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(Circulation. 2005;111:3420-3428.)
© 2005 American Heart Association, Inc.

Hypertension

Improved Myocardial ß-Adrenergic Responsiveness and Signaling With Exercise Training in Hypertension

Scott M. MacDonnell, MS; Hajime Kubo, PhD; Deborah L. Crabbe, MD; Brian F. Renna, MA; Patricia O. Reger, MS, PT, OCS; Jun Mohara, MD; L. Ashley Smithwick, PhD; Walter J. Koch, PhD; Steven R. Houser, PhD; Joseph R. Libonati, PhD

From the Departments of Kinesiology (S.M.M., B.F.R., P.O.R., J.R.L.) and Physiology (S.R.H., J.R.L.) and the Cardiovascular Research Center (H.K., D.L.C., J.M., S.R.H., J.R.L.), Temple University, and the Center for Translational Medicine, Thomas Jefferson University (A.S., W.J.K.), Philadelphia, Pa.

Correspondence to Joseph R. Libonati, PhD, Temple University, 122 Pearson Hall, 1800 N Broad St, Philadelphia, PA 19122. E-mail jlibonat{at}temple.edu

Received September 10, 2004; revision received March 2, 2005; accepted March 25, 2005.

Background— Cardiac responses to ß-adrenergic receptor stimulation are depressed with pressure overload–induced cardiac hypertrophy. We investigated whether exercise training could modify ß-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the ß-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 () 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 ß-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.

Key Words: diastole • exercise • hypertension • hypertrophy • proteins

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