MacDonnell Scott M, Kubo Hajime, Crabbe Deborah L, Renna Brian F, Reger Patricia O, Mohara Jun, Smithwick L Ashley, Koch Walter J, Houser Steven R, Libonati Joseph R
Department of Kinesiology, Temple University, Philadelphia, PA 19122, USA.
Circulation. 2005 Jun 28;111(25):3420-8. doi: 10.1161/CIRCULATIONAHA.104.505784. Epub 2005 Jun 20.
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.
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).
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.
压力超负荷诱导的心肌肥厚会抑制心脏对β-肾上腺素能受体刺激的反应。我们研究了运动训练是否能通过改变β-肾上腺素能受体脱敏激酶GRK2以及一些关键钙循环蛋白的丰度和磷酸化，来改变自发性高血压模型中β-肾上腺素能受体的反应性。
将雌性自发性高血压大鼠（SHR；4月龄）分为跑步机跑步组（SHR-TRD；20米/分钟，每天1小时，每周5天，共12周）或久坐组（SHR-SED）。年龄匹配的Wistar Kyoto（WKY）大鼠作为对照。SHR的平均血压高于WKY（P<0.01），运动后无变化。SHR的左心室（LV）舒张期前后壁厚度大于WKY（P<0.001），训练后增加（P<0.01）。在输注异丙肾上腺素（ISO）（1×10⁻¹⁰至1×10⁻⁷摩尔/升）和起搏应激（8.5赫兹）期间检查Langendorff左心室功能。相对于WKY，SHR中左心室最大压力/ISO剂量反应曲线右移100倍。WKY和SHR-SED之间的ISO左心室最大压力反应峰值相似，而SHR-TRD中增加（P<0.05）。SHR-TRD对ISO表现出最大的舒张期反应（P<0.05），并抵消了WKY和SHR-SED中观察到的起搏诱导的左心室舒张末期压力增加和等容舒张时间常数（tau）增加。SHR-TRD中对ISO的心脏反应改善与心肌GRK2水平正常化有关（P<0.05）。与WKY相比，SHR中L型钙通道和钠钙交换体丰度增加（P<0.001）。训练增加了兰尼碱受体在Ser16和Thr17残基处的磷酸化以及受磷蛋白的磷酸化（P<0.05）。
高血压患者进行运动训练可改善对β-肾上腺素能受体刺激的变力性和舒张期反应，尽管左心室壁厚度增加。较低的GRK2丰度和关键钙循环蛋白磷酸化增加可能是上述假定效应的原因。
