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P K Moore

Publications and source records attributed to P K Moore.

At least 19 recordsLinked to original sources
PubMed2006

Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide?

BACKGROUND AND PURPOSE: The aim of these experiments was to evaluate the significance of the chemical reaction between hydrogen sulphide (H2S) and nitric oxide (NO) for the control of vascular tone. EXPERIMENTAL APPROACH: The effect of sodium hydrosulphide (NaHS; H2S donor) and a range of NO donors, such as sodium nitroprusside (SNP), either alone or together, was determined using phenylephrine (PE)-precontracted rat aortic rings and on the blood pressure of anaesthetised rats. KEY RESULTS: Mixing NaHS with NO donors inhibited the vasorelaxant effect of NO both in vitro and in vivo. Low concentrations of NaHS or H2S gas in solution reversed the relaxant effect of acetylcholine (ACh, 400 nM) and histamine (100 microM) but not isoprenaline (400 nM). The effect of NaHS on the ACh response was antagonized by CuSO(4) (200 nM) but was unaffected by glibenclamide (10 microM). In contrast, high concentrations of NaHS (200-1600 microM) relaxed aortic rings directly, an effect reduced by glibenclamide but unaffected by CuSO4. Intravenous infusion of a low concentration of NaHS (10 micromol kg(-1) min(-1)) into the anaesthetized rat significantly increased mean arterial blood pressure. L-NAME (25 mg kg(-1), i.v.) pretreatment reduced this effect. CONCLUSIONS AND IMPLICATIONS: These results suggest that H2S and NO react together to form a molecule (possibly a nitrosothiol) which exhibits little or no vasorelaxant activity either in vitro or in vivo. We propose that a crucial, and hitherto unappreciated, role of H2S in the vascular system is the regulation of the availability of NO.

Animals↗
PubMed2006

Effect of a nitric oxide releasing derivative of paracetamol in a rat model of endotoxaemia.

BACKGROUND AND PURPOSE: Nitroparacetamol is a nitric oxide-releasing paracetamol with novel anti-inflammatory properties compared to the parent compound. This study has investigated the anti-inflammatory activity of nitroparacetamol in a model of endotoxaemia in rats to probe the mechanisms underlying this effect. EXPERIMENTAL APPROACH: Nitroparacetamol (92 mg kg(-1)), paracetamol (50 mg kg(-1)) or vehicle were administered to male, Wistar rats 15 min prior to or 3 h after lipopolysaccharide (0.5 mg kg(-1), serotype 0127:B8). Mean arterial pressure and heart rate were measured for 5 h and plasma and organs were then obtained to determine organ dysfunction, inducible nitric oxide synthase and cyclooxygenase-2 expression (lung, liver and kidney tissue) and plasma nitrate/nitrite. In separate experiments, nitroparacetamol, paracetamol or vehicle was administered 1 h before acetylcholine (0.1 microg kg(-1)) or sodium nitroprusside (0.25 microg kg(-1)) to determine if nitroparacetamol desensitizes responses to exogenous/endogenous nitric oxide. KEY RESULTS: Nitroparacetamol prevented but did not reverse the lipopolysaccharide-induced hypotension. There was no effect on heart rate or plasma markers of organ dysfunction. Nitroparacetamol prevented the increased plasma nitrate/nitrite and expression of COX-2 and iNOS, whereas paracetamol exerted partial inhibition of COX-2 in lung alone. Nitroparacetamol also reduced responses to acetylcholine and sodium nitroprusside. CONCLUSIONS AND IMPLICATIONS: NO is the active component of nitroparacetamol in this model of endotoxaemia. Pro-inflammatory processes targeted by nitroparacetamol have been shown to include iNOS/COX-2 induction and possibly vascular soluble guanylyl cyclase. Precise mechanisms underlying the NO effect are unclear but inhibition of cytokine formation may be important.

Acetaminophen↗
PubMed2006

Flurbiprofen and its nitric oxide-releasing derivative protect against septic shock in rats.

OBJECTIVE: Flurbiprofen and nitroflurbiprofen were evaluated in a caecal ligation puncture (CLP) model of septic shock in the rat. METHODS AND RESULTS: CLP (12 h) reduced blood pressure (72.5 +/- 1.0 mm Hg c. f. 101.0 +/- 3.6 mm Hg, P < 0.05), and increased plasma NOx (153.0 +/- 11.5 muM c. f. 36.2 +/- 3.2 microM, P < 0.05), IL-1beta (534.0 +/- 93.1 pg/mL c. f.; 9.6 +/- 9.6 pg/mL, P < 0.05), TNF-alpha (88.0 +/- 13.6 pg/mL, P < 0.05), inflammatory damage in lung and liver, and mortality. Both flurbiprofen (21 mg/kg, p. o.) and nitroflurbiprofen (30 mg/kg, p. o.) prevented the fall in blood pressure (e. g. 80.4 +/- 2.1 mm Hg and 79.8 +/- 1.2 mm Hg respectively, 12 h, P < 0.05), reduced organ damage and prolonged survival. Nitroflurbiprofen (but not flurbiprofen) increased plasma NOx and reduced plasma TNF-alpha concentration at all time points (except 1 h). Neither drug affected plasma IL-1beta-levels. CONCLUSIONS: These results suggest a protective effect of flurbiprofen and nitroflurbiprofen in septic shock.

Animals↗
PubMed2003

Nitric oxide releasing acetaminophen (nitroacetaminophen).

The nitric oxide releasing derivative of acetaminophen (nitroacetaminophen) exhibits potent anti-inflammatory and anti-nociceptive activity in a variety of animal models. On a mol for mol basis nitroacetaminophen is some 3-20 times more potent than acetaminophen. Nitroacetaminophen exhibits little or no hepatotoxicity following administration in rat or mouse and indeed protects against the hepatotoxic activity of acetaminophen. Nitroacetaminophen does not affect blood pressure or heart rate of anaesthetised rats but has similar potency to acetaminophen as an anti-pyretic agent. The enhanced anti-inflammatory and anti-nociceptive activity of nitroacetaminophen and the reduced hepatotoxicity in these animal models is likely to be secondary to the slow release of nitric oxide from the molecule. As yet the precise molecular mechanism(s) underlying these actions of nitroacetaminophen are not clear. Evidence for inhibition of cytokine-directed formation of pro-inflammatory molecule production (e.g. COX-2, iNOS) by an effect on the NF-kappaB transduction system and/or nitrosylation (and thence inhibition) of caspase enzyme activity has been reported. Data described in this review indicate that the profile of pharmacological activity of nitroacetaminophen and acetaminophen are markedly different. The possibility that nitroacetaminophen could be an attractive alternative to acetaminophen in the clinic is discussed.

Acetaminophen↗
PubMed2002

The smooth muscle relaxant effect of hydrogen sulphide in vitro: evidence for a physiological role to control intestinal contractility.

1. Sodium hydrogen sulphide (NaHS), a donor of hydrogen sulphide (H(2)S), produced dose-related relaxation of the rabbit isolated ileum (EC(50), 76.4+/-7.9 microM) and rat vas deferens (EC(50), 64.8+/-5.4 microM) and reduced ACh-mediated contraction of the guinea-pig isolated ileum. 2. NaHS also reduced the response of the guinea-pig (EC(50), 80.0+/-5.7 microM) and rat (EC(50), 108.2+/-11.2 microM) ileum preparations to electrical stimulation of the intramural nerves. In guinea-pig ileum this effect was spontaneously reversible and mimicked by sodium nitroprusside (SNP, EC(50), 2.1 microM). Combination of NaHS (20 microM) with SNP (0.5 microM) produced a greater than additive inhibition of the twitch response of the ileum to electrical stimulation. 3. The inhibitory effect of NaHS on the field-stimulated guinea-pig ileum was unaffected by pretreatment with L-NAME (100 microM), indomethacin (10 microM), naloxone (1 microM) or glibenclamide (100 microM). Furthermore, NaHS (200 microM) did not affect the contractile response of the ileum to KCl (10 to 60 mM). 4. Propargylglycine (PAG, 1 mM) and beta-cyanoalanine (BCA, 1 mM) (inhibitors of cystathionine-gamma-lyase) but not aminooxyacetic acid (AOAA, 1 mM) (inhibitor of cystathionine-beta-synthetase) caused a slowly developing increase in the contraction of the guinea-pig ileum to field stimulation. This effect was reversed by cysteine (1 mM). 5. These results show that NaHS relaxes gastrointestinal and urogenital smooth muscle and suggest that H(2)S is responsible for these effects. The possibility that endogenous H(2)S, formed as a consequence of activation of intramural nerves, plays a part in controlling the contractility of the guinea-pig ileum is discussed.

Alanine↗
PubMed2002

Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs.

This review examines the biological significance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the profile of pharmacological activity of the parent, non-steroidal anti-inflammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-inflammatory and anti-nociceptive efficacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic benefit in a wide variety of disease states including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed.

Animals↗
PubMed2001

A comparison of the effect of nitroparacetamol and paracetamol on liver injury.

Paracetamol (5 mmol kg(-1), i.p.) caused liver damage in rats as indicated by increased plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activities. No change in plasma bilirubin or creatinine was noted. An equimolar dose of nitroparacetamol (a nitric oxide (NO)-releasing derivative of paracetamol) did not alter plasma levels of any of the markers of liver/kidney damage. No difference in plasma or liver paracetamol was apparent in animals injected with paracetamol or nitroparacetamol. These results indicate that NO released from nitroparacetamol exhibits hepatoprotective activity in these animals and suggest that nitroparacetamol may therefore be considered as a safer alternative to paracetamol in the clinic.

Acetaminophen↗
PubMed2001

Vasorelaxant effect of nitric oxide releasing steroidal and nonsteroidal anti-inflammatory drugs.

The effect of several nitric oxide releasing-non-steroidal anti-inflammatory drugs (NO-NSAID) and nitroprednisolone on blood vessel relaxation in vitro and in vivo was studied. Nitroflurbiprofen (NOF; EC(50), 688.8+/-93.8 microM), nitroaspirin (NOA; EC(50), 57.9+/-6.5 microM), nitroparacetamol (NOPARA; EC(50), 71.5+/-14.6 microM) and nitroprednisolone (EC(50), 15.1+/-1.4 microM) caused concentration-related relaxation of noradrenaline (NA)-contracted rat aortic rings. All NO releasing compounds tested were approximately three orders of magnitude less potent than sodium nitroprusside (SNP, EC(50), 35.7+/-3.5 nM). The vasorelaxant effect of NOF and NOPARA in the rat aorta was potentiated by zaprinast (5 microM) and reduced by ODQ (5 microM). Flurbiprofen and paracetamol (100 microM) caused minimal (<10%) relaxation of the rat aorta and did not affect the response to SNP. The effect of NOF was unchanged in the presence of L-NAME (100 microM; EC(30), 181.8+/-35.1 microM cf. EC(30), 125.1+/-17.0 microM, P>0.05) but increased by removal of the endothelium (EC(30), 164.3+/-26.3 microM cf. EC(50), 688.8+/-93.8 microM, P<0.05). NOF (0.1 - 50 microM) produced a small but not concentration-related vasodilation of the NA-preconstricted (i.e. "high tone") perfused rat mesentery preparation (cf. SNP, EC(30), 4.4+/-0.7 microM). In contrast, NOF (1 - 100 microM) produced concentration-related vasodilation of the "high tone" perfused rat kidney with an EC(50) of 33.1+/-4.4 microM. Neither NOF (74 mg kg(-1), i.p.) nor NOA (91.9 mg kg(-1), i.p.) nor equimolar doses of flurbiprofen (50 mg kg(-1), i.p.) or aspirin (50 mg kg(-1), i.p.) affected mean arterial blood pressure (MAP) or heart rate (HR) of pentobarbitone-anaesthetized rats over a 1 h period. NO-NSAID relax blood vessels in vitro by an NO-dependent mechanism. The absolute vasorelaxant effect of NO releasing drug varies greatly with the choice of compound and between blood vessel preparations.

Acetaminophen↗
PubMed2000

A comparison of the anti-inflammatory and anti-nociceptive activity of nitroaspirin and aspirin.

1. Nitroaspirin (2.5 - 50 mg kg(-1), i.p. or 2.5 - 100 mg kg(-1), p.o.) and aspirin (2.5 - 100 mg kg(-1), i.p. or p.o.) exhibit anti-inflammatory activity in the carrageenan-induced hindpaw oedema model in the rat. When administered i.p., nitroaspirin was a more effective anti-oedema agent than aspirin particularly in the 'early' phase (i.e. up to 60 min) of the response. The ED(50) values for nitroaspirin and aspirin as inhibitors of the 'late' phase response (measured at 180 min) were 64.3 micromol kg(-1) and >555 micromol kg(-1), respectively. When administered p.o., neither nitroaspirin nor aspirin exhibited significant anti-inflammatory activity in the 'early' phase and were of similar potency in the 'late' phase. Thus, at the highest dose used (100 mg kg(-1), 360 min) orally administered nitroaspirin (aspirin in parenthesis) inhibited oedema formation by 46.9+/-1.6% (47.2+/-3.8%, both n=6, P<0.05). 2. Nitroaspirin and aspirin (25 - 200 mg kg(-1), p.o.) caused dose-related inhibition of the hyperalgesia to mechanical stimulation following intraplantar injection of carrageenan in the rat. ED(50) values were 365 micromol kg(-1) and 784 micromol kg(-1), respectively. Neither drug influenced the threshold for mechanical stimulation in the contralateral (i.e. untreated) hindpaw. 3. Nitroaspirin and aspirin (2.5 - 100 mg kg(-1), p.o.) caused dose-related inhibition of acetic acid induced abdominal constrictions in the mouse (ED(50) values of 154.7 micromol kg(-1) and 242.8 micromol kg(-1), respectively). 4. Nitroaspirin and aspirin (>200 mg kg(-1), p.o.) reduced the 'late' phase (but not the 'early' phase) of the formalin-induced hindpaw licking assay in the mouse. Similarly, nitroaspirin and aspirin (>50 mg kg(-1), p.o.) prolonged tail withdrawal latency following application of a noxious heat stimulus in the mouse.

Acetic Acid↗
PubMed2000

Nitroparacetamol exhibits anti-inflammatory and anti-nociceptive activity.

Nitroparacetamol (NCX-701) is a newly synthesized nitric oxide-releasing derivative of paracetamol. Following i.p. administration, nitroparacetamol inhibits carrageenan-induced hindpaw oedema formation (ED(50), 169.4 micromol kg(-1)) and mechanical hyperalgesia (ED(50), 156 micromol kg(-1)) in the rat. In contrast, the parent compound, paracetamol, exhibits no significant anti-oedema activity in this model (ED(50)>1986 micromol kg(-1), i.p. ) and is markedly less potent than nitroparacetamol as an inhibitor of carrageenan-mediated hyperalgesia (ED(50), 411.6 micromol kg(-1), i.p.). In a second model of nociception (inhibition of acetic acid induced abdominal constrictions in the mouse), nitroparacetamol administered orally (ED(50), 24.8 micromol kg(-1)), was again considerably more potent than paracetamol (ED(50), 506 micromol kg(-1), p.o.). Thus, compared with paracetamol, nitroparacetamol not only exhibits augmented antinociceptive activity in both rat and mouse but, intriguingly, is also anti-inflammatory over a similar dose range.

Acetaminophen↗
PubMed1999

Anode/cathode make and break phenomena in a model of defibrillation.

The goal of this simulation study is to examine, in a sheet of myocardium, the contribution of anode and cathode break phenomena in terminating a spiral wave reentry by the defibrillation shock. The tissue is represented as a homogeneous bidomain with unequal anisotropy ratios. Two case studies are presented in this article: tissue that can electroporate at high levels of transmembrane potential, and model tissue that does not support electroporation. In both cases, the spiral wave is initiated via cross-field stimulation of the bidomain sheet. The extracellular defibrillation shock is delivered via two small electrodes located at opposite tissue boundaries. Modifications in the active membrane kinetics enable the delivery of high-strength defibrillation shocks. Numerical solutions are obtained using an efficient semi-implicit predictor-corrector scheme that allows one to execute the simulations within reasonable time. The simulation results demonstrate that anode and/or cathode break excitations contribute significantly to the activity during and after the shock. For a successful defibrillation shock, the virtual electrodes and the break excitations restrict the spiral wave and render the tissue refractory so it cannot further maintain the reentry. The results also indicate that electroporation alters the anode/cathode break phenomena, the major impact being on the timing of the cathode-break excitations. Thus, electroporation results in different patterns of transmembrane potential distribution after the shock. This difference in patterns may or may not result in change of the outcome of the shock.

Action Potentials↗
PubMed1998

Neurogenic oedema and vasodilatation: effect of a selective neuronal NO inhibitor.

The effects of a neuronal nitric oxide synthase (nNOS) inhibitor, 1-(2-trifluoromethylphenyl)imidazole (TRIM) on rat sensory saphenous nerve-induced neurogenic inflammation were investigated. TRIM (50 mg kg-1, i.p.), but not 2-trifluoromethylphenol (TRIMPOH) which lacks nNOS inhibitory activity, inhibited neurogenic oedema by 55.8 +/- 6.5% (n = 6, p < 0.05). The effect of TRIM was partially reversed by L-arginine (100 mg kg-1, i.v., p < 0.01). TRIM also caused a reduction (p < 0.05) in neurogenic vasodilatation but had no effect on neuropeptide responses induced by substance P + CGRP. Topically applied TRIM (100 microliters of 150-250 mg ml-1) inhibited neurogenic oedema (p < 0.01). Thus, use of this recently described nNOS inhibitor has provided new evidence to further the hypothesis that nNOS plays a role in modulating sensory nerve-mediated neurogenic inflammation.

Animals↗
PubMed1998

Effects of selective inhibitors of neuronal nitric oxide synthase on carrageenan-induced mechanical and thermal hyperalgesia.

The effect of inhibition of nitric oxide synthase (NOS) on hindpaw hyperalgesia (assessed using mechanical and thermal noxious stimuli) and oedema formation following intraplantar injection of carrageenan (150 microl, 2% w v(-1)) in the rat was determined. For this purpose, NOS inhibitors including L-N(G) nitro-arginine methyl ester (L-NAME; isoform non-selective NOS inhibitor), 7-nitroindazole (7-NI) and 1-(2-trifluoromethylphenyl) imidazole (TRIM; both relatively selective inhibitors of neuronal NOS) were used. Mechanical/thermal nociceptive threshold values and hindpaw weight were recorded prior to and 3 h after administration of carrageenan. NOS inhibitors (5-25 mg kg(-1), i.p.) were administered 2.5 h after carrageenan. L-NAME, 7-NI and TRIM inhibited carrageenan-induced mechanical and thermal hyperalgesia. Calculated ED50 values (micromol kg(-1), i.p.) were 63.4, 96.2 and 92.7 (mechanical) and 42.2, 53.9 and 62.1 (thermal), respectively. None of the drugs affected pain perception in the non-injected hindpaw or carrageenan-induced hindpaw weight gain. Thus, 7-NI and TRIM, at doses previously reported not to influence cardiovascular haemodynamics, inhibit hyperalgesia in the rat regardless of the type of noxious stimulus employed. Accordingly, selective inhibitors of neuronal NOS may prove useful for the treatment of prolonged pain in man.

Animals↗
PubMed1998

A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity.

1. Intraplantar injection of carrageenan (150 microl, 1-3% w/v) in the rat resulted in a dose-related increase in hindpaw weight (oedema) characterized by a rapid 'early' phase (up to 2.5 h) response followed by a more sustained 'late' phase (2-6 h) response. No change in weight of either the contralateral (i.e. noninjected) hindpaw or hindpaws injected with saline was observed. 2. Six hours after intraplantar injection of carrageenan (1-3% w/v) hindpaw constitutive (i.e. calcium-dependent) nitric oxide synthase (cNOS) activity (determined ex vivo as the conversion of radiolabelled L-arginine to radiolabelled citrulline) was increased (e.g. 2% w/v; 0.64+/-0.08 pmol citrulline mg(-1) protein 15 min(-1) c.f. 0.08+/-0.04 pmol citrulline mg(-1) protein 15 min(-1) in saline-injected, control animals, n=4, P<0.05). Carrageenan injection also resulted in the appearance in hindpaw homogenates of inducible (i.e. calcium-independent) nitric oxide synthase (iNOS, e.g. 2% w/v; 0.67+/-0.14 pmol citrulline mg(-1) protein 15 min(-1), n=4). Hindpaw cyclic GMP concentration was also significantly increased 6 h after intraplantar injection of carrageenan (e.g. 2% w/v; 379.6+/-26.8 fmol mg(-1) protein c.f. 261.8+/-42.2 fmol mg(-1) protein, in saline-injected, control animals, n=4, P<0.05). 3. Pretreatment (5-25 mg kg(-1), i.p., 30 min before carrageenan, 2% w/v) of animals with L-N(G) nitro arginine methyl ester (L-NAME; isoform nonselective inhibitor of NOS) or 7-nitro indazole (7-NI; inhibitor of neuronal NOS, nNOS) caused dose-related inhibition of both the early (2 h) and late (6 h) phase hindpaw oedema, associated with reduced hindpaw iNOS and cNOS activity and cyclic GMP concentration in animals killed at 6 h. Administration of 7-NI (5-25 mg kg(-1), i.p.) to animals 2.5 h after intraplantar carrageenan (2% w/v) injection (i.e. at the end of the early phase oedema response) produced dose-related inhibition of the late phase response. 4. Pretreatment (5-25 mg kg(-1), i.p., 30 min before carrageenan, 2% w/v) of animals with L-N6-iminoethyllysine (L-NIL, selective inhibitor of iNOS) (5-25 mg kg(-1)) failed to affect the early phase hindpaw oedema response but did produce a dose-related inhibition of the late phase oedema. L-NIL pretreatment also inhibited the carrageenan-induced increase in both hindpaw iNOS and cNOS activity as well as the rise in hindpaw cyclic GMP concentration. 5. The present experiments demonstrate an anti-inflammatory effect of 7-NI as evidenced by inhibition of carrageenan-induced hindpaw oedema in the rat. Inhibition of nNOS (early phase) and iNOS (late phase) at the site of inflammation most probably accounts for the anti-inflammatory activity observed. These data suggest a role for nitric oxide synthesized by the nNOS isoform (most probably within sensory nerves) in this model of inflammation.

Animals↗
PubMed1997

Mechanism of the inhibition of neuronal nitric oxide synthase by 1-(2-trifluoromethylphenyl) imidazole (TRIM).

We have previously reported that 1-(2-trifluoromethylphenyl) imidazole (TRIM) is a potent inhibitor of mouse cerebellar neuronal NOS (nNOS) in vitro with very much reduced activity against bovine aortic endothelial NOS (eNOS). Using purified rat brain nNOS as enzyme source we have now probed the mechanism of action of TRIM. nNOS activity was linear over the first 5 min incubation. Optimal enzyme activity occurred in the presence of NADPH (0.5 mM), calcium chloride (75 microM), tetrahydrobiopterin (12 microM) and calmodulin (10 microg/ml) as cofactors. TRIM was a poor inhibitor of nNOS (IC50, 462.0 microM) compared with L-N(G) nitro arginine (L-NOARG, IC50, 0.32 microM). Removal of tetrahydrobiopterin (but not calmodulin) from the incubation medium greatly enhanced the nNOS inhibitory activity of TRIM (IC50, 32.0 microM) but not L-NOARG (IC50, 0.34 microM). In the absence of added tetrahydrobiopterin, TRIM competed with L-arginine for the substrate binding site on the nNOS enzyme with a Ki value of 47.3 microM. The present experiments suggest that TRIM interferes with the binding of both L-arginine and tetrahydrobiopterin to their respective sites on the nNOS enzyme.

Animals↗
PubMed1997

Selective inhibitors of neuronal nitric oxide synthase--is no NOS really good NOS for the nervous system?

It is now ten years since NO was shown to account for the biological activity of endothelium-derived relaxing factor (EDRF). It is also the tenth anniversary of the identification of L-NG monomethyl arginine (L-NMMA) as the very first inhibitor of NO biosynthesis. That EDRF and NO were one and the same sparked an explosion of interest in the biochemistry and pharmacology of NO which has yet to subside. In contrast, the first ever nitric oxide synthase (NOS) inhibitor slipped seamlessly into the literature virtually without comment at the time. Over the following decade, L-NMMA (and like NOS inhibitors) have proved invaluable as tools for probing the biological roles of NO in health and disease and, in particular, have increased our understanding of the function of NO in the nervous system. Further advances in this important area now require the development of inhibitors selective for the neuronal isoform of NOS (nNOS). Here, Philip Moore and Rachel Handy provide an up-to-date account of the literature regarding the biochemical and pharmacological characterization of NOS inhibitors with particular reference to compounds with greater selectivity for the nNOS isoform.

Animals↗
PubMed1997

Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat.

1. Peroxynitrite (ONOO-) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat. 2. Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125I-labelled albumin over 0-45 min and 0-240 min. Blood flow was measured by laser-Doppler flowmetry over 0-240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique. 3. Intradermal (i.d.) peroxynitrite (100-200 nmol site-1) produced a significant (P < 0.01) dose-dependent increase in plasma extravasation in dorsal skin over 0-45 min which was not increased over 45-240 min. Plasma extravasation was significantly (P < 0.001) decreased in rats pretreated with the anti-inflammatory steroid dexamethasone (1 mg kg-1, i.v.; -180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site-1), or the superoxide scavenger superoxide dismutase (500 u site-1), effective doses of the tachykinin NK1 antagonist SR140333 (1 nmol site-1), the cyclo-oxygenase inhibitor indomethacin (358 mumol site-1), or combined pretreatment with mepyramine (histamine H1-receptor antagonist; 2.8 nmol site-1) and methysergide (5-HT antagonist; 1.9 nmol site-1). 4. Microvascular blood flow was significantly (P < 0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site-1) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg-1, i.v.; -180 min) or indomethacin (10 mg kg-1, s.c.; -30 min). 5. Hind paw volume was significantly (P < 0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw-1) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite. 6. These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs.

Animals↗