Document Detail


Functional activity and expression of the myocardial postreceptor adenylyl cyclase system in pressure overload hypertrophy in rat.
MedLine Citation:
PMID:  8763401     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The aim of the present study was to investigate the functional regulation of the myocardial postreceptor adenylyl cyclase (AC) system in compensated left ventricular hypertrophy (LVH) and the effect of long-term angiotensin converting enzyme (ACE) inhibition. METHODS: Pressure overload LVH was induced in rats by supravalvular aortic banding for 12 weeks. At 12 weeks left ventricular function and inner diameters were analyzed by echocardiography of anesthetized animals, and responsiveness to forskolin (systolic developed pressure) was determined in isolated perfused hearts. Functional activities of AC and the stimulatory G protein Gs were measured as well as mRNA expression (quantitative slot blot analyses) of AC type V, isoforms of Gs alpha and Gi alpha 2. G protein alpha-subunits were also quantified by immunoblotting. Rats were treated with ramipril (Ram, 10 mg/kg per day p.o.) during weeks 7 to 12 to induce regression of LVH or with vehicle (Veh, tap water). RESULTS: Pressure overload induced severe LVH (3.2 +/- 0.09 g/kg in Veh vs. 1.8 +/- 0.03 in sham; P < 0.05) which was significantly reduced by ramipril (2.7 +/- 0.09; P < 0.05 vs. Veh). In-vivo left ventricular function and diameters were unchanged in LVH. In contrast, in hearts with LVH, responsiveness of left ventricles to forskolin was attenuated and basal, GTP gamma S and forskolin as well as manganese chloride-stimulated adenylyl cyclase activity was significantly downregulated by approximately 40% (basal 20.8 +/- 1.9 pmol cAMP/mg per min vs. 34.0 +/- 2.2 in sham; P < 0.01). However, no significant changes of AC type V mRNA were found in hypertrophied left ventricles. Functional activity of the stimulatory G protein Gs was reduced in LVH (48 +/- 7 pmol cAMP/mg per min in Veh vs. 68 +/- 3 in sham), whereas mRNA expression of long and short Gs alpha-isoforms was not altered and that of Gi alpha 2 was only slightly increased in ramipril-treated animals. Western analysis showed no significant differences of Gs alpha or Gi alpha 2 subunits. Long-term blockade of the renin-angiotensin system had no effect on the activity of the adenylyl cyclase system. CONCLUSIONS: Functional desensitization of adenylyl cyclase and stimulatory G protein occurred in rat adaptive LVH prior to the onset of severe left ventricular dysfunction which was not restored by ACE-inhibitor treatment. The desensitization seems not to be mediated by significant changes of mRNA expression of AC type V or abundance of regulatory G proteins.
Authors:
S R Holmer; G Bruckschlegel; H Schunkert; D B Rataj; E P Kromer; G A Riegger
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular research     Volume:  31     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  1996 May 
Date Detail:
Created Date:  1996-09-24     Completed Date:  1996-09-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  719-28     Citation Subset:  IM    
Affiliation:
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Adenylate Cyclase / genetics,  metabolism*
Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
Animals
Blotting, Western
GTP-Binding Proteins / metabolism
Gene Expression
Hypertrophy, Left Ventricular / drug therapy,  metabolism*
Male
Myocardium / metabolism*
Ramipril / therapeutic use*
Rats
Rats, Wistar
Chemical
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 87333-19-5/Ramipril; EC 3.6.1.-/GTP-Binding Proteins; EC 4.6.1.1/Adenylate Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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