Department of Biomedical Science, University of Guelph, Guelph, Ontario, Canada.
J Am Coll Cardiol. 2011 May 17;57(20):2020-8. doi: 10.1016/j.jacc.2010.11.022.
Our objective was to test the hypothesis that there is a significant diurnal variation for the therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors on pressure-overload cardiovascular hypertrophy.
Physiological and molecular processes exhibit diurnal rhythms that may affect efficacy of disease treatment (chronotherapy). Evidence suggests that the heart primarily remodels during sleep. Although a growing body of clinical and epidemiological evidence suggests that the timing of therapy, such as ACE inhibition, alters diurnal blood pressure patterns in patients with hypertension, the benefits of chronotherapy on myocardial and vascular remodeling have not been studied.
We examined the effects of the short-acting ACE inhibitor, captopril, on the structure and function of cardiovascular tissue subjected to pressure overload by transverse aortic constriction (TAC) in mice. Captopril (15 mg/kg intraperitoneally) or placebo was administered at either murine sleep time or wake time for 8 weeks starting 1 week after surgery.
TAC mice given captopril at sleep time had improved cardiac function and significantly decreased heart: body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen versus TAC mice given captopril or placebo during wake time. Captopril induced similar drops in blood pressure at sleep or wake time, suggesting that time-of-day differences were not attributable to blood pressure changes. These beneficial effects of captopril were correlated with diurnal changes in ACE mRNA expression in the heart.
The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo. These studies support the hypothesis that the heart (and vessels) remodel during sleep time and also illustrate the importance of diurnal timing for some cardiovascular therapies.
我们旨在检验下述假说，即血管紧张素转换酶（ACE）抑制剂对压力超负荷性心血管肥大的治疗益处存在显著的昼夜变化。
生理和分子过程存在昼夜节律，这可能会影响疾病治疗的效果（时间治疗学）。有证据表明，心脏主要在睡眠期间进行重塑。尽管越来越多的临床和流行病学证据表明，治疗时机（如 ACE 抑制）改变了高血压患者的昼夜血压模式，但时间治疗学对心肌和血管重塑的益处尚未得到研究。
我们研究了短效 ACE 抑制剂卡托普利对经主动脉缩窄（TAC）造成压力超负荷的心血管组织的结构和功能的影响。在手术后 1 周开始，8 周内每天腹腔注射 15mg/kg 的卡托普利或安慰剂，分别在小鼠睡眠时或清醒时给药。
与在清醒时接受卡托普利或安慰剂治疗的 TAC 小鼠相比，在睡眠时接受卡托普利治疗的 TAC 小鼠的心脏功能得到改善，心脏重量与体重比、心肌细胞横截面积、心肌内血管中膜壁厚度以及血管周围胶原显著降低。卡托普利在睡眠或清醒时均能引起类似的血压下降，表明昼夜时间差异并非归因于血压变化。卡托普利的这些有益作用与心脏中 ACE mRNA 表达的昼夜变化相关。
仅在睡眠时给予 ACE 抑制剂卡托普利可使心血管重塑受益；而在清醒时给予卡托普利 ACE 抑制与给予安慰剂相同。这些研究支持了心脏（和血管）在睡眠期间进行重塑的假说，也说明了某些心血管治疗的昼夜时间安排的重要性。
