The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP).
An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-beta1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-beta1 through an increase in eNOS activity in a hypertensive condition.
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan. moniwa@sapmed.ac.jp
Norihito
N
Moniwa
Jun
J
Agata
Makoto
M
Hagiwara
Nobuyuki
N
Ura
Kazuaki
K
Shimamoto
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D065169:Bradykinin B1 Receptor Antagonists; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
D000959:Antihypertensive Agents; D065169:Bradykinin B1 Receptor Antagonists; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases