Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of
R G Weiss1, M A Mejia, D A Kass
1Peter Belfer Laboratory of the Cardiology Division, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland 21287-8108, USA. rgweiss@rad.jhu.edu
Insights
A novel drug, RSR13, shifts hemoglobin-oxygen affinity, improving cardiac function during ischemia. This therapeutic strategy may reduce metabolic and contractile damage in heart attack patients.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Myocardial ischemia treatments aim to increase blood flow or decrease oxygen demand.
- A rightward shift in the hemoglobin-oxygen saturation curve could potentially mitigate ischemia's effects.
Purpose of the Study:
- To investigate if a synthetic hemoglobin-oxygen affinity modifier (RSR13) reduces metabolic and contractile consequences of myocardial oxygen-supply imbalance during low-flow ischemia.
Main Methods:
- Utilized 31P nuclear magnetic resonance (NMR) spectroscopy to assess high-energy phosphate levels and pH in canine hearts.
- Administered RSR13 or vehicle control during reversible reduction of left anterior descending coronary artery blood flow.
- Evaluated cardiac metabolites and regional ventricular function using pressure segment-length relations.
Main Results:
- RSR13 administration increased hemoglobin p50, attenuating declines in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia.
- No significant changes in regional myocardial blood flow, heart rate, or systolic blood pressure were observed.
- RSR13 improved cardiac PCr/ATP ratios and regional function (fractional shortening, regional work) even when given after ischemia onset.
Conclusions:
- Synthetic allosteric reduction of hemoglobin-oxygen affinity using RSR13 is a potential therapeutic strategy.
- This approach may effectively ameliorate the metabolic and functional damage caused by cardiac ischemia.
Abstract:
Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia.
