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

Abstract

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.

• Authors: 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
• Journal: Circulation (Circulation) Vol. 111 Issue 25 Pg. 3420-8 (Jun 28 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 15967848 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Agonists
• Calcium Channels, T-Type
• Sodium-Calcium Exchanger
• Grk2 protein, rat
• beta-Adrenergic Receptor Kinases
• G-Protein-Coupled Receptor Kinase 2
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Blood Pressure
• Calcium Channels, T-Type (analysis)
• Exercise Therapy (methods)
• Female
• G-Protein-Coupled Receptor Kinase 2
• Heart Ventricles (chemistry)
• Hypertension (therapy)
• Hypertrophy, Left Ventricular
• In Vitro Techniques
• Isoproterenol (pharmacology)
• Myocardial Contraction
• Phosphorylation
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Sodium-Calcium Exchanger (analysis)
• beta-Adrenergic Receptor Kinases (analysis)