Upregulation of cardiac angiotensin II AT1 receptors in congenital cardiomyopathic hamsters.
Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic x control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar1,Ile8]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that 125I-sarile binding sites were exclusively of the AT1 subtype in both groups of animals. Importantly, the density of AT1 receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean Kd, 19.6 and 16.7 nmol/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Lambert
C
C
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Canada.
Massillon
Y
Y
Meloche
S
S
D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D004622:Embryo, Mammalian; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008647:Mesocricetus; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D011869:Radioligand Assay; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan