Background-Cardiac responses to ␤-adrenergic receptor stimulation are depressed with pressure overload-induced cardiac hypertrophy. We investigated whether exercise training could modify ␤-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the ␤-adrenergic receptor desensitizing kinase GRK2 and the abundance and phosphorylation of some key Ca 2ϩ cycling proteins. Ϫ7 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 (PϽ0.05). SHR-TRD showed the greatest lusitropic response to ISO (PϽ0.05) 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 (PϽ0.05). SHR displayed increased L-type Ca 2ϩ channel and sodium calcium exchanger abundance compared with WKY (PϽ0.001). Training increased ryanodine receptor phosphorylation and phospholamban phosphorylation at both the Ser 16 and Thr 17 residues (PϽ0.05). Conclusions-Exercise training in hypertension improves the inotropic and lusitropic responsiveness to ␤-adrenergic receptor stimulation despite augmenting LV wall thickness. A lower GRK2 abundance and an increased phosphorylation of key Ca 2ϩ cycling proteins may be responsible for the above putative effects. (Circulation. 2005;111:3420-3428.)

.-We investigated how exercise training superimposed on chronic hypertension impacted left ventricular remodeling. Cardiomyocyte hypertrophy, apoptosis, and proliferation in hearts from female spontaneously hypertensive rats (SHRs) were examined. Four-month-old SHR animals were placed into a sedentary group (SHR-SED; n ϭ 18) or a treadmill running group (SHR-TRD, 20 m/min, 1 h/day, 5 days/wk, 12 wk; n ϭ 18). Age-matched, sedentary Wistar Kyoto (WKY) rats were controls (n ϭ 18). Heart weight was greater in SHR-TRD vs. both WKY (P Ͻ 0.01) and SHR-SED (P Ͻ 0.05). Morphometricderived left ventricular anterior, posterior, and septal wall thickness were increased in SHR-SED relative to WKY and augmented in SHR-TRD. Cardiomyocyte surface area, length, and width were increased in SHR-SED relative to WKY and further increased in SHR-TRD. Calcineurin abundance was increased in SHR-SED vs. WKY (P Ͻ 0.001) and attenuated in SHR-TRD relative to SHR-SED (P Ͻ 0.05). Protein abundance and mRNA of Akt was not different among groups. The rate of apoptosis was increased in SHR-SED relative to WKY and mitigated in SHR-TRD. The abundance of Ki-67 ϩ cells across groups was not statistically different across groups. The abundance of cardiac progenitor cells (c-Kit ϩ cells) was increased in SHR-TRD relative to WKY. These data suggest that exercise training superimposed on hypertension augmented cardiomyocyte hypertrophy, despite attenuating calcineurin abundance. Exercise training also mitigated apoptosis in hypertension and showed a tendency to enhance the abundance of cardiac progenitor cells, resulting in a more favorable cardiomyocyte number in the exercise-trained hypertensive heart. hypertrophy; myocytes; apoptosis; proliferation CHRONIC HYPERTENSION INDUCES overall cardiac enlargement, which is, in part, due to cardiomyocyte hypertrophy. This is a significant health issue, since pathological cardiac enlargement increases the risk for the development of congestive heart failure (4). Increased apoptosis has also been noted in the hypertensive heart, which may be an integral substrate in overall remodeling and progression to heart failure (33).Several studies have reported that cardiac myocytes are capable of mitotic division and proliferation (13,14). While the control mechanisms for the induction of cardiomyocyte proliferation remain unclear, one theory purports the involvement of a resident population of cardiac progenitor cells (1, 30), which have been shown to increase their activity in stress-induced pathological conditions (1,28,31). In the hypertensive heart, cardiomyocyte proliferation may counteract apoptosis, thus reducing the progressive loss of cardiomyocytes.Recent studies from our laboratory, as well as others, have shown an overall phenotypical improvement for the myocardium with exercise training in hypertension (3,17,24,34,35,42). However, the precise putative mechanisms associated with the observed adaptations with exercise training remain unclear. Our present hypothesis is that exercise training in hypertension ...

Libonati JR, Sabri A, Xiao C, MacDonnell SM, Renna BF. Exercise training improves systolic function in hypertensive myocardium. J Appl Physiol 111: 1637-1643, 2011. First published September 15, 2011 doi:10.1152/japplphysiol.00292.2011The general purpose of this study was to test the effect of exercise training on the left ventricular (LV) pressure-volume relationship (LV/PV) and apoptotic signaling markers in normotensive and hypertensive hearts. Four-month-old female normotensive Wistar-Kyoto rats (WKY; n ϭ 37) and spontaneously hypertensive rats (SHR; n ϭ 38) were assigned to a sedentary (WKY-SED, n ϭ 21; SHR-SED, n ϭ 19) or treadmilltrained (WKY-TRD, n ϭ 16; SHR-TRD, n ϭ 19) group (ϳ60% V O2 peak, 60 min/day, 5 days/wk, 12 wk). Ex vivo LV/PV were established in isovolumic Langendorff-perfused hearts, and LV levels of Akt, phosphorylated Akt (Akt Pi), Bad, phosphorylated Bad (BadPi) c-IAP, x-IAP, calcineurin, and caspases 3, 8, and 9 were measured. Heart-to-body weight ratio was increased in SHR vs. WKY (P Ͻ 0.05), concomitant with increased calcineurin mRNA (P Ͻ 0.05). There was a rightward shift in the LV/PV (P Ͻ 0.05) and a reduction in systolic elastance (E s) in SHR vs. WKY. Exercise training corrected E s in SHR (P Ͻ 0.05) but had no effect on the LV/PV in WKY. Caspase 3 was increased in SHR-SED relative to WKY-SED, while Bad Pi, c-IAP, and x-IAP were significantly lower in SHR relative to WKY (P Ͻ 0.05). Exercise training increased BadPi in both WKY and SHR but did not alter caspase 9 activity in either group. While caspase 3 activity was increased with training in WKY (P Ͻ 0.05), it was unchanged with training in SHR. We conclude that moderate levels of regular aerobic exercise attenuate systolic dysfunction early in the compensatory phase of hypertrophy, and that a differential phenotypical response to moderate-intensity exercise exists between WKY and SHR.

Myocardial tolerance to acidosis is improved during the adaptive phase of compensatory hypertrophy. Furthermore, exercise training in SHR induced a myocardial phenotype that preserved Ca(2+) responsiveness during acidosis.