Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo -inositol trispyrophosphate

Abstract

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 cardiacspecific overexpression of G␣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-1␣ 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.hypoxia ͉ oxygen delivery

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

“…In all animals studies including ours, ITPP was very well tolerated (13)(14)(15)42), and no impact on hematological parameters has been reported (13). Minor in vitro toxicity was noted, however only at doses ~30x higher than we used (16) …”

PET imaging of cardiac hypoxia: Opportunities and challenges

“…This decreased vascularity in hypertrophic myocardium is exacerbated by increases in myocyte size and tissue fibrosis, which increase diffusion distances and decrease oxygen availability to myocytes (and perhaps more importantly, their mitochondria) [27,28]. While up-regulation of hypoxia inducible factor HIF-1α is increasingly being recognized as an important instigator of cardiac hypertrophy [29][30][31] and mediator of decline into heart failure [32][33][34], we have found no reports that successfully demonstrate non-invasive measurement of hypoxia itself in hypertrophic or failing myocardium. As we shall discuss, this is most probably because most existing approaches designed to assess tissue hypoxia have insufficient sensitivity to detect the less extreme levels of hypoxia that are likely to be involved.…”

myo‐Inositol Trispyrophosphate: A Novel Allosteric Effector of Hemoglobin with High Permeation Selectivity across the Red Blood Cell Plasma Membrane

“…[12,13] Furthermore, ITPP was also able to increase exercise capacity in both wild-type and transgenic mice with severe heart failure. [11] All these biological activities seem to be directly related to the ability of ITPP to enhance oxygen delivery through allosteric Hb modulation, as indicated by the induction of marked shifts in the oxygen binding curve and in the corresponding P50 values both in vitro and in vivo. [9] The observation of a P50 shift in intact cells after incubation with ITPP is a clear indication of the capacity of this compound to cross the RBC membrane.…”

“…It is a novel membrane-permeant polyanionic compound, able to increase oxygen release in vitro markedly, both in free Hb and in whole blood, [9,10] as well as in vivo. [11] As a result, ITPP appears in animal models to be a highly effective antiangiogenic and anticancer agent, counteracting the effects of hypoxia and therefore reducing cancer progression and myo-Inositol trispyrophosphate (ITPP), a novel membrane-permeant allosteric effector of hemoglobin (Hb), enhances the regulated oxygen release capacity of red blood cells, thus counteracting the effects of hypoxia in diseases such as cancer and cardiovascular ailments. ITPP-induced shifting of the oxygen-hemoglobin equilibrium curve in red blood cells (RBCs) was inhibited by DIDS and NAP-taurine, indicating that band 3 protein, an anion transporter mainly localized on the RBC membrane, allows ITPP entry into RBCs.…”