Study of Systemic and Microvascular Responses to Progressive Hemolytic Anemia in Rats

Abstract

Hemolytic Anemia (HA) is characterized by an increase in the ratio of red blood cell destruction to production, which results in reduced oxygen carrying capacity, tissue hypoxia, inflammation, and corresponding clinical manifestations. The microvasculature is the primary site of vascular resistance and gas exchange, and is well suited to studying the subclinical progression of HA. HA was induced in male Sprague Dawley rats by intraperitoneal administration of phenylhydrazine (PHZ) per the following dosing schedule: Group 1 (100 mg/kg on Day 1) and Group 2 (100 mg/kg on Day 1, and 50 mg/kg on Day 2). Group 3 (baseline; BL) was an untreated time control. Rats were surgically prepared for the following systemic and microvascular measurements: total hemoglobin (tHb), mean arterial pressure (MAP), heart rate, pulse pressure (PP), arteriolar contractile response to three doses of phenylephrine (PE; 0.01, 0.1, 1 mg/kg; I.V), and tissue oxygenation (PISFO2). PHZ reduced tHb by 47 and 75% for Groups 1 and 2 respectively. The 47% decrease in tHb for Group 1 was associated with the following changes from BL (Group 3): MAP decreased by 12%, PP increased by 121%, and PISFO2 decreased 23%. A 75% decrease in tHb (Group 2) resulted in the following changes from BL: MAP decreased by 34%, PP was no different, and PISFO2 decreased 40%. Heart rate remained unchanged between the three groups. The arteriolar contractile response profile to increasing concentrations of PE was right shifted, or less responsive, as tHb dropped between groups. The data indicate a robust cardiovascular compensatory response to severe hemolytic anemia, which serves to prevent peripheral tissue hypoxia. At a 75% reduction in tHb, though, this system begins to show signs of compromise as arteriolar diameters lose responsiveness to contractile stimuli and compensatory elevations in PP begin to decay. Yet, PISFO2 remains normoxic suggesting that as tHb is reduced, tissue hypoxia occurs precipitously not progressively.Support or Funding InformationSupport: Song Biotechnologies