Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits
Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits
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DOI：
10.1152/ajpheart.00498.2007
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发表时间：
2009-07-01
影响因子：
4.8
通讯作者：
Morales, Celina
中科院分区：
文献类型：
--
作者：
Gonzalez, German E.;Seropian, Ignacio M.;Morales, Celina
Gonzalez GE，Seropian IM，Krieger ML，Palleiro J，洛佩斯Verrilli MA，Gironacci MM，Cavallero S，Wilensky L，Tomasi VH，Gelpi RJ，Morales C.氯沙坦早期和晚期阻断AT（1）受体对兔心肌梗死后心室重构的影响Am J Physiol Heart Circ Physiol 297：H375-H386，2009.首次发表于2009年5月8日; doi：10.1152/ajpheart.00498.2007。为了表征心肌梗死（MI）后家兔肾素-血管紧张素系统的时间激活，我们检测了心肌ANG II 1型受体（AT（1）R）表达和ANG II水平从3小时到35天。还研究了氯沙坦（12.5 mg.kg（-1）.day（-1））在MI后早期（3 h）和晚期（第15天）开始治疗并维持不同时间段[短期（4天）、中期（20天）和长期（35天）]时对功能和组织形态计量学参数的影响。AT（1）R在心肌梗死后15、35天表达增加（P < 0.05）。心肌梗死后24 h非梗死区ANG Ⅱ水平升高（P < 0.05），4d梗死区ANG Ⅱ水平升高（P < 0.05），4d血浆ANG Ⅱ水平升高（P < 0.05），35 d后ANG Ⅱ水平逐渐下降。未治疗MI和早期长期治疗动物的存活率显著较低。MI组35、56天舒张压-容积曲线右移（P < 0.05）。这种变化在长期治疗组中更为明显（P < 0.05）。在未处理组和长期处理组中收缩力降低（与假手术组相比P < 0.05），在中期处理组中减弱。早期给予氯沙坦使MI区的RAM 11阳性巨噬细胞从4.15 +/- 0.05减少到3.05 +/- 0.02个细胞/高倍视野（HPF; P < 0.05），并使MI区的CD 45 RO阳性淋巴细胞从2.23 +/- 0.05减少到1.48 +/- 0.01个细胞/HPF（P < 0.05）。长期治疗减少了疤痕胶原蛋白（MI：70.50 +/- 2.35%和MI +氯沙坦：57.50 ± 2.48，P < 0.05），测定RAM 11阳性巨噬细胞的持续时间（3.02 +/- 0.13个细胞/HPF）和CD 45 RO阳性淋巴细胞（2.77 +/- 0.58个细胞/HPF，P < 0.05 vs. MI），并在35天时降低瘢痕变薄率（P < 0.05）。因此，心肌梗死后兔心脏AT（1）R和ANG II的时间表达与其他物种不同。长期治疗不利地改变了MI后重塑，而中期治疗减弱了这种有害影响。在长期给药动物中观察到的伤口愈合延迟（炎症浸润的早期减少和晚期持续存在）和不良重塑可能解释了在家兔中观察到的不利影响。
Gonzalez GE, Seropian IM, Krieger ML, Palleiro J, Lopez Verrilli MA, Gironacci MM, Cavallero S, Wilensky L, Tomasi VH, Gelpi RJ, Morales C. Effect of early versus late AT(1) receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits. Am J Physiol Heart Circ Physiol 297: H375-H386, 2009. First published May 8, 2009; doi: 10.1152/ajpheart.00498.2007.-To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.