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Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate
Biolo A, Greferath R, Siwik DA, et al.
Reviewers: Claudia Benkwitz, MD, PhD, Theodore A. Alston, MD, PhD
Oral and i.p. drug improved treadmill exercise capacity in normal mice and in transgenic mice with heart-failure. The transgenic mice exhibited dilated cardiomyopathy because of cardiac-specific overexpression of Gαq, a G-protein involved in adrenergic and cholinergic cell signaling.
In normal mice, ITTP increased exercise capacity up to 50% after i.p. administration. In transgenic mice with severe heart failure, baseline capacity was depressed to 60% of that of normal mice. The i.p. drug increased exercise capacity up to the normal baseline level. Oral ITTP increased exercise capacity by 30% in both groups.
To investigate whether the improvements in exercise capacity were related to facilitated O2 unloading from hemoglobin and thereby improved tissue oxygenation, the authors examined the effects of ITTP on hypoxia-inducible factor-1α mRNA expression in the myocardium and on the Bohr curve. Consistent with the working hypothesis, ITTP reduced the expression of HIF-1α as a marker for tissue hypoxia, and ITTP shifted the oxyhemoglobin dissociation curve to the right, indicative of an increased O2-releasing capacity. The authors did not find direct vasodilatatory or inotropic effects of ITTP as potential alternative mechanisms for the improved exercise capacity.
It is surprising that the drug carries its pyrophosphate groups into the red cell, especially from the GI tract. For instance, 2,3-DPG is not similarly “membrane-permeant.” A performance-enhancing drug, ITPP sounds almost too good to be true.
The ITPP strategy resembles an experimental one demonstrated by T. Yonetani at U. Pennsylvania (Adv Exp Med Biol 2003; 510:93-9). Yonetani selectively nitrosylated the α-subunits of α2ß2 hemoglobin tetramers in 2,3-DPG-depleted cells. Even though half of the RBC heme was therefore blocked, oxygen delivery was increased because of better off-loading. Since ITPP does not block any heme sites, it could more than double the oxygen delivery of 2,3-DPG-depleted RBCs
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