Sodium nitrite therapy attenuates the hypertensive effects of HBOC-201 via nitrite reduction.
Hypertension secondary to scavenging of NO remains a limitation in the use of HBOCs (haemoglobin-based oxygen carriers). Recent studies suggest that nitrite reduction to NO by deoxyhaemoglobin supports NO signalling. In the present study we tested whether nitrite would attenuate HBOC-mediated hypertension using HBOC-201 (Biopure), a bovine cross-linked, low-oxygen-affinity haemoglobin. In a similar way to unmodified haemoglobin, deoxygenated HBOC-201 reduced nitrite to NO with rates directly proportional to the extent of deoxygenation. The functional importance of HBOC-201-dependent nitrite reduction was demonstrated using isolated aortic rings and a murine model of trauma, haemorrhage and resuscitation. In the former, HBOC-201 inhibited NO-donor and nitrite-dependent vasodilation when oxygenated. However, deoxygenated HBOC-201 failed to affect nitrite-dependent vasodilation but still inhibited NO-donor dependent vasodilation, consistent with a model in which nitrite-reduction by deoxyHBOC-201 counters NO scavenging. Finally, resuscitation using HBOC-201, after trauma and haemorrhage, resulted in mild hypertension ( approximately 5-10 mmHg). Administration of a single bolus nitrite (30-100 nmol) at the onset of HBOC-201 resuscitation prevented hypertension. Nitrite had no effect on mean arterial pressure during resuscitation with LR (lactated Ringer's solution), suggesting a role for nitrite-HBOC reactions in attenuating HBOC-mediated hypertension. Taken together these data support the concept that nitrite can be used as an adjunct therapy to prevent HBOC-dependent hypertension.
Rodriguez
Cilina
C
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Vitturi
Dario A
DA
He
Jin
J
Vandromme
Marianne
M
Brandon
Angela
A
Hutchings
Anne
A
Rue
Loring W
LW
Kerby
Jeffrey D
JD
Patel
Rakesh P
RP
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects; D001802:Blood Substitutes / Q000378:metabolism* / Q000494:pharmacology*; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000378:metabolism / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009572:Nitrite Reductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012977:Sodium Nitrite / Q000494:pharmacology* / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D001802:Blood Substitutes; D006454:Hemoglobins; D020030:Nitric Oxide Donors; C096798:HBOC 201; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D009572:Nitrite Reductases; D012977:Sodium Nitrite