Sakai Mari, Suzuki Tokiko, Tomita Kengo, Yamashita Shigeyuki, Palikhe Sailesh, Hattori Kohshi, Yoshimura Naoki, Matsuda Naoyuki, Hattori Yuichi
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Department of Thoracic and Cardiovascular Surgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Am J Physiol Heart Circ Physiol. 2017 Jun 1;312(6):H1224-H1237. doi: 10.1152/ajpheart.00828.2016. Epub 2017 Apr 28.
Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.
多巴酚丁胺作为唯一的正性肌力药物用于感染性休克已有多年，但它的益处一直受到质疑。我们比较了多巴酚丁胺和米力农在盲肠结扎穿刺（CLP）诱导的多微生物脓毒症小鼠中作为正性肌力药物的作用。CLP诱导的脓毒症小鼠表现出明显的心脏炎症，促炎细胞因子的mRNA大幅增加以及炎性细胞在心室心肌中的大量浸润表明了这一点。血浆心肌肌钙蛋白I升高表明CLP小鼠存在心脏损伤。对心脏功能的无创超声心动图评估显示，尽管在补液情况下左心室功能得以保留，但与假手术对照组相比，CLP小鼠的多巴酚丁胺正性肌力反应明显受损。相比之下，米力农在假手术小鼠和CLP小鼠中以同样有效的方式发挥正性肌力作用。心肌中β-肾上腺素能受体和三个主要G蛋白家族α亚基的表面表达水平不受CLP诱导的脓毒症影响。假手术小鼠和CLP小鼠在给予米力农后血浆环磷腺苷（cAMP）水平均显著升高，但给予多巴酚丁胺后仅假手术对照组血浆cAMP水平升高。在负责心脏cAMP水解的磷酸二酯酶（PDE）同工型中，PDE4D而非PDE3A在CLP小鼠心肌中显著上调。我们确定了脓毒症中对多巴酚丁胺作为正性肌力药物反应受损的一种新机制，了解PDE4D在调节脓毒症心脏功能反应中的作用可能为需要正性肌力支持的低心输出量脓毒症患者开辟以PDE4D为靶点的治疗选择的潜力。多巴酚丁胺在感染性休克治疗中的实用性建议有限。在此，我们揭示，在盲肠结扎穿刺诱导的脓毒症小鼠中，多巴酚丁胺作为正性肌力药物的作用受损，且由于磷酸二酯酶4D上调导致cAMP分解，心脏β-肾上腺素能受体信号传导未发生变化。
