Topical application of AT1 receptor antagonists prevents medial and neointimal proliferation after balloon injury.
Angiotensin II plays an important role in neointima formation after vascular injury. A rat model of carotid artery injury was used i) to investigate the effect of single topical application of angiotensin II subtype 1 (AT1) receptor antagonists (CV11974, DuP753) in suppressing medial proliferation at day 2 and neointimal proliferation at day 14, and ii) to investigate the antiproliferative effects of additional application of L-arginine (a nitric oxide precursor). Drugs mixed in 25% (W/W) solutions of F127 pluronic gel were applied topically to injured vessels. Early medial proliferation of smooth muscle cells, assessed by the S-bromo-2'-deoxyuridine labelling index, was significantly suppressed by application of CV11974 (5 mg/kg), 7.5% +/- 2.2% vs. 19% +/- 3.9% in the control group. The intima/media ratio following CV11974 (10 mg/kg) or DuP753 (12.5 mg/kg) at day 14 was significantly lower than that in the control group (42% +/- 7%, 43% +/- 14%, and 123% +/- 11%, respectively). Additional application of L-arginine seemed to increase effectiveness, but was not statistically significant. In conclusion, single topical application of AT1 receptor antagonists was effective in suppressing early medial proliferation and neointima formation after balloon injury, suggesting that they may be clinically useful after angioplasty or vascular surgery.
Taguchi
J
J
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Abe
J
J
Ohno
M
M
Schwartz
S M
SM
Kurokawa
K
K
D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001120:Arginine / Q000494:pharmacology; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000209:etiology* / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D007093:Imidazoles / Q000627:therapeutic use*; D019808:Losartan; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017540:Tunica Media / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D001120:Arginine; D001973:Bromodeoxyuridine; D019808:Losartan; C081643:candesartan