Prevention of intimal thickening after endothelial removal by a nonpeptide angiotensin II receptor antagonist, losartan

Abstract

1The 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-' 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 endothelialindependent, sodium nitroprusside (SNP)-induced relaxation remained unaffected in all groups. 5 There were no differences in the noradrenaline (NA)-and endothelin-1 (ET-l)-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 proliferative response of the vascular wall to removal of the endothelium.

AT1 receptor characteristics of angiotensin analogue binding in human synovium

“…(Whitebread et al, 1989;Dudley et al, 1990;Weinstock et al, 1991;Bottari et al, 1991 (Urata et al, 1989) and on cultured vascular smooth muscle cells (Whitebread et al, 1989) and are believed to mediate vasoconstriction (Chiu et al, 1990) and smooth muscle hypertrophy (Millet et al, 1992), both of which may reduce tissue perfusion. Synovial hypoperfusion has been implicated in the pathogenesis of human arthritis (Levick, 1990), and the potential of AT, antagonists to enhance tissue perfusion (Azuma et al, 1992) (Whitebread et al, 1989;Patel et al, 1989). Binding of angiotensins has previously been demonstrated to microvessels in brain (Speth & Harik, 1985), retina (Ferrari-Dileo et al, 1991) and kidney (Sechi et al, 1992).…”

“…In peripheral tissues All is a potent vasoconstrictor and has also been implicated in vascular intimal hyperplasia and stenosis following endothelial damage (Laport & Escher, 1992;Azuma et al, 1992). In addition, All stimulates angiogenesis in some animal models (Fernandez et al, 1985;Le Noble et al, 1991), induces expression of growth factors by vascular smooth muscle (Naftilan et al, 1989) and may itself regulate proliferation of some cell types (Araki et al, 1990).…”

Induction of kinin B1 receptor‐dependent vasoconstriction following balloon catheter injury to the rabbit carotid artery

“…Balloon catheter injury to the rabbit carotid artery produced a significant intimal thickening which was already apparent 7 days after surgery (see also Azuma et al, 1992). At this time, the intima was predominantly devoid of endothelium although some endothelial regrowth was observed at both ends of the injured intraluminal surface and around the orifices of arterial branches.…”

Angiotensin‐II Biochemistry and Physiology: Update on Angiotensin‐II Receptor Blockers

“…but not PD123177, inhibits these growth responses. in part, by blocking AII-induced expression of the proto-oncogene c-fos (5,90,164). Finally, AT, selective antagonists produce beneficial effects on hemodynamics.…”