Document Detail

Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension.
MedLine Citation:
PMID:  15967848     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Cardiac responses to beta-adrenergic receptor stimulation are depressed with pressure overload-induced cardiac hypertrophy. We investigated whether exercise training could modify beta-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the beta-adrenergic receptor desensitizing kinase GRK2 and the abundance and phosphorylation of some key Ca2+ cycling proteins.
METHODS AND RESULTS: Female spontaneously hypertensive rats (SHR; age, 4 months) were placed into a treadmill running (SHR-TRD; 20 m/min, 1 h/d, 5 d/wk, 12 weeks) or sedentary group (SHR-SED). Age-matched Wistar Kyoto (WKY) rats were controls. Mean blood pressure was higher in SHR versus WKY (P<0.01) and unaltered with exercise. Left ventricular (LV) diastolic anterior and posterior wall thicknesses were greater in SHR than WKY (P<0.001) and augmented with training (P<0.01). Langendorff LV performance was examined during isoproterenol (ISO) infusions (1x10(-10) to 1x10(-7) mol/L) and pacing stress (8.5 Hz). The peak LV developed pressure/ISO dose response was shifted rightward 100-fold in SHR relative to WKY. The peak ISO LV developed pressure response was similar between WKY and SHR-SED and increased in SHR-TRD (P<0.05). SHR-TRD showed the greatest lusitropic response to ISO (P<0.05) and offset the pacing-induced increase in LV end-diastolic pressure and the time constant of isovolumic relaxation (tau) observed in WKY and SHR-SED. Improved cardiac responses to ISO in SHR-TRD were associated with normalized myocardial levels of GRK2 (P<0.05). SHR displayed increased L-type Ca2+ channel and sodium calcium exchanger abundance compared with WKY (P<0.001). Training increased ryanodine receptor phosphorylation and phospholamban phosphorylation at both the Ser16 and Thr17 residues (P<0.05).
CONCLUSIONS: Exercise training in hypertension improves the inotropic and lusitropic responsiveness to beta-adrenergic receptor stimulation despite augmenting LV wall thickness. A lower GRK2 abundance and an increased phosphorylation of key Ca2+ cycling proteins may be responsible for the above putative effects.
Scott M MacDonnell; Hajime Kubo; Deborah L Crabbe; Brian F Renna; Patricia O Reger; Jun Mohara; L Ashley Smithwick; Walter J Koch; Steven R Houser; Joseph R Libonati
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-06-20
Journal Detail:
Title:  Circulation     Volume:  111     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-28     Completed Date:  2006-02-03     Revised Date:  2012-06-07    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3420-8     Citation Subset:  AIM; IM    
Department of Kinesiology, Temple University, Philadelphia, PA 19122, USA.
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MeSH Terms
Adrenergic beta-Agonists / pharmacology*
Blood Pressure
Calcium Channels, T-Type / analysis
Exercise Therapy / methods*
G-Protein-Coupled Receptor Kinase 2
Heart Ventricles / chemistry
Hypertension / therapy*
Hypertrophy, Left Ventricular
Isoproterenol / pharmacology
Myocardial Contraction
Rats, Inbred SHR
Rats, Wistar
Sodium-Calcium Exchanger / analysis
beta-Adrenergic Receptor Kinases / analysis
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Calcium Channels, T-Type; 0/Sodium-Calcium Exchanger; 7683-59-2/Isoproterenol; EC protein, rat; EC Receptor Kinase 2; EC Receptor Kinases

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