Xin-sheng Deng M.D. Victoria J. Simpson M.D., Ph.D. and Richard A. Deitrich Ph.D.
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado, USA 80262
Key Words: Propofol; nitric oxide; antioxidant; anesthetic.
Corresponding author: Xin-sheng Deng
Propofol, an intravenous anesthetic, is similar in chemical structure to the active nucleus of antioxidant substances such as alpha-tocopherol (vitamin E), butylhydroxytoluene and acetylsalicylic acid (aspirin). Recent studies have demonstrated that some effects of propofol may lie in its antioxidant properties and the likely involvement of nitric oxide. This review article focuses on the relationship between nitric oxide and propofol. There is an implication that nitric oxide is responsible for the hemodynamic responses of propofol. The antioxidant effect of propofol may also extend its anesthetic application.
Propofol is a rapidly acting intravenous anesthetic agent that has gained widespread acceptance for anesthesia and sedation. The rapid and complete recovery profile associated with propofol offers advantages over other injectable anesthetic agents (1,2). Administration of propofol produces pronounced hemodynamic responses, particularly the decrease in arterial blood pressure (3-11). Published reports have not agreed as to the mechanism of propofol-mediated hypotension, but some investigators have attributed significant decrease in systemic vascular resistance to the blood vessel-dilation property of propofol to (12,13) with the likely involvement of endothelium-derived relaxing factor (nitric oxide) (14). Most importantly, propofol has been found to bear antioxidant capacity due to its structural similarity to -tocopherol (15-43), which is strongly related to free radicals. At this point propofol is not only an anesthetic agent but also an antioxidant drug. In this review, we have focused on published literature relating to free radical nitric oxide and its oxidative reaction with propofol.
Formation, decomposition and reactivity of nitric oxide
Nitric oxide (NO) is an
inorganic gas synthesized by the enzyme nitric oxide synthase (NOS) in which
amino acid L-arginine is oxidized to NO and equal amount of L-citrulline(44-46).
Three NOS isoforms have been identified: neuronal NOS (nNOS),
endothelial NOS (eNOS), and iNOS (47). The former two isozymes are constitutively expressed (constitutive NOS) and have physiologic roles; the last is usually present only after the induction by inflammatory stimuli.
Figure One: Nitric oxide formation, decomposition, transportation and reaction.
The genes encoding eNOS, nNOS and iNOS have been cloned and sequenced (47-49). These isoenzymes are distinct and located on different chromosomes (7, 12 and 17, respectively). They are structurally related to the cytochrome p-450 supergene family and consist of a single polypeptide chain containing L-arginine, heme and calmodulin binding sites as well as a complete NADPH diaphorase. Required co-factors include oxygen, NADPH, calcium (constitutive NOS) and tetrahydrobiopterin (50, 51).
Neuronal NOS (nNOS) is mainly distributed in the nervous system. NO from nNOS functions as a neurotransmitter (52-58) in long-term potentiation (59), gonadotropin secretion (60-64), sexual behavior (65-69), regulates emotional behaviors (70, 71) and autonomic outflow to the cardiovascular system (72,73). nNOS is also present in the kidney (74), skeletal muscle (75-77) and myocardium (78), as well as pancreatic islets (79, 80).
Endothelial NOS is predominately present in the endothelium of blood vessels. NO released from endothelium is found as endothelium-derived relaxing factor, or EDRF, which modulates vascular tone and accommodates change in blood flow (81-84). Endothelial NOS is also present in some immune cells (85, 86). Accordingly, eNOS 'knockout" mice are routinely hypertensive (87-93).
Inducible NOS is expressed in tissues of the immune system (macrophages, leukocytes and other phagocytic cells) on stimulation with cytokines and/or endotoxin (94-96), vascular smooth muscle (94, 97), endothelium (97, 98), kidney (mesangium, tubules) (99,100) and other sites (pancreas, liver, enterocytes, airway, pneumocytes) (101-113). NO from iNOS is present in a large amount. It exerts antimicrobial, cytotoxic effects and immunoregulation (cytokine production, apoptosis and signalling) in the immune system. Therefore, inducible NOS knockout mice exhibit loss of immune function and minor hypotension (113-121).
NO functions by diffusion to kill bacteria and other microbial pathogens (122-124) or possibly acts at the enzyme guanylyl cyclase levels and augmenting cyclic guanosine monophosphate (cGMP) production (125-129). Compared with neurotransmitter receptors or related adenylyl and guanylyl cyclases (130,131), the NO receptor enzyme appears rather unremarkable. It is composed of two different subunits, but only two isoforms have been shown to exist at the protein level: the 11 isoform, which is expressed widely, and the 21 isoform present in human placenta (132-134). Several receptor systems, including N-methyl-D-aspartate (NMDA) (135, 136), muscarinic (137, 138), and gamma-aminobutyric acid ( -GABA) receptors (139, 140) and A2-adrenoceptors (141), have been shown to mediate their action via the NO-cGMP pathway.
NO is a labile species with a half-life of only a few seconds in biological systems. It degrades rapidly to NO2- (nitrite). Nitrite is unstable and it is further converted to the end product NO3- (nitrate). Putative intermediate metabolites include an array of low and high molecular weight thiols--nitrosoglutathione, nitrosoalbumin, S-nitrosohaemoglobin (142). This is not only a mechanism for scavenging NO but also serves to transport NO and is the molecular basis for biological effects in its own right. In the presence of O2, NO reacts with O2- to form ONOO- (peroxynitrite) and other NO radicals as well. Overproduction of NO can lead to cytotoxicity. NO rapidly oxidizes sulfhydryl groups and thioethers in peptide, proteins and lipids (143). In addition, NO nitrates and hydroxylates aromatic compounds, including guanosine (DNA damage) (144), benzene (145, 146)), tyrosine (147), tryptophan (148), 4-hydroxyphenylacetic acid (149), and -tocopherol (150). These deleterious effects of peroxynitrite may disturb cell-signalling processes (Fig. 1).
Structural formulae of propofol, alpha tocopherol, butylhydroxytoluene and acetylsalicylic acid. There is a hydroxyl subsitituent and a benzene group in all four compounds.
Propofol and its clinical relevance with NO
Propofol (2,6-diisopropylphenol) is an intravenous anesthetic that is widely used for both induction and maintenance of general anesthesia. The pharmacokinetics of propofol is best described by a three-compartment model: the central compartment, the shallow peripheral compartment and the deep peripheral compartment. Of the greatest importance is the rapid clearance of propofol (rapid and complete recovery), which is approximately ten times faster than that of thiopental. This made propofol the best controllable intravenous hypnotic from a pharmacokinetic point of view (1,2, 151) Its clinical uses include ambulatory anesthesia, monitored anesthesia care, neuroanesthesia, cardiac anesthesia, pediatric anesthesia and sedation in the intensive care unit (2).
Use of propofol for induction of anesthesia causes decrease in arterial pressure and systemic vascular resistance. Systolic arterial pressure (SAP) is decreased after the start of induction ; diastolic pressure (DAP) is decreased at 60 s after start of induction and further decreases are seen until 210 s after induction (6). The precise mechanism(s) of propofol-induced hypotension is not known. Many studies have attributed the hypotensive responses to decreases in peripheral resistance. This can be prevented by effective volume loading (152), but cannot be attenuated by administration of a fluid preload (10). Induction of anesthesia with an opioid-benzodiazepine combination followed by a maintenance infusion of propofol, supplemented with an inhalational agent or opioid analgesic or both, appears to control blood pressure as well (2). Some studies suggested that propofol-mediated hypotension is due in part to an inhibition of the sympathetic nervous system (153) and to an impairment of baroreflex mechanism (154). A reduction in plasma norepinephrine concentrations after propofol has been demonstrated also (155). Recently, a possible involvement of endothelium-derived relaxing factor or nitric oxide was proposed in the rapid onset of vasodilatation produced by propofol (14). It was reported that propofol stimulated nitric oxide release from cultured porcine aortic endothelia cells and an inhibitor of NO blocked the effects of propofol (156). In a different study, propofol showed a contractile effect in isolated aortas from spontaneously hypertensive rats in the present of a nitric oxide inhibitor (157). However, another study examined the effects of propofol on rat aortic and pulmonary artery rings and demonstrated a marked relaxation, which was endothelium-independent (158). In addition, the same effect was observed in isolated mesenteric arteries from humans (159). Further studies on the mechanism responsible for the reduction in systemic vascular resistance and hypotension of propofol are needed.
Antioxidant activity of propofol
Free radicals are believed to contribute the tissue injuries associated with many pathological processes such as ischemia, tissue anoxia, inflammatory process, infection, carcinogenesis, neurodegenerative disorder and diabetes (160-162). In such diseases, antioxidants can protect tissues by inhibiting lipid peroxide formation or increasing the activity of the glutathione antioxidant system, among other mechanisms (34, 163).
Propofol has a structure (2,6.diisopropylphenol) similar to that of known antioxidants (Fig. 2), such as tocopherol (vitamin E), acetylsalicylic acid and butylhydroxytoluene (16, 17, 34, 164).
The ability of propofol to inhibit the formation of lipid peroxides has been found in several media in which free radicals are produced, e.g., liver and brain microsomes in the rat (16), liver mitochondria in the rat (18, 23), and chemical media enriched in arachidonic acid or linoleic acid (17, 25). Using normal rat tissues (36) and an in vitro model of cerebral anoxia in the rat, it was found that the antioxidant effect of propofol is manifested not only as an inhibition of lipid peroxidation, but also as a decrease in tissue consumption of glutathione (34).
Studies in animals show that propofol, indeed, reduces the formation of lipid peroxides (16, 18, 23, 34, 36). In humans, there was no effect on plasma lipid peroxide levels in patients given propofol (22). However, others showed an increase in plasma antioxidant capacity in patients anesthetized with propofol (31, 33). The highest levels of peroxides occur in cell membranes, rather than in plasma, and the antioxidant glutathione pathway is an important intracellular antioxidant system. In a group of surgical patients who were given propofol anesthesia, propofol showed antioxidant effects as evidenced by the inhibition of lipid peroxidase production in the platelet membrane and changes in the glutathione antioxidant system (42). In other experiments, propofol enhanced red blood cell antioxidant capacity in swine and humans (32).
Propofol, like other phenol-based antioxidant compounds, also acts directly as a free radical scavenger. Studies on the ameliorating effect of propofol in inhibiting radical production revealed that it preferentially scavenges organoradical species. In aqueous
suspension it is more efficient than butylated hydroxy-toluene (BHT) as a free radical scavenger of riboflavin radicals and in blocking formation of malondialdehyde degradation products generated from lipid hydroperoxides of arachidonic acid (20). In additional experiments it was found, using electron spin resonance (ESR), that propofol reacted with oxygen free radicals or peroxynitrite to form phenoxyl radical (17, 165). Moreover, it was demonstrated employing mass spectrometry, that propofol could react with NO to generate nitro-propofol in vitro (forming phenoxyl radical) (166). Thus, propofol is a peroxynitrite scavenger. Because of these reactions, propofol has neuroprotective properties against injuries caused by ischemia/reoxygenation (34, 167-169). Also, propofol prevents and reverses the inhibition of excitatory amino acid uptake in astrocytes exposed to tert-butyl hydroperoxide. The ability of propofol to defend against peroxide-induced inhibition of glutamate clearance may prevent the pathologic increase in extracellular glutamate at synapses, and thus delay or prevent the onset of excitotoxic neuronal death (40, 170). Furthermore, propofol had a protective effect in neurons against acute mechanical injury (171). A water-soluble prodrug of propofol protects from neuronal cell death from oxidative injury caused by glutamate (43). This is consistent with the clinical observation that use of propofol is associated with significant cerebral protection. The same protection was obtained in heart reperfusion injury. Isolated perfused Wistar rat hearts were subjected to either warm global ischaemia (Langendorff) or cold St. Thomas' cardioplegia (working heart mode) in the presence or absence of propofol. It was found that with the presence of propofol the heart injuries were significantly less, probably as a result of diminished oxidative stress (172). In isolated, working rat hearts subjected to ischemia, followed by reperfusion, it was observed that propofol attenuated mechanical dysfunction, metabolic derangement, and lipid peroxidation during reperfusion (24, 173). Additional experiments demonstrated that in vivo, propofol ameliorated dysfunction of the myocardium but not of the coronary endothelium resulting from brief ischaemia and reperfusion. The protection may be related, at least in part, to its ability to reduce lipid peroxidation (174).
However, the antioxidant properties of propofol are different depending on the formulation of propofol. Propofol inhibited the chemiluminescence (CL, a measure of oxidative stress) produced by stimulated polymorphonuclear (PMN) leukocytes in a dose dependent manner (until 5 x 10 -5 M, a clinically relevant concentration), while Diprivan (the commercial form of propofol) and intralipid (IL, vehicle solution of PPF in Diprivan, composition: 1.2% egg phosphatide, 2.25% glycerol) were not dose-dependent inhibitors. The CL produced by endothelial cells was dose-dependently inhibited by Diprivan and PPF, and weakly by IL (not dose-dependent). In cell free systems, dose-dependent inhibitions were obtained for the three products with a lower effect for IL. Diprivan efficaciously protected endothelial cells submitted to an oxidant stress, while IL was ineffective. By HPLC, it was demonstrated that PPF was not incorporated into the cells. The drug thus acted by scavenging the active oxygen species released into the extracellular medium. IL acted in the same manner, but was a less powerful antioxidant (38).
In conclusion, there is an implication that propofol enhances NO production in vascular system and that NO is probably responsible for the hypertension. The unique antioxidant ability and free radical scavenger of propofol may lead to further broaden its current clinical application in the future.
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First Published: September 2003
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