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NEWS
Kevin Johns receives the John Hinckley Lifetime Outstanding Service Award
Pro/Con
Mitral Regurgitation Can Be Reliably Assessed In The Operating Room Under General Anesthesia
Literature Reviews
Acute Kidney Injury After Cardiac Surgery Focus on Modifiable Risk Factors
Intensive versus Conventional Glucose Control in Critically Ill Patients
Glycemic variability: A strong independent predictor of mortality in critically ill patients
Foundation Update
SCA Foundation to host reception honoring Michael Roizen on Sunday, April 19
The Society of Cardiovascular Anesthesiologists (SCA) publishes the SCA Bulletin bimonthly. The information presented in the SCA Bulletin has been obtained by the editors. Validity of opinions presented, drug dosages, accuracy and completeness of content are not guaranteed by SCA.
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.
Proc Natl Acad Sci U S A. 2009; 106(6): 1926-9.
Reviewers: Claudia Benkwitz, MD, PhD, Theodore A. Alston, MD, PhD
Massachusetts General Hospital, Harvard Medical School, Boston, MA
Abstract
Researchers at Boston U. report a novel experimental drug to improve oxygen delivery in heart failure. Active orally and by injection, myo-inositol trispyrophosphate (ITPP) is an analog of 2,3-DPG and, like 2,3-DPG, decreases the affinity of hemoglobin for oxygen. In mice, this effect (“shifting the Bohr curve to the right”) improves oxygen release from hemoglobin to skeletal muscle.
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.
Comments
Since ITPP improves oxygen delivery to skeletal muscle, it is potentially of benefit for critically ill patients suffering respiratory muscle weakness. In principle, it could increase the oxygen supply of any organ, including the heart, which normally requires high extraction from the coronaries. The heart would also benefit if the drug proves to permit adequate oxygen delivery at a lower cardiac output or arterial pressure. An obvious potential use in cardiovascular anesthesia would be to use the drug to rapidly rejuvenate 2,3-DPG-depleted red cells for transfusion. It might also preserve oxygen delivery in hemodilution, and it might favorably shift the Bohr curve in deliberate hypothermia.
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