Glutaraldehyde-polymerized bovine hemoglobin and phosphodiesterase-5 inhibition

Abstract

Objective: Hemoglobin-based oxygen carriers (HBOC) of several types scavenge nitric oxide from the vasculature resulting in vasoconstriction and hypertension, both systemic and pulmonary. Phosphodiesterase-5 (PDE5) inhibitors promote nitric oxide activity and enhance vasodilation. The purpose of this study was to determine whether combined therapy of glutaraldehyde-polymerized bovine hemoglobin (HBOC) with a PDE5 inhibitor would counter the negative hemodynamic consequences of HBOC therapy alone, resulting in improved hemodynamics and oxygen delivery.

Design: A controlled, experimental study.

Setting: A research laboratory at a university.

Subjects: Conscious male Sprague-Dawley rats.

Interventions: Glutaraldehyde-polymerized bovine hemoglobin (HBOC), sildenafil (PDE5 inhibitor), and lactated Ringer's solution (control).

Measurements and main results: Infusion of the HBOC resulted in significant (p < 0.05) systemic and pulmonary vasoconstriction, with reduced cardiac output and reduced oxygen delivery to the periphery. Infusion of lactated Ringer's demonstrated no changes in the measured variables. Infusion of sildenafil alone reduced systemic and pulmonary artery blood pressure, while maintaining cardiac output and oxygen delivery. Combined HBOC and sildenafil infusion resulted in stable systemic blood pressure, cardiac output, and oxygen delivery. However, the addition of sildenafil to HBOC did not fully ameliorate the pulmonary vasoconstriction caused by HBOC.

Conclusion: The HBOC used in this study resulted in pulmonary and systemic hypertension, reduced cardiac output, and oxygen delivery. These negative consequences of HBOC treatment can be largely overcome by combing HBOC treatment with a PDE5 inhibitor (sildenafil). Thus, these data support the continued investigation of combined HBOC and PDE5 inhibitor treatment in circumstances in which HBOC therapy is being considered.

Figure 1

Conceptual presentation of potential enhancements of nitric oxide (NO) vasodilation by sildenafil during scavenging of NO by hemoglobin-based oxygen carriers (HBOC). GMP, guanosine monophosphate; PDE-5, phosphodiesterase-5; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate.

Figure 2

Percent change in mean arterial blood pressure and total peripheral resistance in experimental groups. A and B, For the group comparisons, same letter designations are not significant; different letter designations represent significant (p < 0.05) differences among treatments, within time period (baseline or 2 hours). HBOC, hemoglobin-based oxygen carriers; S-HBOC, sildenafil plus polymerized bovine hemoglobin; S, sildenafil in lactated Ringer’s solution.

Figure 3

Percent change in mean pulmonary artery pressure and pulmonary vascular resistance in experimental groups. A and B, For the group comparisons, same letter designations are not significant; different letter designations represent significant (p < 0.05) differences among treatments, within time period (baseline or 2 hours). HBOC, hemoglobin-based oxygen carriers; S-HBOC, sildenafil plus polymerized bovine hemoglobin; S, sildenafil in lactated Ringer’s solution.

Figure 4

Percent change in cardiac index and oxygen delivery in experimental groups. A and B, For the group comparisons, same letter designations are not significant; different letter designations represent significant (p < 0.05) differences among treatments, within time period (baseline or 2 hours). HBOC, hemoglobin-based oxygen carriers; S-HBOC, sildenafil plus polymerized bovine hemoglobin; S, sildenafil in lactated Ringer’s solution.