Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit, MI 48202, USA.
Circ Heart Fail. 2013 May;6(3):563-71. doi: 10.1161/CIRCHEARTFAILURE.112.000208. Epub 2013 Apr 5.
Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure.
Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro-brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P<0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P<0.05) with a further increase at post (39±2%; P<0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro-brain natriuretic peptide.
In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.
腺苷通过 A1 受体激活产生心脏保护作用。然而，由于完全激动剂的不良作用，如心动过缓，腺苷 A1 受体激动剂的治疗受到限制。本研究探讨了部分腺苷 A1 受体激动剂卡培他滨（CAP）对心力衰竭犬左心室（LV）功能和重构的影响。
12 只犬经微栓塞诱导心力衰竭后，随机分为 12 周口服 CAP 治疗组（7.5mg BID；n=6）或无治疗对照组（n=6）。在治疗前（pre）和治疗后 1 周和 12 周（post）测量 LV 舒张末期和收缩末期容积、射血分数、血浆去甲肾上腺素和 N 端脑利钠肽前体。在 post 时获得的 LV 组织用于评估间质纤维化体积分数、肌浆网钙 ATP 酶-2a 活性、线粒体解偶联蛋白（UCP）和葡萄糖转运蛋白（GLUT）的表达。在对照组中，舒张末期和收缩末期容积增加，射血分数从 pre 到 post 显著降低（射血分数，30±2 对 27±1%；P<0.05）。在 CAP 治疗的犬中，舒张末期容积无变化；1 周后射血分数显著增加（36±2 对 27±2%；P<0.05），post 时进一步增加（39±2%；P<0.05），而收缩末期容积降低。CAP 显著降低间质纤维化体积分数，使肌浆网钙 ATP 酶-2a 活性以及 UCP-2 和 UCP-3、GLUT-1 和 GLUT-2 的表达正常化，并显著降低血浆去甲肾上腺素和 N 端脑利钠肽前体。
在心力衰竭犬中，CAP 改善 LV 功能并防止进行性重构。LV 收缩功能的改善在开始治疗后早期发生。结果支持开发部分腺苷 A1 受体激动剂治疗慢性心力衰竭。
