Biolo Andreia, Greferath Ruth, Siwik Deborah A, Qin Fuzhong, Valsky Eugene, Fylaktakidou Konstantina C, Pothukanuri Srinivasu, Duarte Carolina D, Schwarz Richard P, Lehn Jean-Marie, Nicolau Claude, Colucci Wilson S
Cardiovascular Section, Department of Medicine, Boston University Medical Center, and Myocardial Biology Unit, Boston University School of Medicine, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1926-9. doi: 10.1073/pnas.0812381106. Epub 2009 Feb 9.
A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.
最大运动能力的一个主要决定因素是向运动肌肉输送氧气。肌醇三磷酸（ITPP）是最近发现的一种可透过细胞膜的分子，它能引起血红蛋白氧结合亲和力的变构调节。在正常小鼠中，腹腔注射ITPP（0.5 - 3 g/kg）导致血红蛋白50%饱和时的氧张力（p50）呈剂量依赖性增加，最大增加31%。在平行实验中，ITPP使最大运动能力呈剂量依赖性增加，最大增加57±13%（P = 0.002）。在因心脏特异性过表达Gαq导致严重心力衰竭的转基因小鼠中，腹腔注射ITPP可提高运动能力，最大增加63±7%（P = 0.005）。在正常和衰竭小鼠中，通过饮水口服ITPP可提高血红蛋白p50和最大运动能力（+34±10%；P < 0.002）。与组织氧供应增加一致，ITPP可降低心肌中缺氧诱导因子-1α mRNA的表达。它对分离的小鼠心肌细胞的心肌收缩力没有影响，也不影响小鼠体内的动脉血压。因此，ITPP可降低血红蛋白的氧结合亲和力，增加组织氧输送，并提高正常小鼠和严重心力衰竭小鼠的最大运动能力。因此，ITPP是治疗因心力衰竭导致运动能力下降患者的一个有吸引力的候选药物。
