In vitro and in vivo effects of UP 269-6, a new potent orally active nonpeptide angiotensin II receptor antagonist, on vascular smooth muscle cell proliferation.

Abstract

1. The present studies were designed to measure the affinity of UP 269-6, a newly developed angiotensin AT1 receptor antagonist, for vascular AT1 receptors from normotensive and hypertensive rats and to investigate in vitro, its effects on angiotensin II (AII)-induced hyperplasia and hypertrophy of vascular smooth muscle cells (VSMC). In addition the in vivo effects of UP 269-6 on neointimal proliferation in a carotid artery balloon injury in normotensive rats were also investigated. 2. UP 269-6 selectively inhibited [125I]-Sar1-Ile8-AII binding to vascular AT1 receptors present on VSMC derived from normotensive Wistar rat and from SHR (Ki = 16.6 +/- 3.6 nM and 7.5 +/- 2.0 nM, respectively). In comparison, losartan and its metabolite, EXP 3174, inhibited [125I]-Sar1-Ile8-AII binding to vascular AT1 receptors derived from both cell models with Ki values slightly lower (losartan) and higher (EXP 3174), respectively, than that of UP 269-6. 3. AII (1 microM) induced a weak and variable hyperplastic response (4 to 32% increase in cell number) in Wistar rat VSMC after 96 h. 4. AII (1 microM) induced a time-dependent increase in cell number in VSMC from SHR. UP 269-6 inhibited concentration-dependently this effect with an IC50 value of 159 +/- 58 nM. Losartan was clearly less potent and EXP 3174 showed nearly the same inhibitory potency, compared to UP 269-6. UP 269-6 (1 microM) inhibited nearly completely the action of AII. 5. AII (500 nM) caused maximal stimulation of protein synthesis in Wistar rat VSMC (117 +/- 36%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 28 +/- 6 nM, 3504 +/- 892 nM and 21 +/- 3 nM, respectively. 6. AII (50 nM) induced maximal stimulation of protein synthesis in SHR VSMC (237 +/- 67%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 16 +/- 3 nM, 282 +/- 122 nM and 3.3 +/- 1.0 nM, respectively. 7. UP 269-6 (75 mg kg-1 day-1) administered orally in the diet for 20 days induced a 38% reduction in neointimal area and a 36% reduction in neointima/media ratio associated with the intimal thickening induced by carotid artery balloon injury. 8. In conclusion, UP 269-6 was shown to be a potent antiproliferative agent both in vitro on AII-induced hyperplasia and hypertrophy of VSMC derived from normotensive and hypertensive rats, and in vivo upon intimal thickening induced by carotid artery balloon injury in the rat.

• Authors: A Virone-Oddos, V Desangle, D Provost, M Cazes, F Caussade, A Cloarec
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 120 Issue 3 Pg. 488-94 (Feb 1997) ISSN: 0007-1188 [Print] England
• PMID: 9031754 (Publication Type: Journal Article)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Biphenyl Compounds
• Imidazoles
• Muscle Proteins
• Pyrimidines
• Tetrazoles
• Angiotensin II
• UP 269-6
• losartan carboxylic acid
• Losartan

Topics

• Angiotensin II (metabolism)
• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (pharmacology)
• Biphenyl Compounds (metabolism, pharmacology)
• Carotid Arteries (pathology, physiology)
• Carotid Artery Injuries
• Catheterization
• Cell Division (drug effects)
• Imidazoles (metabolism, pharmacology)
• In Vitro Techniques
• Losartan
• Muscle Proteins (biosynthesis)
• Muscle, Smooth, Vascular (cytology, drug effects)
• Pyrimidines (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Stimulation, Chemical
• Tetrazoles (metabolism, pharmacology)