Prevention of intimal thickening after endothelial removal by a nonpeptide angiotensin II receptor antagonist, losartan.
1. The present experiments were designed to investigate the role of local angiotensin II receptors in the myointimal proliferative response of the vascular wall after endothelial removal, by use of a novel, nonpeptide, angiotensin II receptor antagonist, losartan. 2. When administered 1 week before endothelial removal from the rabbit carotid artery and then continuously until animals were killed 6 weeks later, losartan in a dose of 10 mg kg-1 daily, p.o. had no significant effects on the carotid blood flow (CBF), mean arterial blood pressure (MBP) and heart rate (HR). 3. A full endothelial lining with increased density of regenerated endothelial cells was observed 6 weeks after the endothelial removal. These changes were unaffected by treatment with losartan. 4. Six weeks after endothelial removal, acetylcholine (ACh)- and adenosine diphosphate (ADP)-induced relaxations were greatly reduced though endothelial cells had regenerated. The reduction of the relaxations to these agonists were significantly restored by chronic treatment with losartan. The endothelial-independent, sodium nitroprusside (SNP)-induced relaxation remained unaffected in all groups. 5. There were no differences in the noradrenaline (NA)- and endothelin-1 (ET-1)-induced contractions of the carotid artery strips between vehicle and losartan-treated groups. In contrast, the contractile response of the strips to angiotensin II was significantly decreased in the losartan group, indicating the specific antagonism by chronic losartan against the angiotensin II receptor. 6. Six weeks after endothelial removal, marked myointimal proliferation resulting from new accumulation of proliferating smooth muscle cells and connective tissue was observed in the vehicle group. Losartan treatment greatly suppressed the myointimal proliferative response.7. These results suggest that the local angiotensin II receptors play a role in the myointimal proliferativeresponse of the vascular wall to removal of the endothelium.
Azuma
H
H
Department of Medicinal Chemistry, Tokyo Medical and Dental University, Japan.
Niimi
Y
Y
Hamasaki
H
H
D000109:Acetylcholine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001775:Blood Circulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D008855:Microscopy, Electron, Scanning; D011817:Rabbits; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan; D000109:Acetylcholine