986
LETTERS to the EDITOR
Double-edged role of endogenous nitric oxide SiR,—We suggest that endogenous nitroc oxide (NO) has both beneficial and deleterious roles. Nitrinergic signal transduction1 involves NO synthase types I-III (synthesising NO from Larginine), and soluble guanylyl cyclase, which is activated by NO and forms the "second messenger" cyclic guanosine-3’,5’monophosphate (cGMP). This pathway was first described in vascular endothelial cells, which release NO and thereby increase vascular smooth-muscle cGMP levels and cause vasodilatation. It can also be induced in vascular smooth-muscle cells during sepsis, where NO formation may be responsible for the severe hypotension in septic shock and in which, as Dr Petros and colleagues (Dec 21/28, p 1557) report, pharmacological inhibition of NO biosynthesis by NG-methyl-L-arginine can be beneficial. However, complete inhibition of NO biosynthesis may not be desirable since, as Dr Hotchkiss and colleagues (Feb 15, p 434) and Dr Cohen and Dr Silva (March 21, p 751) remark, several other essential functions of NO such as organ perfusion and inhibition of platelet aggregation would also be blocked. The nitrinergic signal transduction pathway is also present in epithelial cells, endocrine organs, and the nervous system, NO being involved consequently in the regulation of smooth-muscle stimulus-secretion tone, coupling, and neurotransmission, respectively. As first described in immunologically activated macrophages, higher concentrations of NO can exert cGMP-independent effects that convert this signalling molecule into a cytotoxic and mutagenic2 agent. cGMP levels are raised in neoplasms, proliferating tissues, and associated disease states.3 Here, we would like to draw attention to the physiological and pathophysiological implications of the balance of NO formation in three organs (brain, pancreas, and stomach). The so called NO-hypothesis of the brain suggests that postsynaptic cells contain NO synthase and that NO acts as a retrograde messenger to sharpen axonal arbors in an activitydependent manner. This mechanism may, at least in part, account for long-term potentiation4 and other memory-related functions of the brain. Neural NO would also be suited as a mediator coupling cerebral blood-flow to neural activity. Inhibition of NO synthesis decreases cerebral blood-flow.5 The site of action for these effects may be the basal forebrain, especially the perifascicular thalamic nucleus. We have found that hippocampal pyramidal cells and the perifascicular thalamic nucleus contain NO synthase immunoreactivity (unpublished). In contrast to these beneficial effects, NO also has pathophysiological significance in the brain.5 NO and L-arginine cause (or facilitate) glutamate neurotoxicity and the development of epileptic foci,6 The gastrointestinal tract contains NO synthase, located in so-called nitrinergic or nitroxergic nerves, where it mediates reflex relaxation to accommodate food or fluidand in the epithelium where it exerts gastroprotective effects.8 At neutral pH, NO has a very short half-life and is rapidly degraded to nitrite and nitrate; however, in the acid gastric lumen the half-life will be much increased, resulting in concentrations that could induce tissue damage in the stomach and are highly mutagenic.2 In the pancreas NO is likely to be involved in the regulation of stimulus-secretion coupling. NO synthase is found in the B-cells of islets of Langerhans; upon exposure to L-arginine and D-glucose these form NO, display increased cGMP-levels, and release insulin, and inhibition of NO synthesis prevents D-glucose-induced insulin release.9 Insulin release thus seems to be in part caused by or dependent on nitrinergic signal transduction-but again NO seems
have a dual role. Interleukin-lp, at high concentrations,1O can induce a different isoform of NO synthase, which results in a big increase in NO formation in the islets of Langerhans, and eventually in a B-cell destruction indistinguishable from that in type-I diabetes mellitus. Endogenous NO has a double-edged role in specialised tissues and cells. It is a potent and essential physiological signalling molecule but it is also prone to cause potentially cytotoxic and mutagenic effects: to
Benefit
Organ/tissue Brain Stomach Pancreas Blood vessels
Neurotransmitter, longterm potentiation Cytoprotective, reflex dilatation, motility Insulin release
Vasodilator, antithrombotic
Leucocytes
Immune defence
Harm Neurotoxic
Cytotoxic, mutagenic?
(3-cell destruction Reperfusion injury, endotoxic shock, anaphylactic shock Endotoxic shock
Modulation of the NO system may well prove to be of therapeutic significance in future but selective modifications and perturbations of NO synthetic pathways will be required. Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611, USA
H. H. H. W. SCHMIDT
William Harvey Research Institute, St Bartholomew’s Hospital, London EC1
TIMOTHY D. WARNER
Abbott Laboratories, Chicago,
F.MURAD
1. Schmidt
HHHW, Murad F. Purification and characterization of a human NO synthase. Biochem Biophys Res Commun 1991; 181: 1372-77 2. Wink DA, Kasprzak KS, Maragos CM, et al. DNA deamination ability and genotoxicity of nitric oxide and its progenitors. Science 1991; 254: 1001-03. 3. Cnss WE, Murad F, Kimura H. Properties of guanylate cyclase from rat cortex and transplantable kidney tumours. J Cyclic Nucleotide Res 1976; 2: 11-19. 4. Bohme GA, Bon C, Stutzmann J-M, et al. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol 1991; 199: 379-81. 5. Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Develop Physiol 1991; 15: 53-59. 6. Dawson VL, Dawson TM, London ED, et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991; 88: 6368-71. 7. Desai KM, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 1991; 351: 477-79. 8. Whittle BJR, Lopez-Belmonte J, Moncada S. Damage or protection of the gastric mucosa by exogenous nitric oxide. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press). 9. Schmidt HHHW, Warner TD, Ishii K, et al. Insulin-secretion from pancreatic B-cells caused by L-arginine-derived nitrogen oxides. Science 1992; 255: 721-23. 10. Southern C, Delaney C, Schulster D, et al. Nitric oxide-stimulated cGMF production and the dose-dependent effects of IL-1&bgr; on insulin secretion from rat islets of Langerhans. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press).
Coronary heart disease in women SIR,-Dr Isles and colleagues’ (March 21, p 703) fmding of a lower mortality from coronary heart disease (CHD) in women than in men, despite higher serum cholesterol concentrations, illustrates the well known cardiovascular superiority of the female and our ignorance of the physiological basis of this difference. It is, however, astonishing that these researchers’ advice to women was only to stop smoking, treat hypertension, take regular physical exercise, and reduce weight. Despite the abundant evidence (admittedly based on large-scale studies from the USA)
LETTERS to the EDITOR
Double-edged role of endogenous nitric oxide SiR,—We suggest that endogenous nitroc oxide (NO) has both beneficial and deleterious roles. Nitrinergic signal transduction1 involves NO synthase types I-III (synthesising NO from Larginine), and soluble guanylyl cyclase, which is activated by NO and forms the "second messenger" cyclic guanosine-3’,5’monophosphate (cGMP). This pathway was first described in vascular endothelial cells, which release NO and thereby increase vascular smooth-muscle cGMP levels and cause vasodilatation. It can also be induced in vascular smooth-muscle cells during sepsis, where NO formation may be responsible for the severe hypotension in septic shock and in which, as Dr Petros and colleagues (Dec 21/28, p 1557) report, pharmacological inhibition of NO biosynthesis by NG-methyl-L-arginine can be beneficial. However, complete inhibition of NO biosynthesis may not be desirable since, as Dr Hotchkiss and colleagues (Feb 15, p 434) and Dr Cohen and Dr Silva (March 21, p 751) remark, several other essential functions of NO such as organ perfusion and inhibition of platelet aggregation would also be blocked. The nitrinergic signal transduction pathway is also present in epithelial cells, endocrine organs, and the nervous system, NO being involved consequently in the regulation of smooth-muscle stimulus-secretion tone, coupling, and neurotransmission, respectively. As first described in immunologically activated macrophages, higher concentrations of NO can exert cGMP-independent effects that convert this signalling molecule into a cytotoxic and mutagenic2 agent. cGMP levels are raised in neoplasms, proliferating tissues, and associated disease states.3 Here, we would like to draw attention to the physiological and pathophysiological implications of the balance of NO formation in three organs (brain, pancreas, and stomach). The so called NO-hypothesis of the brain suggests that postsynaptic cells contain NO synthase and that NO acts as a retrograde messenger to sharpen axonal arbors in an activitydependent manner. This mechanism may, at least in part, account for long-term potentiation4 and other memory-related functions of the brain. Neural NO would also be suited as a mediator coupling cerebral blood-flow to neural activity. Inhibition of NO synthesis decreases cerebral blood-flow.5 The site of action for these effects may be the basal forebrain, especially the perifascicular thalamic nucleus. We have found that hippocampal pyramidal cells and the perifascicular thalamic nucleus contain NO synthase immunoreactivity (unpublished). In contrast to these beneficial effects, NO also has pathophysiological significance in the brain.5 NO and L-arginine cause (or facilitate) glutamate neurotoxicity and the development of epileptic foci,6 The gastrointestinal tract contains NO synthase, located in so-called nitrinergic or nitroxergic nerves, where it mediates reflex relaxation to accommodate food or fluidand in the epithelium where it exerts gastroprotective effects.8 At neutral pH, NO has a very short half-life and is rapidly degraded to nitrite and nitrate; however, in the acid gastric lumen the half-life will be much increased, resulting in concentrations that could induce tissue damage in the stomach and are highly mutagenic.2 In the pancreas NO is likely to be involved in the regulation of stimulus-secretion coupling. NO synthase is found in the B-cells of islets of Langerhans; upon exposure to L-arginine and D-glucose these form NO, display increased cGMP-levels, and release insulin, and inhibition of NO synthesis prevents D-glucose-induced insulin release.9 Insulin release thus seems to be in part caused by or dependent on nitrinergic signal transduction-but again NO seems
have a dual role. Interleukin-lp, at high concentrations,1O can induce a different isoform of NO synthase, which results in a big increase in NO formation in the islets of Langerhans, and eventually in a B-cell destruction indistinguishable from that in type-I diabetes mellitus. Endogenous NO has a double-edged role in specialised tissues and cells. It is a potent and essential physiological signalling molecule but it is also prone to cause potentially cytotoxic and mutagenic effects: to
Benefit
Organ/tissue Brain Stomach Pancreas Blood vessels
Neurotransmitter, longterm potentiation Cytoprotective, reflex dilatation, motility Insulin release
Vasodilator, antithrombotic
Leucocytes
Immune defence
Harm Neurotoxic
Cytotoxic, mutagenic?
(3-cell destruction Reperfusion injury, endotoxic shock, anaphylactic shock Endotoxic shock
Modulation of the NO system may well prove to be of therapeutic significance in future but selective modifications and perturbations of NO synthetic pathways will be required. Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611, USA
H. H. H. W. SCHMIDT
William Harvey Research Institute, St Bartholomew’s Hospital, London EC1
TIMOTHY D. WARNER
Abbott Laboratories, Chicago,
F.MURAD
1. Schmidt
HHHW, Murad F. Purification and characterization of a human NO synthase. Biochem Biophys Res Commun 1991; 181: 1372-77 2. Wink DA, Kasprzak KS, Maragos CM, et al. DNA deamination ability and genotoxicity of nitric oxide and its progenitors. Science 1991; 254: 1001-03. 3. Cnss WE, Murad F, Kimura H. Properties of guanylate cyclase from rat cortex and transplantable kidney tumours. J Cyclic Nucleotide Res 1976; 2: 11-19. 4. Bohme GA, Bon C, Stutzmann J-M, et al. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol 1991; 199: 379-81. 5. Beckman JS. The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Develop Physiol 1991; 15: 53-59. 6. Dawson VL, Dawson TM, London ED, et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991; 88: 6368-71. 7. Desai KM, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 1991; 351: 477-79. 8. Whittle BJR, Lopez-Belmonte J, Moncada S. Damage or protection of the gastric mucosa by exogenous nitric oxide. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press). 9. Schmidt HHHW, Warner TD, Ishii K, et al. Insulin-secretion from pancreatic B-cells caused by L-arginine-derived nitrogen oxides. Science 1992; 255: 721-23. 10. Southern C, Delaney C, Schulster D, et al. Nitric oxide-stimulated cGMF production and the dose-dependent effects of IL-1&bgr; on insulin secretion from rat islets of Langerhans. In: Moncada S, Marletta MA, Hibbs JJB, et al, eds. Biology of nitric oxide. Colchester: Portland (in press).
Coronary heart disease in women SIR,-Dr Isles and colleagues’ (March 21, p 703) fmding of a lower mortality from coronary heart disease (CHD) in women than in men, despite higher serum cholesterol concentrations, illustrates the well known cardiovascular superiority of the female and our ignorance of the physiological basis of this difference. It is, however, astonishing that these researchers’ advice to women was only to stop smoking, treat hypertension, take regular physical exercise, and reduce weight. Despite the abundant evidence (admittedly based on large-scale studies from the USA)
