caa a22 4500 477072666 CHVBK 20180405111430.0 cr unu---uuuuu 170330e19961001xx s 000 0 eng 10.1007/BF00823586 doi (NATIONALLICENCE)springer-10.1007/BF00823586 Prevention of neointima formation by mibefradil after vascular injury in rats: Comparison with ACE inhibition [Elektronische Daten] [R. Schmitt, J. Clozel, N. Iberg, F. Bühler] Summary: Cilazapril, and angiotensin-converting enzyme inhibitor, and mibefradil, a selective T-type voltage-operated calcium channel blocker, have been shown to prevent neointima formation after vascular injury. The goal of the present study was to evaluate the mechanism of action of both drugs. For this purpose, the influence of the renin angiotensin system on the effects of mibefradil (30 mg/kg po) and cilazapril (10 mg/kg po) on neointima formation after carotid injury were evaluated in normotensive rats (normal renin angiotensin system) and DOCA hypertensive rats (suppressed renin angiotensin system). In addition, in order to differentiate an effect on cell migration or cell proliferation, both drugs were given either before or after the smooth muscle migration phase. Finally, cilazapril and mibefradil were given in combination. In normotensive rats, mibefradil and cilazapril decreased neointima formation, resulting in neointima/media ratios of 38% (p<0.05) and 53% (p<0.01), respectively. However, in DOCA hypertensive rats, mibefradil was active, with a reduction of the neointima/media ratio by 63% (p<0.001), whereas cilazapril reduced it only slightly (19%) and not significantly. In addition, cilazapril was active only when treatment started before the migration phase (63%, reduction in neointima/media ratio, p<0.001) but not when started thereafter (13% reduction in neointima/media ratio, n.s.). In contrast, treatment with mibefradil was also active when started after the migration phase (51% reduction in neointima/media ratio, p<0.001 when treatment started 1 day before balloon injury and 41%, p<0.01 when treatment started 5 days after balloon injury). The combination of both drugs was additive (67% reduction in neointima/media ratio, p<0.001 vs. control). These experiments clearly show that mibefradil and cilazapril have a different mechanism of action after vascular injury. Mibefradil most likely prevents the proliferation of smooth muscle cells. In contrast, cilazapril most likely inhibits the migration of smooth muscle cells. These two different mechanisms of action explain why the effects of both drugs are additive. Kluwer Academic Publishers, 1996 mibefradil nationallicence cilazapril nationallicence ACE inhibition nationallicence hypertension nationallicence vascular injury nationallicence smooth muscle cells nationallicence Schmitt R. Clinical Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut Clozel J. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut Iberg N. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut Bühler F. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut Cardiovascular Drugs and Therapy Kluwer Academic Publishers 10/2(1996-10-01), 101-105 0920-3206 10:2<101 1996 10 10557 https://doi.org/10.1007/BF00823586 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00823586 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Schmitt R. Clinical Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut NATIONALLICENCE 700 1- Clozel J. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut NATIONALLICENCE 700 1- Iberg N. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut NATIONALLICENCE 700 1- Bühler F. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Kluwer Academic Publishers 10/2(1996-10-01), 101-105 0920-3206 10:2<101 1996 10 10557 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer