bis(3-5-dibromosalicyl)fumarate and succinyldisalicylic-acid

It is believed that the hypertensive effect of diaspirin crosslinked hemoglobin, a viable blood substitute, can be resolved by polymerization, which reduces the diffusion of this derivative into the interstitial space between nitric oxide-producing endothelium and the target vascular smooth muscle. We studied the systemic and renal responses to infusion of three cell-free human hemoglobins in anesthetized isovolemic rats: unmodified (HbA0), crosslinked (alpha-DBBF), and polymerized crosslinked (poly alpha-DBBF). HbA0 produced a significant increase in mean arterial blood pressure (MAP) throughout the 60-minute infusion. alpha-DBBF, on the other hand, produced a more marked and prolonged increase in MAP over 120 minutes. Only a moderate increase in MAP was observed in rats after a 30-minute infusion with poly alpha-DBBF. The extent of renal insufficiency produced by these proteins, as determined by the glomerular filtration rate, was in the following order: HbA0 > poly alpha-DBBF > alpha-DBBF. Infusion of poly alpha-DBBF, under hypovolemic but not isovolemic conditions in rats, produced an increase in heart rate, cardiac output, and stroke volume and a decrease in total peripheral resistance after 60 minutes. Chemical polymerization to increase the size of alpha-DBBF does not appear to improve its hemodynamic properties in rats, especially under partial exchange transfusion, a more clinically relevant indication for a hemoglobin-based blood substitute.

Topics: Analysis of Variance; Animals; Aorta; Aspirin; Blood Pressure; Blood Substitutes; Cardiac Output; Cross-Linking Reagents; Endothelium, Vascular; Enzyme Induction; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Hemoglobins; Humans; Hypertension; Male; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Polyethylene Glycols; Potassium; Rats; Rats, Sprague-Dawley; Sodium; Stroke Volume; Vascular Resistance

Double-headed aspirins with bridging groups of different length and molecular structure have been examined for their reactivity with hemoglobin A or S. The compounds constructed are bound in the beta-cleft and show a wide range of beta-beta cross-linking effectiveness. Oxygenation curves of the modified hemoglobins in the presence of inositol hexaphosphate are strikingly modified. Many of the diaspirins also produce substantial changes in the minimum gelling concentration of sickle hemoglobin. These reagents offer possibilities for further enhancement of specificity toward hemoglobin, particularly by taking advantage of stereoselectivities.

Topics: Aspirin; Cross-Linking Reagents; Hemoglobin A; Hemoglobin, Sickle; Humans; Indicators and Reagents; Methods; Oxyhemoglobins; Protein Binding; Structure-Activity Relationship