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Improved Myocardial &bgr;-Adrenergic Responsiveness and Signaling With Exercise Training in Hypertension

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