Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension.
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.


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.
MacDonnell
Scott M
SM
Department of Kinesiology, Temple University, Philadelphia, PA 19122, USA.
Kubo
Hajime
H
Crabbe
Deborah L
DL
Renna
Brian F
BF
Reger
Patricia O
PO
Mohara
Jun
J
Smithwick
L Ashley
LA
Koch
Walter J
WJ
Houser
Steven R
SR
Libonati
Joseph R
JR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D020747:Calcium Channels, T-Type / Q000032:analysis; D005081:Exercise Therapy / Q000379:methods*; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2; D006352:Heart Ventricles / Q000737:chemistry; D006973:Hypertension / Q000628:therapy*; D017379:Hypertrophy, Left Ventricular; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000032:analysis; D051552:beta-Adrenergic Receptor Kinases / Q000032:analysis
D000318:Adrenergic beta-Agonists; D020747:Calcium Channels, T-Type; D019831:Sodium-Calcium Exchanger; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D007545:Isoproterenol