Control of Plasma Nitric Oxide Bioactivity by Perfluorocarbons

Abstract

Background-Perfluorocarbons (PFCs) are promising blood substitutes because of their chemical inertness and unparalleled ability to transport and upload O 2 and CO 2 . Here, we report that PFC emulsions also efficiently absorb and transport nitric oxide (NO). Methods and Results-Accumulation of NO and O 2 in PFC micelles results in rapid NO oxidation and generation of reactive NO x species. Such micellar catalysis of NO oxidation leads to formation of vasoactive S-nitrosothiols (RSNO) in vitro and in vivo as detected electrochemically. The efficiency of PFC-mediated S-nitrosation depends on the amount of PFC in aqueous solution. The optimal PFC concentration that produced the maximum level of RSNO was Ϸ1% (vol/vol). Larger PFC amounts were progressively less efficient in generating RSNO and functioned simply as NO sink. These results explain the characteristic hemodynamic effects of PFCs. Intravenous bolus application of PFC (0.14 g/kg, Ϸ1% vol/vol) to Wistar-Kyoto rats decreased mean arterial pressure significantly (Ϫ10 mm Hg over 40 minutes). PFC-induced hypotension could be further stimulated (Ϫ17 mm Hg over 140 minutes) by exogenous thiols (cysteine and glutathione). In contrast, a larger amount of PFC (1 g/kg, Ϸ7% vol/vol) exhibited a strong hypertensive effect (11 mm Hg over 40 minutes). Conclusions-The present study reveals a physiologically significant pool of endogenous plasma NO and underscores the crucial role of the circulating hydrophobic phase in modulating its bioactivity. The results also establish PFC as a conceptually new pharmacological tool for various cardiovascular complications associated with NO imbalance.

Dietary Nitrate, Nitric Oxide, and Cardiovascular Health

“…A wide variety of techniques have been used to measure NO status including photolysis chemiluminescence (Hausladen et al, 2007;Wang et al, 2006), spectrophotometry , HPLC (Bryan and Grisham, 2007), GC-MS (Tsikas, 2000), electron paramagnetic resonance spectroscopy (Rocks et al, 2005), electrochemistry (Rafikova et al, 2004), immunological (Jaffrey et al, 2001) and fluorescent based methods (Bryan and Grisham, 2007).…”

Detection of S-nitrosothiols in biological fluids: A comparison among the most widely applied methodologies

“…An alternative assay for plasmatic RSNOs has been proposed, which is essentially based on the formation of NO from RSNOs by using CuCl 2 ; the released NO is in turn detected electrochemically with an NO electrode [4,112]. Values measured with this method are in the 50-1000 nM range for RSNOs and 10 nM for LMM RSNOs in rat plasma.…”

Assessment of nitric oxide signals by triiodide chemiluminescence

“…Additionally, NO can be transported in endocrine or paracrine fashion by reacting with heme iron and cysteine thiols in proteins [hemoglobin (Hb) and albumin] and peptides (glutathione and cysteinlyglycine) to form NO adducts with longer biological lifetimes (3)(4)(5); release of NO bioactivity from stable adducts is effected by allosteric and redox-based mechanisms that alter FeNO or S-nitrosothiol (SNO) reactivity (5,6). An updated discussion of the factors influencing reactivity of S-nitrosohemoglobin, S-nitrosoalbumin, and low-molecular-weight SNO in the context of vasoregulation (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) can be found in supporting information (SI) Text.…”