Pauletto P, Da Ros S, Tonello M, Capriani A, Chiavegato A, Sartore S, Pessina A C
Istituto di Medicina Clinica, Università di Padova, Italy.
Am J Hypertens. 1996 Jul;9(7):687-94. doi: 10.1016/0895-7061(96)00032-5.
The aim of this study was to evaluate the effect of anipamil, a phenyalkylamine-derived Ca(2+)-antagonist, on aortic intimal thickening and smooth muscle cell (SMC) phenotype in 2K-1C hypertensive rabbits. Monoclonal antimyosin antibodies [SM-E7, NM-G2, and NM-F6, which respectively, recognize smooth muscle (SM), A-type-, and B-type-like nonmuscle (NM) myosin heavy chains (MyHC)] identify different aortic SMC types: adult (SM-E7-positive), postnatal (SM-E7- and NM-G2-positive), and fetal (SM-E7-, NM-G2-, and NM-F6-positive). Twenty-four hypertensive rabbits were studied 2.5 months (n = 12) and 4 months (n = 12) after clipping. Six animals from each group were given anipamil (40 mg orally, once daily) immediately after surgery. The remaining 2K-1C were given a daily oral placebo. Normotensive age-matched controls were also studied. Transverse cryosections of aorta were taken for computerized morphometry 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-treated 2K-1C rabbits revealed absent or negligible intimal thickening and a decrease of postnatal-type SMC from the underlying media. In culture experiments, growth inhibition of SMC by anipamil was accompanied by the expression of SM-MyHC in all SMC, ie, the appearance of a more differentiated cell phenotype compared to control cultures. In conclusion, prevention of intimal thickening in anipamil-treated 2K-1C was achieved through selective reduction in the media of the postnatal-type SMC. This could be achieved by reducing NM-MyHC content or increasing synthesis of SM-MyHC expression. As blood pressure was not significantly lowered by anipamil treatment, a direct and specific antiproliferative action of this drug on medial SMC is likely to take place.
本研究旨在评估苯烷基胺类钙拮抗剂阿尼帕米对二肾一夹（2K-1C）高血压兔主动脉内膜增厚和平滑肌细胞（SMC）表型的影响。单克隆抗肌球蛋白抗体[SM-E7、NM-G2和NM-F6，它们分别识别平滑肌（SM）、A型和B型非肌肉（NM）肌球蛋白重链（MyHC）]可识别不同类型的主动脉SMC：成年型（SM-E7阳性）、出生后型（SM-E7和NM-G2阳性）和胎儿型（SM-E7、NM-G2和NM-F6阳性）。对24只高血压兔在夹闭后2.5个月（n = 12）和4个月（n = 12）进行研究。每组6只动物在手术后立即给予阿尼帕米（口服40 mg，每日1次）。其余2K-1C兔给予每日口服安慰剂。还研究了年龄匹配的正常血压对照兔。取主动脉横向冰冻切片进行计算机形态计量学和免疫细胞化学研究。原代和传代SMC培养用于确定在培养基中加入阿尼帕米后细胞表型的潜在变化。在未治疗的2K-1C兔中，夹闭后2.5个月发现内膜增厚，主要由出生后型SMC组成。对接受阿尼帕米治疗的2K-1C兔进行的形态计量学和免疫荧光研究显示，内膜增厚不明显或可忽略不计，且下层中膜的出生后型SMC减少。在培养实验中，阿尼帕米对SMC的生长抑制伴随着所有SMC中SM-MyHC的表达，即与对照培养相比出现了更分化的细胞表型。总之，阿尼帕米治疗的2K-1C兔内膜增厚的预防是通过选择性减少中膜中出生后型SMC实现的。这可以通过降低NM-MyHC含量或增加SM-MyHC表达的合成来实现。由于阿尼帕米治疗未显著降低血压，该药物对中膜SMC可能具有直接和特异性的抗增殖作用。
