Author:

Keywords:

Analysis of Variance, Angiotensin-Converting Enzyme Inhibitors, Animals, Carotid Arteries, Carotid Artery Injuries, Carotid Stenosis, Cell Division, Cricetinae, Drug Evaluation, Preclinical, Drug Therapy, Combination, Isoquinolines, Male, Muscle, Smooth, Vascular, Peptides, Cyclic, Platelet Membrane Glycoproteins, Receptors, Vitronectin, Reference Values, Sulfoxides, Tetrahydroisoquinolines, Tunica Intima, Science & Technology, Life Sciences & Biomedicine, Hematology, Peripheral Vascular Disease, Cardiovascular System & Cardiology, ANGIOTENSIN-CONVERTING ENZYME, VASCULAR INJURY, GROWTH-RESPONSE, PROLIFERATION, RESTENOSIS, INHIBITION, INDUCTION, Quinapril, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences

Abstract:

The prevention of neointima formation by the tissue selective angiotensin converting enzyme (ACE) inhibitor quinapril and by the combination quinapril/G4120 (a platelet alpha Ub beta 3 and smooth muscle cell alpha v beta 3 antagonist) was investigated in a hamster carotid artery injury model. Quinapril at 10 mg/kg/day reduced neointima formation by about 45%, 1 and 2 weeks after injury to the artery, i.e. significantly better than the non-tissue selective ACE inhibitor captopril at 100 mg/kg/day. Quinapril did not decrease the early smooth muscle cell (SMC) proliferation in the media, but in agreement with its inhibition of the carotid artery ACE activity by 62%, SMC proliferation was reduced by 70% in the newly forming intima. To improve the inhibition of early medial SMC proliferation, quinapril (10 mg/kg/day) was complemented with G4120 (100 micrograms/kg/h). This combined treatment reduced the proliferation of medial SMCs to about 50% throughout the first week following injury, whereas intima SMC proliferation was reduced by 70% throughout treatment. Accordingly, the drug combination reduced neointima formation more potently than each drug separately by 70%. The disruption of medial elastic laminae, observed in the control and G4120 treated group, was consistently reduced when G4120 was complemented with quinapril. Thus, the present study shows in a hamster model of carotid artery injury, that combining drugs that prevent SMC migration and proliferation via different modes of action can lead to the effective prevention of neointima formation.