Beneficial Effects of Combined Blockade of ACE and AT ₁ Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery

Abstract

Objective-The present study was undertaken to elucidate the effect of the ACE inhibitor and the angiotensin II type 1 (AT 1 ) receptor antagonist in combination on neointimal hyperplasia after balloon injury. Methods and Results-Temocapril (an ACE inhibitor), CS-866 (an AT 1 receptor antagonist), or their combination was given orally to rats, and their effects were compared on vascular hyperplasia induced by balloon injury. The maximal preventive effect of temocapril and CS-866 alone on neointimal thickening after balloon injury was obtained at a dose of 20 and 10 mg/kg per day, respectively. However, compared with either agent alone, combined temocapril and CS-866 (20 and 10 mg/kg per day, respectively) prevented intimal thickening to a larger extent. Furthermore, compared with either agent alone, combined temocapril and CS-866 prevented vascular smooth muscle cell proliferation in the intima more potently. The increase in platelet-derived growth factor receptor tyrosyl phosphorylation was reduced more potently by the combination of both agents compared with either agent alone. The nonpeptide bradykinin B 2 receptor antagonist or the NO synthase inhibitor reduced the prevention of intimal thickening by combined temocapril and CS-866. Conclusions-Compared with either agent alone, the combination of an ACE inhibitor and an AT 1 receptor antagonist is more effective in the prevention of vascular hyperplasia due to bradykinin or NO. (Arterioscler Thromb Vasc Biol. 2002;22:1299-1304.)Key Words: balloon injury Ⅲ intimal thickening Ⅲ angiotensin Ⅲ angiotensin-converting enzyme Ⅲ combination therapy A ccumulating evidence indicates that the renin-angiotensin system plays an important role in the pathophysiology of vascular thickening and remodeling. [1][2][3] Either ACE inhibitors 4,5 or angiotensin II (Ang II) type 1 (AT 1 ) receptor antagonists 6,7 significantly prevent neointimal hyperplasia in the balloon-injured rat artery independent of their hypotensive effect. However, in contrast to the preventive effect of ACE inhibitors on neointimal formation after balloon injury in rats, a multicenter clinical trial (the Multicenter European Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis [MERCATOR] study) showed that ACE inhibition with cilazapril does not prevent restenosis after percutaneous transluminal coronary angioplasty; this finding does not support the usefulness of the ACE inhibitor in the treatment of vascular restenosis in humans. 8 It remains unclear whether the failure of prevention of restenosis by the ACE inhibitor in humans was due to the insufficient dose used or the species difference.Recently, in hypertensive rats, a combination of low doses of ACE inhibitor and AT 1 receptor antagonist has been shown to induce greater reductions in blood pressure and cardiac weight than have been found with monotherapy with the same or higher doses. 9,10 In pigs subjected to myocardial ischemia, infarct size is reduced more effectively by an ACE inhibitor an...

Effects of Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Antagonist Combination on Nitric Oxide Bioavailability and Atherosclerotic Change in Watanabe Heritable Hyperlipidemic Rabbits

“…Kim et al have demonstrated that combination treatment with temocapril (an ACEI) and CS-866 (an ARB) prevented vascular smooth muscle cell proliferation in the intima to a greater extent than monotherapy in a rat balloon-injury model. They also demonstrated that L-NMMA, an NO synthase inhibitor, significantly attenuated the diminished intimal hyperplasia induced by combined administration of temocapril and CS-866 (34). Taking these findings together, one may speculate that the anti-atherosclerotic effect of the combination therapy in the present study was derived from the inhibition of NO synthesis.…”

Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

“…Finally, the combination of an ACE inhibitor with an AT1R antagonist at maximally effective doses prevented structural and phenotypic changes to the vascular wall after balloon injury to a larger extent than single-site blockade. 43 …”

Combined Treatment with an AT1 Receptor Blocker and Angiotensin Converting Enzyme Inhibitor Has an Additive Effect on Inhibiting Neointima Formation via Improvement of Nitric Oxide Production and Suppression of Oxidative Stress

“…Kim et al reported that combination treatment with temocapril (an ACE inhibitor) and CS-866 (an AT1 receptor antagonist) along with blood pressure reduction prevent vascular smooth muscle cell proliferation in the intima to a greater extent than monotherapy with either agent and blood pressure reduction. They also demonstrated that L-NAME, an NO synthase inhibitor, significantly attenuated the diminished intimal hyperplasia induced by combined administration of temocapril and CS-866 (32). In another study, soluble guanylate cyclase α1 and β1 gene transfer to balloon-injured rat carotid arteries increased the NO responsiveness of vascular smooth muscle cells, and reduced neointima formation after balloon injury in rats (33).…”