TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats.
Inhibitory effects of TCV-116 [(+-)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate], a novel angiotensin II AT1 subtype receptor antagonist, on the proliferation of vascular smooth muscle cells and the impairment of endothelium-dependent vascular relaxation were examined in the rat carotid balloon injury model. DNA content in the carotid artery was increased 3 days after carotid balloon injury and reached a plateau 14 days after the injury. Beneficial effects of TCV-116 in this model were examined 14 days after the injury. Oral administration of TCV-116 at 1 and 10 mg/kg/day significantly inhibited the increase in DNA content by 69 and 85%, respectively. Histological examination demonstrated that TCV-116 at 1 and 10 mg/kg significantly inhibited intimal thickening by 43 and 58%, respectively. Cilazapril (10 mg/kg/day p.o.) also inhibited intimal thickening by 48%. Contracting or relaxing vascular responses to phenylephrine or sodium nitroprusside did not differ between uninjured and injured arteries. However, acetylcholine-induced endothelium-dependent relaxation was greatly reduced in injured arteries; maximal relaxation was 6 +/- 2% (n = 17). TCV-116 at 1 and 10 mg/kg significantly ameliorated the impairment of vascular relaxation; maximal relaxation was 25 +/- 8 (n = 7) and 51 +/- 12% (n = 5), respectively. In uninjured arteries, L-NG-monomethyl arginine (300 microM), an inhibitor of endothelium-derived relaxing factor synthesis, inhibited acetylcholine (10 microM)-induced relaxation by 58 +/- 4% (n = 5). Scanning electron micrographs demonstrated that TCV-116 (10 mg/kg/day) enhanced restoration of endothelial cells in the carotid artery 14 days after injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Kawamura
M
M
Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, Japan.
Terashita
Z
Z
Okuda
H
H
Imura
Y
Y
Shino
A
A
Nakao
M
M
Nishikawa
K
K
D000109:Acetylcholine / Q000494:pharmacology; D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000737:chemistry / Q000503:physiopathology*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008855:Microscopy, Electron, Scanning; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles; D017539:Tunica Intima / Q000187:drug effects* / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D004247:DNA; D000109:Acetylcholine; C077793:candesartan cilexetil