Showing papers by "Louis J. Ignarro published in 1995"
TL;DR: Observations indicate that co-induction of iNOS and AII occurs by distinct transcriptional mechanisms, AII induction could diminish NO production by decreasing L-arginine availability, and IFN-gamma can prevent A II induction.
219 citations
TL;DR: It is demonstrated that direct exposure to soluble nitric oxide, produced in vitro from aNitric oxide donor chemical, ultimately kills oligodendrocytes by necrosis.
197 citations
TL;DR: It is concluded that a majority of neuronal NOS is converted quickly to a catalytically inactive ferrous-nitrosyl complex during NO synthesis independent of the external NO concentration, which indicates that NO binding to the NOS heme may be a fundamental feature of catalysis and functions to down-regulate NO synthesis by neurons.
193 citations
TL;DR: The observations clearly indicate that NO inhibits NOS activity and that nNOS and eNOS are more sensitive than iNOS to the inhibitory action of NO, and are consistent with the view that enzymatically generated NO may play an important negative-feedback regulatory role on eNos, and therefore on vascular endothelial cell function.
Abstract: Publisher Summary Nitric oxide (NO) inhibits nitric oxide synthase (NOS) activity and nNOS and eNOS are more sensitive than iNOS to the inhibitory action of NO. Not only exogenously added NO but also enzymatically generated NO inhibits the activity of nNOS and eNOS. The original observation that proved NO inhibits NOS activity has been made using unpurified preparations of nNOS obtained from rat cerebellum. Enzymatically generated NO also inhibits nNOS activity. For this purpose, NO was tested for its inhibitory effect on unpurified membrane-bound preparations of eNOS derived from cultured bovine aortic endothelial cells. Both constitutive isoforms of NOS appeared to be equally sensitive to the inhibitory actions of added NO. Subsequent experiments using unpurified cytosolic iNOS derived from cytokine-activated rat alveolar macrophages revealed that although iNOS is inhibited by NO, relatively higher concentrations of NO are required to inhibit iNOS than either nNOS or eNOS. This chapter includes the experimental results pertaining to these observations. The mechanism by which NO inhibits NOS appears to involve the heme iron prosthetic group of NOS. Moreover, the oxidation state of the heme iron is critical in determining the magnitude of inhibition of NOS by NO. Conditions that favor the higher oxidation state of Fe III markedly increase the inhibitory action of NO, whereas conditions that favor the lower oxidation state of Fe II markedly decrease the inhibitory action of NO. One of the cofactor roles of tetrahydrobiopterin may be to reduce the negative-feedback effect of NO on NOS by favoring the formation of the ferrous heme state in NOS.
158 citations
Book•
01 Jan 1995
TL;DR: Chemistry of nitric oxide - biologically relevant aspects, J.P. Crow and J.R. Beckman oxygen radical-nitric oxide reactions in vascular diseases, B.A. Mehta why tetrahydrobiopterin?
Abstract: Chemistry of nitric oxide - biologically relevant aspects, J.M. Fukuto reactions between nitric oxide, superoxide and peroxynitrite - footprints of peroxynitrite "in vivo", J.P. Crow and J.S. Beckman oxygen radical-nitric oxide reactions in vascular diseases, B.A. Freeman et al nitric oxide synthases - gene structure and regulation, Y. Wang and P.A. Marsden transcription of the human neuronal nitric oxide synthase gene in the central nervous system is mediated by multiple promoters, A.P. Young et al regulation of the expression of the inducible isoform of nitric oxide synthase, C. Szabo and C. Thiemermann regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation, J.M. Wong and T.R. Billiar expression and expressional control of nitric oxide synthases in various cell types, U. Forstermann et al control and consequences of endothelial nitric oxide formation, I. Fleming and R. Busse control of electron transfer in neuronal nitric oxide synthase by calmodulin, substrate, substrate analogs and nitric oxide, D.J. Stuehr et al negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds, J.M. Griscavage et al regulation of nitric oxide synthase - role of oxygen-radicals and cations in nitric oxide formation, C.K. Mittal and C.S. Mehta why tetrahydrobiopterin?, B. Mayer and E.R. Werner nitric oxide and cyclic GMP signalling, L.J. McDonald and F. Murad nitric oxide and intracellular heme-1, Y.-M. Kim et al high level expression of biologically active soluble guanylyl cyclase using the baculovirus system is strongly heme-dependent, W.A. Buechler et al cGMP signalling through cAMP- and cGMP-dependent protein kinases, T.M. Lincoln et al physiological and toxicological actions of nitric oxide in the central nervous system, V.L. Dawson and T.M. Dawson S-nitrosothiols - chemistry, biochemistry and biological actions, G.R. Upchurch et al glyceraldehyde-3-phosphate dehydrogenase - a target for nitric oxide signalling, B. Brune and E.G. Lapetina nitric oxide donors - biochemical pharmacology and therapeutics, J.A. Bauer et al nitric oxide donors - a continuing opportunity in drug design, S.R. Hanson et al nitric oxide and peripheral adrenergic neuromodulation, R. Levi et al a study on tumor necrosis factor, tumor necrosis factor receptors and nitric oxide in human fetal glial cultures, B.A. St.Pierre et al inhaled nitric oxide, clinical rationale and applications, C.G. Frostell and W.M. Zapol inhaled nitric oxide therapy of pulmonary hypertension and respiratory failure in premature and term neonates, S.H. Abman and J.P. Kinsella clinical applications of inhaled nitric oxide in children with pulmonary hypertension, D.L. Wessel and I. Adatia.
136 citations
TL;DR: It is reported here that sodium salicylate, aspirin, ibuprofen, and indomethacin markedly inhibited the appearance of the inducible inflammatory nitric oxide synthase in rat alveolar macrophages activated with lipopolysaccharide and interferon gamma.
126 citations
TL;DR: Although the precise mechanism for the slower rate of development of atherosclerosis in the female rabbits as compared with males is not clear, the greater basal release of NO in females before they were fed a hyperlipidemic diet, as well as other factors, may be involved.
Abstract: The mechanism by which women in the reproductive age group are protected from developing coronary heart disease (CHD) as compared with men of similar age is not known. To elucidate whether there is a gender difference in the rate of atherosclerosis formation, we investigated the rate of development of atherosclerosis in both male and female rabbits fed an identical diet consisting of 2% cholesterol for 10 and 15 weeks. The extent of atherosclerosis was correlated with the amount of basal and stimulated release of nitric oxide (NO) from endothelium-intact aortic rings obtained from these animals. Under identical dietary conditions, the female rabbits fed a high cholesterol diet (HCD) for 10 weeks developed very little atherosclerosis (10% surface involvement) as compared with male rabbits (42% surface involvement). However, no significant gender differences in atherosclerosis were observed after 15 weeks of the HCD. The serum cholesterol, high and low density lipoprotein (HDL and LDL) cholesterol were similar in animals fed the HCD for 10 and 15 weeks. The basal release of NO from endothelium-intact aortic rings was significantly greater in control females as compared with males. The magnitude of endothelium-dependent relaxation of aortic rings obtained from both male and female rabbits fed the HCD were impaired to a similar extent, and this impairment correlated with the duration of hyperlipidemia but not with the extent of atherosclerosis. The arginine content of aortic rings were not different between males (257 +/- 52 nmol/g wet weight) and females (345 +/- 62 nmol/g wet weight) or between control and hyperlipidemic groups (males 312 +/- 69; females 301 +/- 65 nmol/g wet weight). Although the precise mechanism for the slower rate of development of atherosclerosis in the female rabbits as compared with males is not clear, the greater basal release of NO in females before they were fed a hyperlipidemic diet, as well as other factors, may be involved. The impairment of endothelium-dependent relaxation in hyperlipidemic animals is not due to a decrease in the availability of arginine, the substrate for NO.
77 citations
TL;DR: No has a selective role in mediating changes in pancreatic perfusion and secretion and seems to be important in stimulus-secretion coupling with both secretin and cholecystokinin but is only responsible for the accompanying increase in pancreatIC blood flow with chole Cytokinin.
51 citations
TL;DR: Evidence is provided that lipid peroxidation contributes to myocardial dysfunction after reoxygenation after cardiopulmonary bypass and the close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardian conjugated diene production (r = 0.752) provides in vivo evidence that lipidperoxidation contributed to my Cardiac Peroxidation.
29 citations
TL;DR: Results are consistent with a protective mechanism by which BH4 may act as a nonstoichiometric reducing agent for a redox active enzyme component, such as the ironheme, to prevent NO ligation.
28 citations
TL;DR: This study tests the hypotheses that a) controlled reoxygenation of cyanotic immature hearts when starting cardiopulmonary bypass with high pO2 pressure of oxygen produces a re oxygengenation injury, and b) this oxygen-related damage is avoidable by controlling the circumstances of the reoxyGENation period.
Abstract: Reintroduction of high levels of molecular oxygen after a hypoxic period is followed by a burst of nitric oxide (NO), peroxynitrite, and oxygen free radicals, which are highly cytotoxic. This study tests the hypotheses that a) uncontrolled reoxygenation of cyanotic immature hearts when starting cardiopulmonary bypass (CPB) with high pO 2 pressure of oxygen produces a reoxygenation injury, and b) this oxygen-related damage is avoidable by controlling the circumstances of the reoxygenation period (controlled reoxygenation). Of 40 immature piglets (2-3 weeks), 5 normoxic instrumented piglets served as control, and 6 underwent 1 h of CPB including 30 min of aortic clamping with blood cardioplegic (BCP) arrest without preceding hypoxia (BCP control). Twenty-nine others were made hypoxic (arterial pO 2 20-30 mmHg) for up to 2 h by lowering the forced inspiratory oxygen (FiO 2 ) on a ventilator. They were then reoxygenated on CPB as follows, 1) abrupt reoxygenation at pO 2 400 mmHg in 5, (Reox), 2) gradual increase in pO 2 from 30 to 400 mmHg in 5 (Graded Reox), both without BCP arrest, 3) starting CPB at different pO 2 levels (hyperoxic, normoxic or hypoxic) for 5 min, followed by BCP arrest (Reox + BCP: pO 2 >400, 100 or 20-30 mmHg), in 19 others. Reoxygenation on CPB at pO 2 more than 400 mmHg depressed contractility (endsystolic elastance {Ees} to 25 ± 5% of control; P < 0.05), accompanied by reduced antioxidant reserve capacity {AORC} (P < 0.05 vs control), which was only slightly improved by Graded Reox (Ees 34±4%, P<0.05 vs control). In contrast to BCP control, brief reoxygenation at pO 2 more than 400 mmHg, followed by BCP arrest (Reox+BCP) resulted in marked conjugated diene (CD) (42±4 vs 3±1 A 233 nm/min per 100 g; P < 0.05), and NO production (4500 ± 500 vs 450 ± 32 μmol/min per 100 g; P < 0.05), reduced AORC (P < 0.05), and profound myocardial dysfunction (Ees 21+2% vs 104±7; P < 0.05). Conversely, controlling the initial pO 2 to normoxic (100 mmHg) or hypoxic (20-30 mmHg) levels reduced lipid peroxidation and NO production, restored AORC and allowed significant functional recovery in a pO 2 dependent fashion (P<0.05). We conclude that reoxygenation of hypoxemic immature hearts by initiating hyperoxic CPB causes oxidant-related damage, leading to functional depression. These detrimental effects can be reduced in a pO 2 dependent fashion on CPB and subsequent reoxygenation during BCP arrest. Simply lowering pO 2 on CPB without BCP arrest is not effective.
TL;DR: It is suggested that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cycling GMP levels in platelets with potential physiological and therapeutic consequences.
TL;DR: Blood cardioplegic arrest without hypoxemia did not cause myocardial nitric oxide or conjugated diene production, reduce antioxidant reserve capacity, or change left ventricular functional recovery, and function and antioxidants reserve capacity were measured.