Role of endothelin in the cardiovascular effects of diaspirin crosslinked and stroma reduced hemoglobin.

OBJECTIVES Diaspirin crosslinked hemoglobin is a resuscitative solution with excellent oxygen-carrying capacity. Diaspirin crosslinked hemoglobin produces an immediate increase in blood pressure and marked regional circulatory changes in rats and pigs. Our objective was to determine the role of endothelin in the cardiovascular actions of diaspirin crosslinked hemoglobin (modified) and (unmodified) stroma reduced hemoglobin solutions. DESIGN Prospective, randomized comparison of cardiovascular effects of diaspirin crosslinked and stroma reduced hemoglobin in control rats and in rats pretreated with cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), an endothelin-A receptor antagonist. SETTING Research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Modified, highly purified, and heat pasteurized (diaspirin crosslinked) and unmodified (stroma reduced) hemoglobin in control (untreated) and BQ-123 (5 mg/kg/hr iv)-treated rats. MEASUREMENTS AND MAIN RESULTS Infusion of stroma reduced hemoglobin (400 mg/kg iv) in control rats produced an increase in blood pressure (43%) and total peripheral resistance (65%) without any change in heart rate, cardiac output, and stroke volume. Stroma reduced hemoglobin decreased blood flow to the kidneys and liver, increased blood flow to the heart, and had no effect on blood flow to the brain, gastrointestinal tract, spleen, musculoskeletal system, skin, and mesentery and pancreas. Infusion of stroma reduced hemoglobin in rats treated with BQ-123 (5 mg/kg/hr iv) increased the blood pressure to a similar degree when compared with control rats, but the increase in total peripheral resistance was significantly attenuated. The stroma reduced hemoglobin-induced decrease in blood flow to the kidneys and liver was significantly attenuated in BQ-123-treated rats as compared with control rats. However, the stroma reduced hemoglobin-induced increase in blood flow to the heart of BQ-123-treated rats was similar to the increase in control rats. Infusion of diaspirin crosslinked hemoglobin (400 mg/kg iv) produced increases in blood pressure (81%), cardiac output (36%), stroke volume (30%), and total peripheral vascular resistance (45%), along with increases in blood flow to the heart, spleen, gastrointestinal tract, and skin of control rats. The blood flows to the brain, kidneys, liver, musculoskeletal system, and mesentery and pancreas were not altered by diaspirin crosslinked hemoglobin in control rats. The increases in blood pressure, cardiac output, stroke volume, and total peripheral vascular resistance by diaspirin crosslinked hemoglobin were significantly blocked in BQ-123-treated rats as compared with control rats. The increases in blood flow to the heart, spleen, and skin by diaspirin crosslinked hemoglobin were significantly blocked in BQ-123-treated rats as compared with control rats. Diaspirin crosslinked hemoglobin produced an increase in the blood flow to the brain and a decrease in blood flow to the kidney and musculoskeletal system of BQ-123-treated rats as compared with control rats. Blood plasma endothelin-1-like immunoreactivity was found to be significantly increased after treatment with diaspirin crosslinked hemoglobin or stroma reduced hemoglobin. CONCLUSIONS The endothelin-A receptor antagonist, BQ-123, could attenuate the systemic hemodynamic and regional circulatory effects of diaspirin crosslinked hemoglobin and stroma reduced hemoglobin. However, the increase in blood flow to the heart induced by stroma reduced hemoglobin could not be attenuated by BQ-123.