypic modulation. These molecular effects of the AT1-receptor antagonist may contribute to their protective effects on cardiovascular and renal diseases.
AuthorsS Kim, H Iwao
JournalJournal of hypertension. Supplement : official journal of the International Society of Hypertension (J Hypertens Suppl) Vol. 15 Issue 6 Pg. S3-7 (Dec 1997) ISSN: 0952-1178 [Print] England
PMID9493120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Benzimidazoles
  • Biphenyl Compounds
  • Fibronectins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Tetrazoles
  • Angiotensin II
  • candesartan cilexetil
Topics
  • Angiotensin II (physiology)
  • Angiotensin Receptor Antagonists
  • Animals
  • Antihypertensive Agents (pharmacology)
  • Benzimidazoles (pharmacology)
  • Biphenyl Compounds (pharmacology)
  • Cardiomegaly (metabolism, physiopathology, prevention & control)
  • Fibronectins (genetics, metabolism)
  • Gene Expression (drug effects)
  • Humans
  • Hypertension (drug therapy, metabolism, physiopathology)
  • Nephrosclerosis (metabolism, physiopathology, prevention & control)
  • Proto-Oncogene Proteins (genetics, metabolism)
  • RNA, Messenger (metabolism)
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin (physiology)
  • Tetrazoles

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