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.
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.
Teng
Jian
J
Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Suzuki
Ryo
R
Takagi
Hiroto
H
Ikeda
Yukihiro
Y
Tahira
Yoshiko
Y
Kanmatsuse
Katsuo
K
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; C055603:temocapril hydrochloride; C437965:olmesartan