The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice.
Endothelin (ET)-1 and ET-2 are potent vasoconstrictor peptides with mitogenic activity. In this study, we investigated roles of ET system in renin-angiotensin system (RAS)-mediated hypertension, using transgenic hypertensive mice (THM) with over-expression of both human renin and angiotensinogen genes. In the first step, it was revealed that expression of ET system was locally enhanced, i.e. increases in cardiac preproET-1 mRNA and renal preproET-2 mRNA in THM, compared with the control (wild type) mice. In the next step, we studied the chronic effects of an ET antagonist (SB209670) on THM. Blood pressure (BP) in THM was significantly higher than that in the normal mice during the investigation. However, in the later phase of the study, from 12 to 20 weeks of treatment, THM receiving SB 209670 showed significantly lower BP than that in THM receiving saline. SB 209670 treatment for 20 weeks significantly attenuated phenotypes of cardiac hypertrophy, vascular wall thickening and hypertensive nephropathy observed in THM, suggesting that the ETA/B receptor antagonist is also effective even in the extraordinarily activated RAS condition. These findings suggest that organ specifically activated ET system in THM develops the phenotypes, hypertension, cardiac hypertrophy, and hypertensive nephropathy.
Maki
Shinichi
S
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Miyauchi
Takashi
T
Kakinuma
Yoshihiko
Y
Sakai
Satoshi
S
Kobayashi
Tsutomu
T
Sugiyama
Fumihiro
F
Fukamizu
Akiyoshi
A
Goto
Katsutoshi
K
Yamaguchi
Iwao
I
D000818:Animals; D001794:Blood Pressure; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D006652:Histological Techniques; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D012084:Renin-Angiotensin System / Q000235:genetics*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D014665:Vasodilator Agents