20-HETE-mediated vasoconstriction by hemoglobin-O₂carrier in Sprague-Dawley but not Wistar rats

Abstract

thetically either decreased nitric oxide (NO) or increased O 2 could initiate 20-HETE-mediated vasoconstriction associated with hemoglobin-based blood substitutes (HBOC). To test this hypothesis, we infused Tm-Hb, an HBOC with low O 2 affinity, into isofluraneanesthetized Wistar (W) and Sprague-Dawley (SD) rats after exchanging 20% of their blood with Ringer lactate. For comparison we infused an equal amount of BSA or BSA with N G -nitro-L-arginine methyl ester (BSAϩNAME). Tm-Hb increased blood pressure (BP) and renal vascular resistance (RVR) equally in W and SD rats. Renal blood flow (RBF; Doppler ultrasound) decreased. BSA decreased RVR and raised glomerular filtration rate. BSAϩNAME raised BP, RVR, and GFR. HET0016, an inhibitor of 20-HETE production, blunted BP and RVR responses to Tm-Hb and BSAϩNAME in SD but not W rats. Arterial O 2 content with BSA was lower than with Tm-Hb but O2 delivery was 60% higher with BSA because of higher RBF. BSA raised PO 2 (Oxylite) in cortex and medulla and reduced RVR. Tm-Hb decreased PO2 and increased RVR. Switching rats from breathing air to 100% O 2 raised intrarenal PO2 two-to threefold and increased BP and RVR. HET0016 did not alter hyperoxic responses. In conclusion, 20-HETE contributes to vasoconstriction by Tm-Hb in SD but not in W rats, and increased 20-HETE activity results primarily from decreased NO. blood substitutes; kidney; nitric oxide; N -nitro-L-arginine methyl ester; autoregulation; blood pressure IF THEY DID NOT INCREASE vascular resistance, relatively small amounts of cell-free hemoglobin could effectively replace blood in hemorrhaged rats (29). Unfortunately increased vascular resistance has limited the effectiveness of most hemoglobin-based oxygen carriers (HBOC). Two primary triggers for HBOC-induced vasoconstriction have been identified: nitric oxide (NO) scavenging and O 2 -mediated autoregulation. The potent vasconstrictor 20-HETE (1, 6, 28) could be involved in the vascular response to either of these stimuli, because it is known to mediate vasconstriction in response to increased PO 2 (12) and decreased NO (16).The vascular response to NO scavenging by HBOC has been recognized for many years. More recently O 2 -mediated autoregulatory vasoconstriction by HBOC with low O 2 affinity has been postulated (19). By releasing O 2 in small arteries and arterioles, low-affinity HBOCs could stimulate 20-HETE production, which is linearly related to PO 2 between 20 and 140 mmHg, with half-maximal production at ϳ60 mmHg in renal arterioles (5). Increased 20-HETE production plays an important role in the response to hyperoxia (20) and accounts for up to 80% of the vasoconstrictor response to raised tissue PO 2 in cremaster muscles (4). 20-HETE production is also increased when tonic inhibition by NO and its by-products is reduced by inhibiting NO synthase (1, 6). 20-HETE contributes significantly to the renal vascular response after L-NAME inhibition of NO synthase in Sprague-Dawley rats (6).The following experiments were designed to examine the role of 20-H...

20-Hydroxyeicosatetraenoic Acid is a Potential Therapeutic Target in Cardiovascular Diseases

“…Also carbon dioxide (CO 2 ) was found to modulate CYP4As and control the levels of 20-HETE which mediate cerebrovascular reactivity in response to changes in partial pressure of CO 2 in the arterial blood (PaCO 2 ); CO 2 decreases the expression of brain CYP4As during hypercapnia while increasing its expression during hypocapnia [44]. Vasoconstriction associated with hemoglobin-based blood substitutes was supposed to be a result of 20-HETE stimulation by decreased NO production or increased O 2 consumption [45]. 20-HETE was also reported to be responsible for oxygen contraction in the systemic microvasculature [46].…”

Intrinsic Toxicity of Hemoglobin: How to Counteract It

“…They proposed the “autoregulation theory” where increased diffusive oxygen delivery paradoxically decreased oxygen uptake by the tissue because of vasoconstriction (49). Hb‐based oxygen carriers with low oxygen affinity (high P 50 ) by increasing pO 2 in small vessels, stimulate production of 20‐hydroxyeicosatetraenoic acid (20‐HETE) (50). 20‐HETE contributes to arteriolar constriction to prevent over‐oxygenation.…”