Betaxolol inhibits extracellular signal-regulated kinase and P70S6 kinase activities and gene expressions of platelet-derived growth factor A-chain and transforming growth factor-beta1 in Dahl salt-sensitive hypertensive rats.
We evaluated the protective effects of long-term treatment with betaxolol, a specific beta-antagonist, on platelet-derived growth factor (PDGF) A-chain and transforming growth factor (TGF)-beta1 gene expression in the left ventricle of Dahl salt-sensitive hypertensive rats fed a high-salt diet. In addition, we evaluated the relations between these effects and coronary microvascular remodeling, expression of extracellular signal-regulated kinases (ERK) belonging to one subfamily of mitogen-activated protein kinases, and expression of p70S6 kinase belonging to one subfamily of ribosomal S6 kinases. Betaxolol (0.9 mg/kg/day, subdepressor dose) was administered for 5 weeks, from 6 weeks of age to the left ventricular hypertrophy stage at 11 weeks of age. Increased PDGF A-chain and TGF-beta1 mRNA and protein expression were suppressed by betaxolol. Upregulated activities of ERK1/2 and p70S6 kinase phosphorylations were decreased by betaxolol. Betaxolol administration resulted in significant improvements in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis. Thus, we conclude that ERK1/2 and p70S6 kinase activities may play a key role in coronary microvascular remodeling of Dahl salt-sensitive hypertensive rats, and that beneficial effects of betaxolol on cardiovascular remodeling may be at least partially mediated by decreased PDGF A-chain and TGF-beta1 expression in the left ventricle.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Shimotsuga-gun, Tochigi, Japan. a-fukuda@dokkyomed.ac.jp
Nakano
Shigefumi
S
Mori
Yousuke
Y
Mita
Shin-ichiro
S
Kobayashi
Tsutomu
T
Honda
Takeaki
T
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D015784:Betaxolol / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000319:Adrenergic beta-Antagonists; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D015784:Betaxolol