Ryan Michael J, Didion Sean P, Mathur Satya, Faraci Frank M, Sigmund Curt D
Ph.D. Professor, Department of Internal Medicine, 3181 MERF, University of Iowa, Department of Internal Medicine Iowa City, IA 52242, USA.
Hypertension. 2004 Mar;43(3):661-6. doi: 10.1161/01.HYP.0000116303.71408.c2. Epub 2004 Jan 26.
The peroxisome proliferator activated receptor (PPARgamma) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R(+)A(+)). Rosiglitazone decreased systolic (138+/-5 versus 128+/-5 mm Hg) and mean blood pressure (145+/-5 versus 126+/-7 mm Hg) of R(+)A(+) mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R(+)A(+) mice when compared with littermate controls (RA(-)). There were no effects of rosiglitazone on RA(-) mice; however, relaxation to acetylcholine (49+/-10 versus 82+/-9% at 100 micromol/L) and nitric oxide (51+/-11 versus 72+/-6% at 10 micromol/L) was significantly improved in treated R(+)A(+) mice. Rosiglitazone treatment of R(+)A(+) mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R(+)A(+) and RA(-) mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARgamma-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (200 micromol/L) or the PPARgamma antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 micromol/L). These data suggest that in addition to potential genomic regulation caused by PPARgamma activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
据报道，过氧化物酶体增殖物激活受体（PPARγ）激动剂罗格列酮可通过一种尚未完全明确的机制为患者带来心血管益处。我们测试了口服罗格列酮（每天25毫克/千克，持续21天）治疗是否能改善同时表达人肾素和人血管紧张素原转基因的转基因小鼠（R(+)A(+)）的血压和血管功能。通过尾套法和颈内动脉留置导管测量发现，罗格列酮降低了R(+)A(+)小鼠的收缩压（分别为138±5毫米汞柱和128±5毫米汞柱）和平均血压（分别为145±5毫米汞柱和126±7毫米汞柱）。与同窝对照小鼠（RA(-)）相比，R(+)A(+)小鼠的颈动脉对乙酰胆碱和一氧化氮的舒张反应受损，但对罂粟碱的舒张反应未受损。罗格列酮对RA(-)小鼠无影响；然而，在接受治疗的R(+)A(+)小鼠中，对乙酰胆碱（100微摩尔/升时为49±10%对82±9%）和一氧化氮（10微摩尔/升时为5±11%对72±6%）的舒张反应显著改善。罗格列酮治疗R(+)A(+)小鼠并未改变包括内皮型一氧化氮合酶（eNOS）、血管紧张素1受体和前内皮素原-1在内的基因表达，也未改变eNOS或可溶性鸟苷酸环化酶蛋白的水平。在单独的研究中，来自R(+)A(+)和RA(-)小鼠的颈动脉对罗格列酮呈浓度依赖性舒张，提示罗格列酮在血管系统中可能存在不依赖PPARγ的作用。这种反应不受一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸甲酯（200微摩尔/升）或PPARγ拮抗剂双酚A二缩水甘油醚；4,4'-异丙叉二苯酚二缩水甘油醚（100微摩尔/升）的抑制。这些数据表明，除了PPARγ激活可能引起的潜在基因组调控外，罗格列酮在血管中的直接作用可能有助于改善血压和血管功能。
