Myocardial adrenergic dysfunction in rats with transgenic, human renin-dependent hypertension

Citation
J. Bohlender et al., Myocardial adrenergic dysfunction in rats with transgenic, human renin-dependent hypertension, J HYPERTENS, 19(8), 2001, pp. 1453-1463
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Journal title
JOURNAL OF HYPERTENSION
ISSN journal
0263-6352 → ACNP
Volume
19
Issue
8
Year of publication
2001
Pages
1453 - 1463
Database
ISI
SICI code
0263-6352(200108)19:8<1453:MADIRW>2.0.ZU;2-D
Abstract
Objectives We investigated cardiac function in rats transgenic for the huma n renin and angiotensinogen genes (TGR) to test the hypothesis that elevate d local angiotensin II precipitates adrenergic dysfunction and abnormal con tractile function. Methods Hearts from TGR and Sprague-Dawley control rats, aged 6 weeks, were studied using the Langendorff model and papillary muscle preparations (n = 6-10 per group). Incremental isoproterenol (1-1000 nmol/l) and external Ca 2+-concentrations (0.75-6.0 mmol/l) were tested. Cardiac protein and mRNA e xpression levels were determined by Western blot and RNAase protection assa y. Results TGR rats showed left ventricular hypertrophy (54%), higher blood pr essures (76 mmHg), and elevated plasma renin activity (seven-fold) compared to controls (P <0.01). The effect of isoproterenol on TGR rat systolic and diastolic left ventricular performance was decreased in both in-vitro mode ls compared to controls (two- to threefold, P <0.01). TGR rat papillary mus cles showed impaired force generation with abnormal basal and Ca2+-dependen t relaxation. G(i alpha2) and G(i alpha3) protein levels were increased (20 -30%) and SERCA2a and adenylyl cyclase protein levels were decreased (23 an d 37%, respectively) in TGR hearts compared to controls, while G(s alpha) o r beta (1) and beta (2)-receptor levels were unchanged. Cardiac angiotensin converting enzyme and atrial natriuretic peptide mRNA levels were increase d more than four-fold in TGR with no differences for the angiotensin type 1 receptor, beta (1)-receptor, SERCA2a, phospholamban, adenylyl cyclase V an d angiotensinogen genes. Conclusions TGR rat hearts develop severe adrenergic dysfunction with decre ased adenylyl cyclase and abnormal intracellular Ca2+-homeostasis. Our find ings emphasize angiotensin II as a major risk factor promoting early functi onal decline in cardiac hypertrophy. The data may have implications for pat ients with activating polymorphisms of the renin-angiotensin system and sup port the need for an early therapeutic intervention. (C) 2001 Lippincott Wi lliams & Wilkins.