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

Abstract

Background— Cardiac responses to β-adrenergic receptor stimulation are depressed with pressure overload–induced cardiac hypertrophy. We investigated whether exercise training could modify β-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the β-adrenergic receptor desensitizing kinase GRK2 and the abundance and phosphorylation of some key Ca 2+ 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 (1×10 −10 to 1×10 −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 (τ) 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 Ca 2+ channel and sodium calcium exchanger abundance compared with WKY ( P <0.001). Training increased ryanodine receptor phosphorylation and phospholamban phosphorylation at both the Ser 16 and Thr 17 residues ( P <0.05). Conclusions— Exercise training in hypertension improves the inotropic and lusitropic responsiveness to β-adrenergic receptor stimulation despite augmenting LV wall thickness. A lower GRK2 abundance and an increased phosphorylation of key Ca 2+ cycling proteins may be responsible for the above putative effects.