Inhibitory effect of a novel angiotensin II type 1 receptor antagonist RNH-6270 on growth of vascular smooth muscle cells from spontaneously hypertensive rats: different anti-proliferative effect to angiotensin-converting enzyme inhibitor

J Cardiovasc Pharmacol. 2002 Feb;39(2):161-71. doi: 10.1097/00005344-200202000-00002.

Abstract

The current study was undertaken to evaluate the anti-proliferative effect of a novel angiotensin II type 1 (AT1) receptor antagonist, RNH-6270, on exaggerated growth of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR), in comparison with the effects of an angiotensin-converting enzyme (ACE) inhibitor. RNH-6270 and temocapril significantly inhibited basal DNA synthesis in VSMCs from SHRs in a dose-dependent manner, but not in cells from Wistar-Kyoto (WKY) rats. SHR-derived VSMC showed a hyperresponse of DNA synthesis to serum and angiotensin II compared with that of WKY rats-derived VSMC. RNH-6270 did not affect serum-stimulated DNA synthesis in VSMCs from both rat strains. RNH-6270 abolished angiotensin II-stimulated DNA synthesis in VSMC from both rat strains. RNH-6270 significantly inhibited proliferation of VSMC from both rat strains, but the ACE inhibitor temocapril did not exert such an effect. RNH-6270 decreased the specific binding of angiotensin II to VSMC in a competitive manner for angiotensin II receptors in both rat strains. RNH-6270 and temocapril significantly decreased the expression of growth factor mRNAs and proteins in VSMC from SHR, but not in cells from WKY rats. These results suggest that RNH-6270 is a potent AT1 receptor antagonist and has anti-proliferative effects on VSMCs from SHR, which was not seen with an ACE inhibitor. The growth inhibitory effect of RNH-6270 may be associated with the inhibition of growth factors via antagonism to AT1 receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin Receptor Antagonists*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Blotting, Western
  • Cell Division / drug effects
  • Cells, Cultured
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism
  • Imidazoles / pharmacology*
  • Male
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism
  • RNA, Messenger / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrazoles / pharmacology*
  • Thiazepines / pharmacology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1

Substances

  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazoles
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Tetrazoles
  • Tgfb1 protein, rat
  • Thiazepines
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • platelet-derived growth factor A
  • Fibroblast Growth Factor 2
  • Angiotensin II
  • temocapril hydrochloride
  • olmesartan