Molecular mechanism of angiotensin II type I and type II receptors in cardiac hypertrophy of spontaneously hypertensive rats.
We administered angiotensin (Ang) II receptor type 1 (AT1) blockade (losartan; 10 or 40 mg/kg per day), type II receptor (AT2) blockades (PD123319; 100 mg/kg per day), or angiotensin-converting enzyme (ACE) inhibitor (enalapril; 30 mg/kg per day) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. At the end of the treatment, high doses of losartan and enalapril significantly reduced the arterial systolic blood pressure compared with the untreated SHR to the level of WKY rats. But low doses of losartan and PD123319 were without effect. High doses of losartan and enalapril also significantly reduced both the left ventricular (LV) weight and the ratio of LV to body weight compared with the untreated SHR, which were still larger than that of WKY rats. However, the collagen concentration of SHR treated with high doses of losartan or enalapril was completely reduced to the level of WKY rats. Using reverse transcription polymerase chain reaction, we examined the mRNA expression for ACE, AT1, and AT2 in experimental animals. The enhanced AT1 mRNA expression was significantly decreased in the SHR treated with a high dose of losartan or PD123319 compared with the untreated SHR. The level of ACE mRNA was also decreased in the SHR treated with a high dose of losartan or enalapril. The level of AT2 mRNA was not significantly different between the Wistar-Kyoto rats and the SHR; however, this expression was decreased significantly after the treatment with a high dose of losartan or PD123319. These results indicate that AT1 receptor and ACE, but not AT2 receptor, play a crucial role in the remodeling of matrix tissue but a smaller role in the development of the hypertrophy of LV myocyte in SHR and that the LV/body weight changes do not fully account for the complete suppression of hypertension.
Makino
N
N
Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Sugano
M
M
Otsuka
S
S
Hata
T
T
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004656:Enalapril / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; C073402:PD 123319; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D019808:Losartan