The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition.
Smooth muscle cell (SMC) proliferation and formation of extracellular matrix in the intima of muscular arteries are major processes that can lead to vascular stenosis in arteriosclerosis or after coronary angioplasty. These processes are also seen in the proliferative response to balloon catheter-induced vascular injury of the rat carotid artery, and result in marked neointima formation by 14 days after catheterization. We have shown recently that the angiotensin-converting enzyme (ACE) inhibitor cilazapril strongly suppressed this development of neointima. In this report, we show that the beneficial effects on neointima formation persist for at least 8 weeks after stopping treatment with cilazapril, and that continuous treatment may have additional inhibitory effects during the late phases of vascular remodeling after injury. To investigate further the possible mechanisms, we examined several vasoactive compounds in this model. Another ACE inhibitor of a different chemical class, captopril, reduced neointima formation as strongly as cilazapril (67 and 78%, respectively), but the calcium antagonist verapamil was not active as an inhibitor of neointima formation, despite similar lowering of blood pressure. Hydralazine and a new calcium antagonist, Ro 40-5967, partially suppressed neointima formation (36%, p less than 0.005 and 33%, p less than 0.05, respectively). In vitro, neither cilazapril nor its active metabolite, cilazaprilate, had any effect on SMC proliferation in response to serum or PDGF. To characterize further the role of angiotensin II (Ang II), we tested in cell culture the effects of Ang II and cilazaprilate on mRNA levels of several proteins potentially involved in regulating the SMC response.(ABSTRACT TRUNCATED AT 250 WORDS)
Powell
J S
JS
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Müller
R K
RK
Rouge
M
M
Kuhn
H
H
Hefti
F
F
Baumgartner
H R
HR
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002216:Captopril / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D017315:Cilazapril; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects; D006133:Growth Substances / Q000096:biosynthesis; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000473:pathology* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D006133:Growth Substances; D011724:Pyridazines; D017315:Cilazapril; D002216:Captopril; D014700:Verapamil