title: [A comparative study of cardiac function in transgenic hypertensive rats, in spontaneously hypertensive rats and in normotensive rats].
abstract: Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.
authors.affiliation: Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin-Buch, Allemagne.
authors.forename: J
authors.initials: J
authors.lastname: Bohlender
authors.forename: U
authors.initials: U
authors.lastname: Hildenbrand
authors.forename: W P
authors.initials: WP
authors.lastname: Schlegel
authors.forename: P
authors.initials: P
authors.lastname: Hempel
authors.forename: E
authors.initials: E
authors.lastname: Nissen
authors.forename: E G
authors.initials: EG
authors.lastname: Krause
authors.forename: S
authors.initials: S
authors.lastname: Bartel
mesh_terms: D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D009320:Atrial Natriuretic Factor / Q000032:analysis; D001794:Blood Pressure / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight; D002316:Cardiotonic Agents / Q000627:therapeutic use; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000032:analysis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000032:analysis; D005786:Gene Expression Regulation / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology; D007545:Isoproterenol / Q000627:therapeutic use; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009929:Organ Size; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000235:genetics; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D015842:Serine Proteinase Inhibitors; D014665:Vasodilator Agents; D000808:Angiotensinogen; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol