MXPA97009695A - Liquid emulsion of fluorocarbon as vascular reserve of oxide nitr - Google Patents

Abstract

Compatible fluorocarbon emulsions are used to inhibit the removal of endogenous nitric oxide from the blood flow, and thus inhibit vascular stenosis, vasoconstriction, and any other physiological condition of disturbance that arises wholly or in part from nitric oxide deficiency. endogenous. Fluorocarbon liquid emulsions are also used to improve the effectiveness of intravenous hemoglobin by limiting the ability of methaemoglobin to form nitrous oxide dissolved in the plasma.

Description

LIQUID EMULSION OF FLUOROCARBON AS VASCULAR RESERVE OF NITRIC OXIDE FIELD OF THE INVENTION The present invention relates to the use of liquid fluorocarbon emulsions to treat the conditions of systemic or local diseases resulting, at least in part, from a deficiency in endogenous nitric oxide.

BACKGROUND ART Endogenous nitric oxide is the key in the maintenance of microcirculatory homeostasis. It is biologically formed by the oxidation of L-arginine by the synthesis of nitric oxide. Among other functions, nitric oxide is known to inhibit thrombogenicity, regulate immunity, serve as a neurotransmitter and participate in the healing of wounds. For example, a dramatic increase in the levels of nitrate excretion through urine and the synthesis activity of nitric oxide in tissues has been observed after non-severe burn injuries. Biochemical Journal (United Kingdom) 304/1 pp 201-204 (1994). Nitric oxide is also an effective vasodilator, and its absence locally or systemically is associated with vasoconstriction. It is known to be secreted by vascular endothelial cells, and when released into the underlying vascular wall, it is able to induce relaxation of soft muscle cells, therefore, subsequently, causes vasodilation. The formation of nitric oxide has been shown to play a significant role in the vasodilation induced by the administration of capcamycin in the structures of the oral tissue of a rat such as the gum, tongue and submandibular glands. Research in Experimental Medicine 194/6 pp 357-365 (1994). In addition, the pulmonary administration of nitric oxide has been proposed as an alternative to various vasodilators such as tolazoline, protacillin and nitroprusside in the treatment of pulmonary hypertension and respiratory distress syndrome in newborns. European Journal of Pedia tri cs 153/9 Suppl. 2 pp S7-S11 (1994). However, the nitric oxide that is released from the vascular endothelium in the adjacent plasma of the blood is rapidly depleted by the plasma hemoglobin. The average life of nitric oxide plasma is limited to a few seconds. This continuous loss of nitric oxide from plasma adjacent to the vascular endothelium may limit the effectiveness of endogenously produced nitric oxide. In addition to limiting the effectiveness of nitric oxide produced endogenically, and locally, this low persistence of the plasma gives a pulmonary vasodilator of a specific organ of exogenous nitric oxide. This is because the nitric oxide introduced into the respiratory tract (when breathing an air supplemented with nitric oxide gas) is removed from the circulation by the hemoglobin that passes through the pulmonary arteries. Consequently, only the vascularization of the lungs is affected by this route of nitric oxide administration, and the nitric oxide therapies have limitations to treat pulmonary difficulties, until now. In addition to the removal of nitric oxide dissolved in plasma, the depletion of nitric oxide by hemoglobin has another significant result. Nitric oxide binds to hemoglobin and is known as hemoglobin-deactivated by forming methemoglobin. Although the red blood cells within the hemoglobin are protected from this deactivation by the enzyme system, the extracellular hemoglobin in the surrounding plasma is subject to deactivation by endogenous nitric oxide. Although the average life of nitric oxide plasma is short, its presence may still inhibit the effectiveness of therapies involving the administration of hemoglobin that is external to the cells of red blood cells. This is a particularly important problem for the liposome encapsulated in hemoglobin products.

Thus, there is a need to regulate the presence of nitric oxide dissolved in the plasma. First, the conditions of systemic or local difficulties resulting at least in part from the deficiency of endogenous nitric oxide can be alleviated by extending the life of nitric oxide in the circulating plasma and thus maximizing the diffusion of nitric oxide in the vascular wall to through the circulatory system. In addition, therapies involving the administration of exogenous hemoglobin can be improved by reducing the availability of the methaemoglobin that forms the nitric oxide dissolved in the plasma.

Summary of the Invention The present invention utilizes compatible fluorocarbon emulsions to improve the beneficial effects of endogenously produced nitric oxide, and also improves the efficacy of therapies involving the administration of endogenous nitric oxide. Although fluorocarbon emulsions have been used as carriers of oxygen and delivery agents, their efficacy as carriers of nitric oxide has not been previously recognized or has not been used in the treatment protocols. The relatively high solubility of liquid fluorocarbon gases allows the discontinuous phase of a fluorocarbon emulsion injected intravenously to function as a reserve of nitric oxide. The liquid fluorocarbon droplets provide a separate space in which the nitric oxide dissolved in the plasma can diffuse and remain protected from contact with plasma hemoglobin. Accordingly, the invention provides the use of a fluorocarbon emulsion for the production of drugs to increase the amount and stable life of nitric oxide circulating in the blood of the patient who needs an increase in the amount and stability of life of circulating nitric oxide in which the effective amount of the liquid fluorocarbon emulsion is administered intravenously. Another embodiment of the invention provides the use of the liquid fluorocarbon emulsion for the production of a medicament for decreasing the induced deactivation of the nitric oxide of the exogenous hemoglobin by circulating in the blood flow of a vertebrate animal in which the effective amount of the liquid fluorocarbon emulsion is administered intravenously before or together with the administration of an effective amount of exogenous hemoglobin. Another embodiment of the invention provides the use of a fluorocarbon emulsion for the treatment resulting in whole or in part, from the deficiency in the endogenous nitric oxide in which the effective amount of the fluorocarbon emulsion is administered via intravenously before or together with the pulmonary administration of an effective amount of exogenous nitric oxide. Another embodiment of the invention provides the use of a fluorocarbon emulsion for the production of a drug that promotes vasodilation in which the effective amount of the fluorocarbon emulsion is administered to the patient in need of vasodilation. In accordance with the foregoing, the method for increasing the amount of nitric oxide circulating in the bloodstream of a patient in need of increasing circulating nitric oxide, comprising the intravenous administration of an effective amount of the liquid fluorocarbon emulsion, is presented. The levels of circulating nitric oxide can be improved by pulmonary administration of an effective amount of exogenous nitric oxide, or by dissolving an effective amount of nitric oxide in the fluorocarbon prior to intravenous administration of the fluorocarbon emulsion. Physiological conditions that can be treated more effectively using the methods of the present invention include vasospasm and vascular stenosis. The promotion of nitric oxide will also attenuate the increased peripheral vascular resistance. It is another aspect of the present invention that the treatments involved in the administration of exogenous hemoglobin can be improved with the concurrent administration of liquid fluorocarbon emulsions. Concurrent administration of fluorocarbon will reduce the ability of free nitric oxide in plasma, thereby reducing the deactivation of nitric oxide induced in hemoglobin.

Brief description of the Figure The figure is a graph of renal blood flow measurements in rabbits that were injected with a fluorocarbon emulsion compared to rabbits injected with both a fluorocarbon emulsion and L-NAME, an inhibitor of the production of Nitric oxide.

DETAILED DESCRIPTION OF THE INVENTION Fluorocarbon emulsions present uses both as diagnostic and therapeutic agents. Because fluorocarbon liquids are known to dissolve high concentrations of gases such as oxygen and carbon dioxide, most therapeutic applications of fluorocarbon are related to their ability to transport oxygen, both liquid and fluorocarbon emulsions. aqueous fluorocarbon have been used successfully as oxygen delivery agents. A commercially available fluorocarbon emulsion, Fluosol (Green Cross Corp., Osaka, Japan) can be used as a gas carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Natio, K. Yokoyama, Technical Information Series No. 5 and 7, 1981). In addition, cancer therapies have been developed, involving the supply of oxygen to tumor tissues by means of a fluorocarbon carrier. Inhalation of an oxygen enriched atmosphere has been used before or in conjunction with the intravenous injection of the fluorocarbon emulsion to maximize cancer radiation therapy. U.S. Patent No. 4, 781, 676 to Schweigahrdt et al., Presents the injection of an oxygenated fluorocarbon emulsion directly into the tumor cells, with the objective of improving the effectiveness of radiation therapy in the hypoxic regions. of the mass of the tumor. The oxygen-carrying capacity of liquid fluorocarbons has also led to their use as blood substitutes, and in the applications of partial liquid ventilation, where the subject animal or the patient breathes oxygenated liquid fluorocarbon to deliver oxygen to the lungs even the blood flow. Fluorocarbon emulsions have also been used in diagnostic imaging applications. Radiopaque fluorocarbon such as perfluorooctyl bromide (C8F17Br, "PFOB" or "perflubron") is used for this purpose, and 1-bromoperfluorooctane is particularly preferred. Although there are no models developed to predict the accuracy of gas solubilities in liquid fluorocarbon, the solubilities of gases generally increase with increasing molecular volume. Therefore, nitric oxide could have an intermediate liquid fluorocarbon solubility between molecular oxygen (02) and molecular nitrogen (N2). Based on molecular volume, the solubility of 02 can be estimated at about 20 nM to 37 at a temperature of 37 ° C, while the solubility of N2 can be estimated at about 14 nM. Therefore, nitric oxide appears to have an approximate solubility of 17 nM at a temperature of 37 ° C, which corresponds to about 38% v / v of a fluorocarbon / nitric oxide mixture. The ability of liquid fluorocarbon to deliver clinically significant amounts of nitric oxide to the respiratory tract has been demonstrated in animal studies. In these studies, she induced pulmonary hypertension in six lambs by intravenous administration of U46619 (2 mcg / kg / min). The animals were ventilated both conventionally with an atmosphere containing up to 80 ppm of nitric oxide, and with ventilation by partial liquid ventilation using liquid fluorocarbon containing nitric oxide. In both cases, a reduction in pulmonary arterial pressure and vascular resistance was observed. No difference was observed in the pharmacokinetics of nitric oxide, between nitric oxide administered conventionally or that administered dissolved in liquid fluorocarbon. However, as mentioned above, the problem persists as the clinical effects of nitric oxide therapy are limited to the tissue of the lungs. The present invention provides a method for promoting high levels of nitric oxide in plasma in a subject who needs a concentration of nitric oxide increased in a different part of the body to the vasculature of the lung. The average removal of free nitric oxide from the circulating blood plasma would be reduced if the nitric oxide was separated from the hemoglobin also present. The relatively high solubility of the gases in the liquid fluorocarbon allows the discontinuous phase of the fluorocarbon emulsion injected intravenously to carry out this function. The liquid fluorocarbon droplets provide a separate space in which the nitric oxide dissolved in the plasma can diffuse and remains protected from coming into contact with the plasma hemoglobin. An additional increase in the supply of nitric oxide to tissues and remote organs can be achieved by dissolving nitric oxide in fluorocarbon before injection, unlike the injection of a fluorocarbon emulsion free of nitric oxide, and having diffuse endogenous nitric oxide of the plasma in the emulsion droplets. Therefore, nitric oxide therapies are improved by the concurrent use of intravenously injected fluorocarbon emulsions. The fluorocarbon emulsion comprises a continuous aqueous phase and a discontinuous liquid fluorocarbon phase. Methods of creating compatible fluorocarbon emulsions suitable for intravenous injection into an animal or a human are known to those skilled in the art. Although the fluorocarbon particle size is not particularly crucial when the emulsion is used in non-venous systems in the body such as the ventricles and cavities of the cerebrospinal fluid, for intravenous use, it is preferable to have a particle size small, preferably about 0.05 to 0.3 microns. Larger particle sizes are dangerous because they tend to collect in the liver, spleen, lungs and some other organs, enlarging them and hindering their function. Typically, the emulsion is stable with an emulsifying agent. Biocompatible osmotic agents and pH buffers are included in the aqueous phase to maintain biologically stable osmolarity and pH. The maintenance of normal osmolarity, that is between approximately 290 to 300 milliosmoles, can help to avoid damage to cells such as red blood cells and vascular endothelial cells, which come into contact with the emulsion after injection. However, in some applications, remarkable oxygenation during cardiopulmonary bypass, it has been found that the performance of the emulsion improves by providing a solution of high osmolarity, preferably about 700 or 800 milliosmoles. This aspect of the fluorocarbon emulsion used is described in U.S. Patent No. 5,114,932 to Runge, the mention of which is incorporated herein by reference. A large number of various commercially available fluorocarbons and combinations thereof are known to make suitable emulsions. The fluorocarbon onobrominated, such as operfluorooctyl bromide (C8F17Br, "PFOB" or "perflubron"), 1-bromopentadecafluoroseptan (C7F15Br), and 1-bromotridecafluorohexane (C6F13Br, perfluorohexylbromu.ro, or "PFHB") are known to make suitable emulsions and are also known to have high solubility of oxygen. Preferably, the fluorocarbon present in the aqueous phase at about 5-125% by weight in grams for an emulsion volume in millimeters. The emulsifying agent may comprise a surfactant such as for example lecithin, a polyoxyethylene-polyoxypropylene copolymer, or a fatty acid. Fluorinated surfactants are also considered adequate. The ingredients described above are emulsified using the known techniques, for example, by high pressure homogenization in a commercially available microfluidizer. The osmotic agent can be hexahydric alcohol such as for example mannitol, or sorbitol or a sugar such as glucose, mannose or fructose. Osmolarity is also affected by the buffers, which can be selected from imidazole or tri-hydroxymethyl-aminomethane (both are beneficial as they do not precipitate in calcium) or can also be selected from the buffering agents such as sodium chloride, sodium bicarbonate, magnesium chloride, mono or di basic potassium phosphate, calcium chloride, magnesium sulfate, or sodium bicarbonate mono or di base. The compatible combinations of these agents provided for the reduction of damage in the red blood cells in vivo and in vitro for the reduction of the viscosity and for the reduction in the average of oxidation. Those liquid fluorocarbon emulsions that are effective as oxygen carriers will also have sufficient nitric oxide solubility to be effective in terms of the promotion of nitric oxide dissolved in plasma. Accordingly, the fluorocarbon emulsions according to the present invention can be prepared to have suitable properties in thermal life, biocompatibility, and particle size stability. Descriptions of some methods for the preparation of biocompatible fluorocarbon emulsions suitable for use with the present invention are presented in U.S. Patent No. 4,895,876 to Sche eighard et al., U.S. Patent No. 4,866,096 to Schweighardt. , in the Patents of the United States No. 4,865,836, No. 4,987,154 and the NO. 4,927,623 to Long, and the international application with No. PCT / US93 / 10286 (International Publication No. WO 94/09625) to Weers et al., The disclosure of which is referred to herein by reference. Thus, in one embodiment of the present invention, a patient in need of vasodilation is given an intravenous dose of a quantity of nitric oxide of the fluorocarbon emulsion. The effect is expected to persist for approximately the average life of the circulating emulsion, which is known to vary with the different fluorocarbons and mixtures thereof, but which is in the order of hours to days. Repetition of the dose is also contemplated. As described above, the nitroxide nitroglycerine function is also useful in conjunction with hemoglobin therapies. In this embodiment of the invention, the patient receiving the exogenous hemoglobin receives an effective, protective amount of the hemoglobin from the fluorocarbon emulsion prior to or in conjunction with or immediately after the administration of the hemoglobin. In another embodiment of the invention, the patient suffering from any other physiological condition arising entirely, or in part from the deficiency of endogenous nitric oxide is provided an effective amount of nitric oxide of the intravenous fluorocarbon emulsion. The physiological conditions that can be treated with this therapy include circulatory shock, arteriosclerosis and restensis followed by vascular damage. In any of these treatments, the amount of the fluorocarbon emulsion administered is generally between about 0.5 and 5.0 g-PFC / kg, more preferably from about 1.0, 1.2 nitric oxide 1.4 g-PFC / kg to about 1.6, 2.0 nitric oxide 3.0 g-PFC / kg, expressed as the total weight in grams of the fluorocarbon administered in the emulsion per kilogram of body weight. Due to the physiological changes, more particularly the hemodynamic changes, associated with the administration of fluorocarbon emulsions are relatively easy to measure, the optimal dose for any particular disease or condition can be determined without the proper experimentation to determine the dose / response ratio for a particular fluorocarbon in the patient. Some therapies could also be improved by including an exogenous nitric oxide in the emulsion before injection. To achieve this, methods known in the art for dissolving gas in the discontinuous phase of the fluorocarbon emulsions can be used. Due to the use of fluorocarbon emulsions as oxygen delivery agents, these techniques have been previously applied in fluorocarbon oxygenation. In the simplest embodiment, the gas and liquid fluorocarbon are contacted. Blood oxygenators and the like are examples of suitable commercially available equipment. In an exemplary process, the emulsion is placed in a flexible bag with the gas to be dissolved in the fluorocarbon. This method has the advantage that, in fact, fluorocarbon and fluorocarbon emulsions tend to form a layer or film on the inner surface of the flexible container due to the low surface tension of the emulsion. Preferably, the emulsion fills less than half the bag when the bag is inflated with the gas. After the bag is inflated with the appropriate gas, the bag moves around and rotates in such a way that the emulsion coats the inner surface of the bag in the form of a film. Then, the gas dissolves easily in the discontinuous phase of the fluorocarbon. This and other methods of gas dissolution are described in U.S. Patent No. 4,927,623 to Long, incorporated herein by reference, in accordance with the present invention, the gas is preferably nitrogen mixed with an effective amount of nitric oxide. . The concentration of nitric oxide in the gas to be dissolved can vary widely, from almost zero to 50, 80 nitric oxide 100 ppm or higher. Nitric oxide can also be delivered to the emulsion in vivo by exposing the subject to an atmosphere containing nitric oxide after or in conjunction with the intravenous injection of the biocompatible emulsion as described above. The concentration of nitric oxide in the inhaled gas can vary widely. This method of nitric oxide administration has been shown to be effective at concentrations below 5 ppm. Preferably, the inhaled gas will be from 20 to 150 ppm of nitric oxide. Therapies involving the exogenous nitric oxide inhalation are well known in the art. Some are described in more detail in Lancet 340: 818-819 (1992), J. Pediatrics 122: 743-750 (1993), J. Pediratrics 123: 103-108 (1993) and N. Eng. J. Med. 329 : 207 (1993), whose presentation is incorporated herein by reference. In this embodiment of the present invention, the amount of fluorocarbon emulsion administered is also generally, between about 0.5 and 5.0 g-PFC / kg, more preferably from about 1.0, 1.2 or 1.4 g-PFC / kg up to about 1.6, 2.0 nitric oxide 3.0 g-PFC / kg, expressed as the total weight in grams of the fluorocarbon administered in the emulsion per kilogram of body weight. Again, the optimal dose for a particular disease or condition can be determined without performing an experiment by determining the dose / response relationship for a particular fluorocarbon in a patient. NeverthelessIt can be emphasized that the benefits of the fluorocarbon emulsion as a nitric oxide reserve is not limited to therapies involving the administration of exogenous nitric oxide. The fluorocarbon droplets in the blood flow provide a protective separation in which the nitric oxide in the plasma will diffuse, thereby promoting the levels of nitric oxide in the blood flow, especially in those tissues where the fluorocarbon has a collect. It can also be noted that the administration of the fluorocarbon emulsion associated with the introduction of exogenous hemoglobin is preferably carried out without adding nitric oxide either in the fluorocarbon or in the respiratory tract.

EXAMPLE Increase of blood flow in the kidney of a rabbit after the injection of a perflubron emulsion Seven rabbits were anesthetized and a device for measuring Doppler flow in the renal artery was installed. After an appropriate period of stabilization and continuous anesthesia, the rabbits were injected intravenously with 2.7 g-PFC / kg 90% w / v of a perflubron emulsion stabilized with egg yolk phospholipid (type AF104, Alliance Pharmaceutical , San Diego, CA) while monitoring the effects of renal vasodilation.

Subsequently, after the renal flow returned to the baseline, three of the rabbits were injected with 10 mg / kg L-NAME, an inhibitor of endothelial nitric oxide production. The seven rabbits were injected intravenously again with 2.7 g-PFC / kg of a perflubron emulsion (type AF104, Alliance Pharmaceutical, San Diego, CA) while monitoring the effects of renal vasodilation. The figure illustrates the response of the renal blood flow of the rabbits for the second intravenous administration of the liquid fluorocarbon emulsion. As can be seen in the figure, the emulsion produces only a 60% increase in blood flow in the kidney in 5 minutes and persists for more than 30 minutes. In contrast, injection with L-NAME (N6 nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthases, reduces or eliminates the increase in blood flow. This indicates that the sufficient amount of fluorocarbon taken from endogenous nitric oxide increases the life of stable nitric oxide in the plasma and therefore improves the renal vasodilation induced by nitric oxide. The foregoing description details certain preferred embodiments of the present invention and describes the best way to contemplate it. However, it will be appreciated that no matter how detailed is presented in the text, the invention can be practiced in many forms and the invention should be constructed in accordance with the appended claims and any equivalence thereof.

Claims (26)

1. The use of a liquid fluorocarbon emulsion in a form suitable for intravenous administration, to produce a medicament that increases the amount and stable life of the nitric oxide circulating in the blood flow of a patient who needs an increase in the amount and the stable life of circulating nitric oxide.

2. The use of a liquid fluorocarbon emulsion in a form suitable for intravenous administration, for the manufacture of a medicament for reducing the nitric oxide-induced deactivation of the exogenous hemoglobin circulating in the blood flow of a vertebrate animal.

3. The use of a fluorocarbon emulsion in a suitable form of intravenous administration, for the preparation of a medicament for the treatment of conditions that result, in whole or in part, from the deficiency of endogenous nitric oxide.

4. The use of a fluorocarbon emulsion in a suitable form of intravenous administration for the preparation of a medicament that promotes vasodilation in a patient that requires it.

5. The use according to claim 1 or 4, wherein the effective amount of the exogenous nitric oxide is administered pulmonarily.

6. The use according to claim 1 or 4, wherein the effective amount of nitric oxide is dissolved in fluorocarbon prior to intravenous administration of the fluorocarbon emulsion.

The use according to claim 1, wherein the fluorocarbon in the emulsion comprises perfluorooctylbromide.

8. The use according to claim 1, wherein the patient is a human.

9. The use of liquid fluorocarbon emulsion to increase the amount and stable life of nitric oxide circulating in a patient's blood flow, which needs an increase in the amount and stable life of circulating nitric oxide, using an amount Effective liquid fluorocarbon emulsion, which is administered intravenously.

10. The use of a liquid fluorocarbon emulsion to reduce the nitric oxide-induced deactivation of the exogenous hemoglobin circulating in the blood flow of a vertebrate in which an effective amount of the liquid fluorocarbon emulsion is administered is administered intravenously before or together with the administration of an effective amount of exogenous hemoglobin.

11. The use of a fluorocarbon emulsion for the treatment of conditions that result, in whole or in part, from the deficiency in the endogenous nitric oxide in which the effective amount of a fluorocarbon emulsion is administered via intravenously before or together with the pulmonary administration of an effective amount of exogenous nitric oxide.

12. The use of a fluorocarbon emulsion to promote vasodilation by administering intravenously an effective amount of the fluorocarbon emulsion to 1 patient in need of vasodilation.

13. The use according to claim 9 or 12, wherein the effective amount of exogenous nitric oxide is administered pulmonarily.

The use according to claim 9 or 12, wherein the effective amount of nitric oxide is dissolved in the fluorocarbon prior to intravenous administration of the fluorocarbon emulsion.

15. The use according to claim 9, wherein the fluorocarbon is the emulsion comprises perfluorobromide.

16. The use according to claim 9, wherein the patient is human.

17. The use according to claim 2, wherein the liquid fluorocarbon emulsion is in combination with exogenous hemoglobin.

18. The use according to claim 3, wherein the liquid fluorocarbon emulsion is in combination with exogenous nitric oxide in a form suitable for pulmonary administration.

19. A method for increasing the amount and stable life of nitric oxide circulating in the bloodstream of a patient who needs an increase in the amount and stable life of circulating nitric oxide, which comprises the intravenous administration of an effective amount of a liquid fluorocarbon emulsion.

The method according to claim 19, further comprising the passage of pulmonary administration of an effective amount of exogenous nitric oxide.

The method according to claim 19, further comprising the step of dissolving the effective amount of nitric oxide in the fluorocarbon prior to intravenous administration of the fluorocarbon emulsion.

22. The method according to claim 19, wherein the fluorocarbon in the emulsion comprises perfluorobromide.

23. The method according to claim 19 wherein the patient is human.

24. A method for reducing the deactivation induced by nitric oxide of exogenous hemoglobin by circulating in the blood of a vertebrate comprising the intravenous administration of an effective amount of a liquid fluorocarbon emulsion before or together with the administration of an effective amount of exogenous hemoglobin .

25. A method for treating conditions resulting in whole or in part, from deficiency in endogenous nitric oxide comprising intravenous administration of an effective amount of a fluorocarbon emulsion before or in conjunction with pulmonary administration of an effective amount of exogenous nitric oxide.

26. A method for promoting vasodilation comprising intravenous administration to a patient in need of an effective amount of a fluorocarbon emulsion.