Molecular effects of M17055, furosemide and thiazide on cardiac hypertrophy of spontaneously hypertensive rats.
Although diuretics have been clinically shown to reduce cardiovascular morbidity and mortality, the effects of diuretics on cardiac hypertrophy are poorly understood. In this study, we examined the molecular effects of diuretics on hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHR) were given p.o. M17055 (a novel "high ceiling" diuretic) 1.25, 2.5 or 5 mg/kg/day, furosemide 50 mg/kg/day or trichlormethiazide 30 mg/kg/day for 5 weeks. After the treatment, cardiac myosin isoforms were analyzed by gel electrophoresis, and cardiac hypertrophy-related gene expressions were examined by Northern blot analysis. These three diuretics significantly reduced cardiac hypertrophy of SHR. M17055 and furosemide, but not trichlormethiazide, significantly increased the proportion of cardiac V3 myosin of SHR by enhancing the gene expression of beta-myosin heavy chain. On the other hand, trichlormethiazide, but not M17055 or furosemide, suppressed the increased cardiac gene expression of skeletal alpha-actin in SHR. Cardiac collagen type III expression of SHR was decreased only by treatment with M17055. Plasma thyroid hormone levels of SHR were slightly decreased by M17055 and by furosemide and were negatively correlated with cardiac V3 myosin contents. Thus the effects on the gene expression of cardiac contractile proteins and collagen are significantly different among these three types of diuretics, which suggests that these diuretics may have different cardiac actions independent of their diuretic and antihypertensive actions. The increased cardiac V3 myosin induced by M17055 and by furosemide may be partially due to the decreased plasma thyroid hormone.
Kim
S
S
Department of Pharmacology, Osaka City University Medical School, Japan.
Hamaguchi
A
A
Shinkawa
T
T
Kato
Y
Y
Tsuchiya
N
N
Miura
K
K
Ohta
K
K
Iwao
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy*; D003094:Collagen / Q000235:genetics; D004232:Diuretics / Q000494:pharmacology*; D004573:Electrolytes / Q000652:urine; D005665:Furosemide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000150:complications* / Q000378:metabolism; D008297:Male; D018995:Myosin Heavy Chains / Q000235:genetics; D010091:Oximes / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014237:Trichlormethiazide / Q000494:pharmacology*
D004232:Diuretics; D004573:Electrolytes; D010091:Oximes; D015363:Quinolones; D012333:RNA, Messenger; C079648:7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid; D005665:Furosemide; D003094:Collagen; D018995:Myosin Heavy Chains; D014237:Trichlormethiazide