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Response by Lundberg et al to Letter Regarding Article, "Hemoglobin 93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell" The idea that red blood cells can export nitric oxide bioactivity is fascinating but has been met with skepticism over the years; the most common critique being that nitric oxide should not be able to exit the red blood cells given its extremely rapid reaction with oxygenated hemoglobin. Our present study, along with some other recent reports, give strong support to the notion that nitric oxide bioactivity can be exported from RBCs albeit most likely not in the form of free nitric oxide, and definitely not dependent of the presence of 93Cys in hemoglobin.[1]. [Extracted from the article]

The article focuses on the findings of a study on the approach to modulate the relationship between nitric oxide (NO) and smooth muscle relaxation. Researchers focus on enhancing the effectiveness of the remaining NO available after PBH infusion by using a phosphodiesterase-5 inhibitor (PDE5). Moreover, it states that the results of the study illustrates the potential for a new therapeutic modality targeting the role of cGMP in NO-mediated vaosodilation.

Objectives: Dilutional coagulopathy after resuscitation with crystalloids/colloids clinically often appears as diffuse microvascular bleeding. Administration of fibrinogen reduces bleeding and increases maximum clot firmness, measured by thromboelastometry. Study objective was to implement a model where microvascular bleeding can be directly assessed by visualizing clot formation in microvessels, and correlations can be made to thromboelastometry.Design: Randomized animal study.Setting: University research laboratory.Subjects: Male Syrian Golden hamsters.Interventions: Microvessels of Syrian Golden hamsters fitted with a dorsal window chamber were studied using videomicroscopy. After 50% hemorrhage followed by 1 hour of hypovolemia resuscitation with 35% of blood volume using a high-molecular-weight hydroxyethyl starch solution (Hextend, Hospira, MW 670 kD) occurred. Animals were then treated with 250 mg/kg fibrinogen IV (Laboratoire français du Fractionnement et des Biotechnologies, Paris, France) or an equal volume of saline before venular vessel wall injuries was made by directed laser irradiation, and the ability of microthrombus formation was assessed.Measurements and Main Results: Thromboelastometric measurements of maximum clot firmness were performed at the beginning and at the end of the experiment. Resuscitation with hydroxyethyl starch and sham treatment significantly decreased FIBTEM maximum clot firmness from 32 ± 9 mm at baseline versus 13 ± 5 mm after sham treatment (p < 0.001). Infusion of fibrinogen concentrate significantly increased maximum clot firmness, restoring baseline levels (baseline 32 ± 9 mm; after fibrinogen administration 29 ± 2 mm). In vivo microthrombus formation in laser-injured vessels significantly increased in fibrinogen-treated animals compared with sham (77% vs 18%).Conclusions: Fibrinogen treatment leads to increased clot firmness in dilutional coagulopathy as measured with thromboelastometry. At the microvascular level, this increased clot strength corresponds to an increased prevalence of thrombus formation in vessels injured by focused laser irradiation. [ABSTRACT FROM AUTHOR]

The development of oxygen (O2)-carrying blood substitutes has evolved from the goal of replicating blood O2 transport properties to that of preserving microvascular and organ function, reducing the inherent or potential toxicity of the material used to carry O2, and treating pathologies initiated by anemia and hypoxia. Furthermore, the emphasis has shifted from blood replacement fluid to "O2 therapeutics" that restore tissue oxygenation to specific tissues regions. This review covers the different alternatives, potential and limitations of hemoglobin-based O2 carriers (HBOCs) and perfluorocarbon-based O2 carriers (PFCOCs), with emphasis on the physiologic conditions disturbed in the situation that they will be used. It describes how concepts learned from plasma expanders without O2-carrying capacity can be applied to maintain O2 delivery and summarizes the microvascular responses due to HBOCs and PFCOCs. This review also presents alternative applications of HBOCs and PFCOCs namely: 1) How HBOC O2 affinity can be engineered to target O2 delivery to hypoxic tissues; and 2) How the high gas solubility of PFCOCs provides new opportunities for carrying, dissolving, and delivering gases with biological activity. It is concluded that the development of current blood substitutes has amplified their applications horizon by devising therapeutic functions for O2 carriers requiring limited O2 delivery capacity restoration. Conversely, full, blood-like O2-carrying capacity reestablishment awaits the control of O2 carrier toxicity.

Objective: To determine how top loads with different doses of carbon monoxide (CO)-saturated saline solutions (CO-saline) affect microvascular and systemic hemodynamics and to delineate the corresponding biochemical mechanisms., Design: Prospective study., Setting: University research laboratory., Subjects: Male Golden Syrian hamsters., Interventions: Hamsters implemented with a dorsal window chamber were given different volumes (characterized as percent of blood volume, BV) by intravenous injection of CO-saturated saline., Measurements and Main Results: Hamsters were observed until 90 mins after infusion of CO-saline solution. In the 20% BV CO-saline infusion group, observation was extended until 180 mins. Systemic variables measured included mean arterial pressure, heart rate, systemic arterial blood gases, and cardiac output and index. Microvascular hemodynamic measurements included vessel diameter, red blood cell velocity, and functional capillary density. Cyclic guanosine monophosphate (cGMP) content in the chamber tissue was measured by enzyme immunoassay. 10% BV of CO-saline increased flow maximally in the microcirculation at 30 mins after infusion (207% in arterioles and 238% in venules, p < .05 vs. baseline). Functional capillary density was significantly increased in both 10% and 15% groups (p < .05 vs. baseline), and cardiac index increased 130% (p < .05 vs. baseline) at 10 mins after 10% CO-saline infusion. There were no changes of microhemodynamic variables and functional capillary density with 2.5%, 5%, and 20% CO-saline infusion during the observation period. Microvascular hemodynamic changes by 10% CO-saline infusion were inhibited completely by L-NAME pretreatment and partially by 1H-[1,2,4]oxadiazole[4,3-a]quinoxqalin-1-one pretreatment. cGMP content in skin fold tissues was related to changes of vessel diameter., Conclusions: Intravenous injection of CO-saturated saline caused vasodilation and improved microvascular hemodynamics in the hamster window chamber model in a dose-dependent manner. These changes were related to increased cardiac output and local cGMP content. These results support the possible use of CO-saturated solutions as a vasodilator in critical conditions.