title: Prevention of neointima formation by mibefradil after vascular injury in rats: comparison with ACE inhibition.
abstract: Cilazapril, an 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.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Schmitt
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: N
authors.initials: N
authors.lastname: Iberg
authors.forename: F R
authors.initials: FR
authors.lastname: Bühler
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002339:Carotid Arteries / Q000502:physiology; D020212:Carotid Artery Injuries; D016893:Carotid Stenosis / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017315:Cilazapril / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D020748:Mibefradil; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D017315:Cilazapril; D020748:Mibefradil