ANIPAMIL PREVENTS INTIMAL THICKENING IN THE AORTA OF HYPERTENSIVE RABBITS THROUGH CHANGES IN SMOOTH-MUSCLE CELL PHENOTYPE

The aim of this study was to evaluate the effect of anipamil, a phenya lkylamine-derived Ca2+-antagonist, on aortic intimal thickening and sm ooth muscle cell (SMC) phenotype in 2K-1C hypertensive rabbits. Monocl onal antimyosin antibodies [SM-E7, NM-G2, and NM-FG, which respectivel y, recognize smooth muscle (SM), A-type-, and B-type-like nonmuscle (N M) myosin heavy chains (MyHC)] identify different aortic SMC types: ad ult (SM-E7-positive), postnatal (SM-E7- and NM-G2-positive), and fetal (SM-E7-, NM-G2-, and NM-F6-positive). Twenty-four hypertensive rabbit s were studied 2.5 months (n = 12) and 4 months (n = 12) after clippin g. Six animals from each group were given anipamil (40 mg orally, once daily) immediately after surgery. The remaining 2K-1C were given a da ily oral placebo. Normotensive age-matched controls were also studied. Transverse cryosections of aorta were taken for computerized morphome try and immunocytochemical studies. Primary and secondary SMC cultures were used to define potential changes in cell phenotype after adding anipamil to the culture medium. In untreated 2K-1C, intimal thickening , mainly composed of postnatal-type SMC, was found by 2.5 months after clipping. Morphometric and immunofluorescence studies in anipamil-tre ated 2K-1C rabbits revealed absent or negligible intimal thickening an d a decrease of postnatal-type SMC from the underlying media. In cultu re experiments, growth inhibition of SMC by anipamil was accompanied b y the expression of SM-MyHC in all SMC, ie, the appearance of a more d ifferentiated cell phenotype compared to control cultures. In conclusi on, prevention of intimal thickening in anipamil-treated 2K-1C was ach ieved through selective reduction in the media of the postnatal-type S MC. This could be achieved by reducing NM-MyHC content or increasing s ynthesis of SM-MSTHC expression. As blood pressure was not significant ly lowered by anipamil treatment, a direct and specific antiproliferat ive action of this drug on medial SMC is likely to take place.