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368 Heart 2001;86:368–372

REVIEW Heart: first published as 10.1136/heart.86.4.368 on 1 October 2001. Downloaded from

Nitric oxide: an emerging role in cardioprotection?

R D Rakhit, M S Marber

Over a decade of research has shown nitric products of NO.5–7 The isoform specific oxide (NO) to be a ubiquitous modulator of amount of NO generated may account, in part, biological phenomena from cell signal to eVec- for physiological versus pathological eVects of tor and from physiology to pathophysiology. NO in biological systems; low concentrations The involvement of NO in cardiovascular biol- are associated with cytostasis and high concen- ogy has contributed significantly to our under- trations are associated with cytotoxicity.8 standing of complex disease states including A further explanation for the dichotomous atherosclerosis, systemic and pulmonary eVects of NO may lie in its complex interaction hypertension, endotoxic shock, pre-eclampsia,1 with reactive oxygen species, which is particu- cardiomyopathy,2 and cardiac allograft rejec- larly pertinent in the context of ischaemia– tion.3 However, the emerging role of NO in the maintenance of cell physiology from immu- reperfusion. NO can interact in direct equimo- nomodulation to calcium signalling has high- lar concentrations with superoxide to form the lighted the importance of this fascinating mol- potent oxidant , which is toxic to 9 ecule in cytostasis. This dichotomy of eVector cardiac myocytes. The amount of peroxyni- function is the “double edged sword” of NO in trite production therefore depends on the ratio biological systems. However, the balance be- of superoxide to NO. The greater availability of tween cytostatic and cytotoxic eVects of NO superoxide may therefore favour peroxynitrite may lie in the tissue concentration of NO pro- production and toxicity. Thus, superoxide may duced, the particular NO synthase (NOS) iso- be an important rate limiting factor determin- form activated (that is, “high output” or “low ing the protective versus toxic eVects of NO.10 output”), and the complex interaction with Although the interaction of NO with reactive other free radicals such as superoxide. How- oxygen species is very complex, this simple http://heart.bmj.com/ ever, a much greater understanding of the hypothesis may explain why, even though the molecular and cellular actions of NO as a majority of animal studies have shown cytopro- physiological regulator has resulted in a body of tective eVects11–14 of NO against ischaemia– recent research increasing our understanding reperfusion injury, others have shown cytotox- of NO, and thus NO releasing agents, in cyto- icity.15 16 protection. Current evidence is outlined below. Emerging evidence suggests that a funda- mental explanation for the dichotomous roles

The NO dichotomy: physiology versus of NO may lie at a subcellular level. NO has on October 3, 2021 by guest. Protected copyright. pathology? been shown to modulate mitochondrial func- NO is produced by the catalytic action of NOS tion through reversible and irreversible interac- on the substrate L-. The reaction tions with respiratory chain complexes.17 Physi- involves the oxidation of one of the guanidi- ological concentrations of NO inhibit nonitrogens of arginine and the process cytochrome oxidase (complex IV) in a revers- involves the oxidation of NADPH (nicotina- ible manner, in competition with oxygen. mide adenine dinucleotide phosphate, reduced However, long term exposure can irreversibly form) and the reduction of molecular oxygen. inhibit complex I by S- of critical Three NOS have been characterised: thiols in the complex. The reversible type I (ncNOS), type II (iNOS), and type III interaction may play an important part in the Waller Department of (ecNOS). ncNOS and ecNOS are calcium Cardiology, St Marys dependent and low output enzymes associated physiological regulation of mitochondrial func- Hospital, Praed Street, tion by reducing oxygen consumption without London W2 1NY, UK with NO production in the picomolar range, R D Rakhit whereas iNOS is a calcium independent and causing adenosine triphosphate (ATP) deple- high output enzyme associated with NO tion. This may be beneficial during ischaemia. Department of production in the nanomolar (nmol) range. All Cardiology, St three NOS isoforms have been shown to be Thomas’s Hospital, 4 London, UK present in human myocardium and may be M S Marber activated in response to hypoxia or ischaemia. Novel cellular mechanisms of protection Laboratory studies of experimental myocardial ANTIAPOPTOSIS Correspondence to: infarction have shown an increased induction Apart from promoting apoptosis NO can also Dr Rakhit of iNOS, ecNOS, and NO concentrations in paradoxically inhibit apoptosis. Proposed [email protected] the heart, together with increased plasma con- mechanisms include the suppression of caspase Accepted 16 May 2001 centrations of and , the oxidation 1 and 3 activity by NO induced S-nitrosation;

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cyclic guanosine monophosphate (GMP) me- oxygen consumption28 and that reduced oxy- diated suppression of calcium mediated apop- gen consumption by this mechanism may con-

totic cell death; and induction of the cytopro- tribute to cardioprotection during precondi- Heart: first published as 10.1136/heart.86.4.368 on 1 October 2001. Downloaded from tective stress proteins heat shock protein 70 tioning.29 Mitochondrial dysfunction is a and heat shock protein 32 (haemoxygenase).18 critical component of ischaemia–reperfusion injury, which is characterised by dissipation of the membrane potential, ATP depletion, in- ANTIOXIDANT EFFECTS NO has been shown to induce the expression of duction of the mitochondrial permeability transient, and mitochondrial calcium over- haemoxygenase in vascular and smooth muscle 30 cells. Haemoxygenase and carbon monoxide, load. We have data to suggest that NO the product of the breakdown of haeme by induced depolarisation of the mitochondrial haemoxygenase, can bind the haeme moieties membrane potential protects cardiomyocytes by reducing mitochondrial calcium overload of NOS and soluble and 31 thereby inhibit NO production. This may during hypoxia–reoxygenation injury. This therefore provide a novel adaptive defence may be a novel explanation linking the NO mechanism against the oxidative stress associ- mediated modulation of mitochondrial ener- ated with sustained production of NO.19 getics to cytoprotection.

INHIBITION OF MYOCARDIAL DYSTROPHIN ANTI-INFLAMMATORY EFFECTS PROTEOLYSIS NO has for a long time been linked to the Recent exciting data have shown that NO inac- modulation of the immune response and tivates coxsackieviral protease 2A, which eVects on cell mediated immunity may have a cleaves human and mouse dystrophin in a dose role in cytoprotection. High doses of NO have dependent manner.32 This provides a further been shown to modulate the production of novel mechanism for protection by NO against interleukin 12 negatively, thus reducing the T viral myocarditis and may explain why NO helper cell 1 immune response.20 In addition concentrations are significantly raised in idio- NO appears to reduce polymorphonuclear leu- pathic dilated cardiomyopathy. cocyte mediated endothelial dysfunction in myocardial ischaemia–reperfusion, probably NO and clinical cardioprotection through the specific interaction with adhesion The known physiological eVects of NO in molecules.21 reducing left or right ventricular filling pres- sure, augmenting collateral coronary flow, and 33 CYCLIC GMP inhibiting platelet aggregation provide a pow- This important second messenger is produced erful theoretical basis for the routine use of NO by the action of NO on soluble guanylate in the treatment of acute coronary syndromes, cyclase, which catalyses the conversion of gua- myocardial infarction, and heart failure. De- nasine triphosphate (GTP) to cyclic GMP. spite this the routine use of NO donors, such as http://heart.bmj.com/ Cyclic GMP may exert protective eVects by , for clinical cardioprotection remains a reducing the influx of calcium through L type controversial area. The clinical evidence for the calcium channels and by stimulating a cyclic use of NO in cardiovascular disease is re- GMP sensitive phosphodiesterase with a re- viewed. sultant reduction in concentrations of cyclic AMP. This, together with the known eVect of MYOCARDIAL INFARCTION NO in reducing myocyte contractility,22 would In a small number of myocardial infarction trials predating the thrombolytic era intra- serve to reduce oxygen consumption and on October 3, 2021 by guest. Protected copyright. energy demand. venous nitrates were thought to have beneficial eVects on infarct size and mortality. Subse- quent meta-analysis of these trials indicated up PRECONDITIONING to a 49% reduction in mortality with the use of Ischaemic preconditioning is a powerful adap- prolonged intravenous glyceryl trinitrate.34 tive phenomenon whereby exposure to peri- However, the later and larger megatrials such od(s) of sublethal ischaemia protects against as ISIS-4 (fourth international study of infarct subsequent lethal ischaemia. NO may trigger 35 23 survival) and GISSI-3 (Gruppo Italiano per an early preconditioned state, and an exten- lo studio della sopravvivenza nell’infarto mio- sive body of evidence has implicated NO as a 36 24 cardico) could not confirm a beneficial eVect trigger and mediator of late preconditioning. on mortality in contradiction to previously The mechanism of protection by NO in late published data. In GISSI-3 the only positive preconditioning may involve the mitochondrial 25 elements were a significant 10% reduction of potassium ATP dependent channel and the the combined rate of death and left ventricular isoform selective activation of specific protein 26 dysfunction in patients over the age of 70 years, kinase C isoforms. and in women a more pronounced eVect of lisinopril on mortality when nitrates were MODULATION OF MITOCHONDRIAL FUNCTION coprescribed. One major criticism of the A reversible suppression of mitochondrial ISIS-4 and GISSI-3 megatrials is the wide- respiration has been shown to explain myocyte spread use of open label oral nitrates in the adaptation to chronic hypoxia without compro- placebo and control groups (62% and 57%, mising cell survival or accelerating ATP deple- respectively), which may have diluted the true tion.27 Recent studies have shown that NO is eVects of nitrates in both studies.37 Of course indeed a physiological regulator of myocardial the use of intravenous nitrates was not

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addressed in these studies and no study has with placebo or prazosin. In addition favour- specifically assessed the potential benefit of able eVects of NO on diastolic relaxation

nitrate treatment before myocardial infarction. suggest a beneficial eVect in diastolic heart Heart: first published as 10.1136/heart.86.4.368 on 1 October 2001. Downloaded from The eVects of the NO donor intravenous failure.44 linsidomine followed by oral within 48 hours of myocardial infarction were CARDIAC SURGERY studied in the ESPRIM (European study of 38 Ischaemia–reperfusion injury is an important prevention of infarct with molsidomine) trial. phenomenon during cardiac surgery and the No reduction in mortality was seen but, as in pharmacological manipulation of cardioplegic the ISIS-4 and GISSI-3 studies, nitrates were solutions is a powerful clinical tool in the pres- frequently used in the placebo group. ervation of myocardial integrity. Two studies The delay often associated with reperfusion have addressed the cardioprotective role of NO therapy in patients with ongoing myocardial during cardiac surgery by supplementation of infarction provides a clear indication for the blood cardioplegia with L-arginine45 and SPM- use of adjunctive cardioprotective agents. The 5185, a cysteine containing NO donor.46 These known cytoprotective actions of NO during agents respectively produced both reduced inf- ischaemia–reperfusion and favourable eVects 39 arct size and improved postischaemic contrac- on diastolic dysfunction, often associated tile performance. If NO can precondition the with reperfusion injury, provide a rationale for myocardium then NO releasing agents may the use of NO releasing agents in this context. also have a protective role before routine cardiac surgery. ANGINA Despite clear demonstrable eVects in relieving symptoms and electrocardiographic changes of ischaemia, nitrates have not been shown to NO donors influence mortality in stable or unstable The development of a number of NO donors angina. The observation that preinfarction has allowed the investigation and application of angina may be a correlate of preconditioning in biologically active NO in experimental re- humans has been shown in several studies but search and therapeutic trials. However, com- remains controversial. In one of the largest mercially available compounds vary consider- studies analysing patients in the TIMI 4 ably in the rate, amount of NO release, and the (thrombolysis in myocardial infarction (phase possibility that some agents also release other 4)) study40 the presence of preinfarction angina radicals. reduced the combined end points of inhospital + Glyceryl trinitrate as an organic nitrate death, severe congestive heart failure or shock requires the biotransformation of nitrate to from 12% in patients with no preceding angina release NO. This is a multistep enzymatic to 4%. As expected the use of oral process, involving the formation of S-nitrosothiols, dependent on the availabil- medication was higher in the angina group http://heart.bmj.com/ before myocardial infarction. In particular ity of glutathione. nitrate usage was 34% in the angina group + SIN-1 is the hepatic metabolite of molsid- compared with 14% in the no angina group, omine, which is available in systemic form and it is interesting to speculate as to the con- (linsidomine). SIN-1 releases nitrate, nitrite, tribution of antecedent nitrate treatment to and superoxide anions during the liberation cardioprotection. of NO. + SNP, a nitroprusside dianion consisting of a ANGIOPLASTY complex of ferrous ion with five cyanide on October 3, 2021 by guest. Protected copyright. The ACCORD (angioplastie coronaire, cor- ions, releases NO by interaction with a thiol vasal et diltiazem) study41 investigated the reducing agent in the presence of light. eVect of direct NO donors linsidomine and + SNAP is a nitrosothiol that directly releases molsidomine on angiographic restenosis after NO slowly without prior biotransformation. coronary balloon angioplasty. Pretreatment The long half life leads to prolonged action with the NO donor was associated with a mod- and stable release pharmacokinetics. est improvement in immediate angiographic + DETA-NO is a diazenium diolate with a 20 result compared with diltiazem, which was hour half life. The prolonged duration of maintained at six months. action opens up a therapeutic potential for this compound.

HEART FAILURE + NO aspirins are a new class of NO donors The beneficial haemodynamic eVects of ni- attached to an aspirin moiety originally designed for gastric mucosal protection. trates in preload reduction inducing a reduc- 47 tion in pulmonary and left ventricular end Examples are NCX 4016 and NCX 4215. diastolic pressure are helpful in heart failure. A recent study of the use of intravenous nitrates in acute severe pulmonary oedema showed a Drugs with NO modulating properties significant reduction in seven day mortality.42 ADENOSINE No study has assessed the sole use of nitrates in This purine nucleotide produces NO via the chronic heart failure but the V-HeFT activation of constitutive NOS (cNOS). Apart (vasodilator-heart failure) trials I and II43 from its vasodilatory and atrioventricular nodal showed that the combination of isosorbide blocking actions it is thought to be an dinitrate and hydralazine produced a 38% important trigger of preconditioning in animals reduction in mortality at one year compared and patients.48

www.heartjnl.com Nitric oxide in cardioprotection 371

SILDENAFIL of complex physiological systems. A greater Originally developed as an antihypertensive, understanding of the molecular basis of NO

the cyclic GMP type V phosphodiesterase mediated actions in cellular homeostasis will Heart: first published as 10.1136/heart.86.4.368 on 1 October 2001. Downloaded from inhibitor sildenafil (Viagra; Pfizer) has revolu- allow us to harness its actions as a potentially tionised the treatment of erectile impotence. powerful cardioprotective agent. What is first Sildenafil has been shown to enhance flow needed is the development of more refined mediated in patients with chronic pharmacological NO donors together with heart failure,49 and the development of new and clinical trials based on emerging biological more cardiospecific cyclic GMP phosphodi- principles. This may lead to the use of NO type esterase inhibitors may well herald a new era of agents as adjunctive pharmacotherapy for use cardioprotective agents for use in clinical in the future management of acute coronary cardiology. syndromes, before high risk percutaneous transluminal coronary angioplasty, surgical cardioplegia, and heart failure. Substantial interest has focused on the non- cholesterol lowering or pleiotropic eVects of 1 Warren JB, Pons F, Brady AJB. Nitric oxide biology: impli- cations for cardiovascular therapeutics. Cardiovasc Res this group of drugs. The statins have favourable 1994;28:25–30. eVects on endothelial function and NO may be 2 Habib FM, Springall DR, Davies GJ, et al. Tumour necrosis implicated in the mechanism. Pravastatin factor and inducible in dilated cardio- myopathy. Lancet 1996;347:1151–5. sodium has been shown to cause endothelial 3 Szabolcs MJ, Ravalli S, Minanov O, et al. Apoptosis and dependent vasorelaxation of aortic rings by increased expression of inducible nitric oxide synthase in human allograft rejection. Transplantation 1998;65:804–12. activating cNOS and releasing NO in a dose 4 Kelly RA, Balligand J-L, Smith TW. Nitric oxide and dependent manner.50 The mechanism of cNOS cardiac function. Circ Res 1996;79:363–80. 5 Akiyama K, Suzuki P, Grant P, et al. Oxidation products of activation by statins is unknown. nitric oxide, NO2 and NO3, in plasma after experimental myocardial infarction. J Mol Cell Cardiol 1997;29:1–9. 6 Lecour S, Maupoil V, Zeller M, et al. Levels of nitric oxide in the heart after experimental myocardial ischaemia. J Nicorandil is a selective potassium dependent Cardiovasc Pharmacol 2001;37:55–63. 7 Felaco M, Grilli A, Gorbunov N, et al. Endothelial NOS ATP channel blocker but also has an NO expression and ischemia-reperfusion in isolated working rat releasing moeity. It has been implicated in the heart from hypoxic and hyperoxic conditions. Biochim Bio- phys Acta 2000;1524:203–11. preconditioning phenomenon and shown to be 8 Lincoln J, Hoyle CHV, Burnstock G. Basic principles and protective in unstable angina.51 It is possible recent advances. In: Lincoln J, Hoyle CHV, Burnstock G, eds. Nitric oxide in health and disease. Cambridge: that the NO producing eVect of this drug con- Cambridge University Press, 2997:12–27. tributes to its cardioprotective properties. 9 Ishida H, Ichimori K, Hirota Y, et al. Peroxynitrite-induced cardiac myocyte injury. Free Radic Biol Med 1996;20:343– 50. 10 Beckman JS, Crow JP. Pathological implications of nitric ANGIOTENSIN CONVERTING ENZYME INHIBITORS oxide, superoxide and peroxynitrite formation. Biochem Soc Angiotensin converting enzyme (ACE) inhibi- Trans 1992;21:330–4. 11 Agullo L, GarciaDorado D, Inserte J, et al. L-arginine limits tors prevent the breakdown of bradykinin that myocardial cell death secondary to hypoxia-reoxygenation

in turn increases NO production by the activa- by acGMP-dependent mechanism. Am J 1999;45:H1574– http://heart.bmj.com/ tion of cNOS. ACE inhibitors appear to have a 80. 12 Jones SP, Girod WG, Palazzo AJ, et al. Myocardial number of protective eVects independent of ischemia-reperfusion injury is exaccerbated in the absence ACE inhibition. Recent evidence suggests that of endothelial nitric oxide synthase. Am J Physiol (Heart Circ Physiol) 1999;276:H1567–73. this might be explained by an NO mediated 13 Siegfried MR, Erhardt J, Rider T, et al. Cardioprotection improvement in endothelial function.52 and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Phar- macol Exp Ther 1992;260:668–75. 14 Johnson G III, Tsao PS, Lefer AM. Cardioprotective eVects NEVIBOLOL of authentic nitric oxide in myocardial ischemia with reper- Nevibolol is a new cardioselective blocker fusion. 1991;19:244–52. â Crit Care Med on October 3, 2021 by guest. Protected copyright. 53 15 Woolfson RG, Patel VC, Nield GH, et al. Inhibition of nitric with NO modulating properties licensed for oxide synthesis reduces infarct size by an adenosine- treating hypertension. However, these com- dependent mechanism. Circulation 1995;91:1545–51. bined eVects may prove useful in the treatment 16 Cope JT, Banks D, Laubach VE, et al. exacerbates myocardial ischemia-reperfusion injury. Ann of coronary disease and heart failure. Thorac Surg 1997;64:1656–9. 17 Cassina A, Radi R DiVerential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron trans- AMLODIPINE port. Arch Biochem Biophys 1996;328:309–16. 18 Kim Y-M, de Vera ME, Watkins SC, et al. Nitric oxide pro- This calcium blocker was found unexpectedly tects cultured rat hepatocytes from tumour necrosis factor- to release NO from coronary microvessels á-induced apoptosis by inducing HSP 70 expression. J Biol 54 Chem 1997;272:1402–11. through a kinin mediated mechanism. Am- 19 Siow RCM, Sato H, Mann GE oxygenase-carbon lodipine also releases NO from coronary monoxide signalling pathway in atherosclerosis: anti- microvessels in human failing hearts, which atherogenic actions of bilirubin and carbon monoxide. Cardiovasc Res 1999;41:385–94. may have provided a novel mechanism for its 20 Lamas S, Perez-Sala D, Moncada S Nitric oxide: from dis- cardioprotective eVects in a recent heart failure covery to the clinic. Trends Pharmacol Sci 1998;19:436–8. 21 Vinten-Johansen J, Zhao ZQ, Nakamura M, et al. Nitric trial.55 oxide and the vascular endothelium in myocardial ischemia-reperfusion injury. Ann NY Acad Sci 1999;874: Evidence for the NO mediated eVects of 354–70. ACE inhibitors, amlodipine, and nevibolol is 22 Brady AJB, Warren JB, Poole-Wilson PA, et al. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; speculative and controversial. Further evidence 265:H176–82. is needed to explore the potential NO modulat- 23 Rakhit RD, Edwards RJ, Mockridge JW, et al. Nitric oxide- ing properties of these drugs. induced cardioprotection in cultured rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2000;278: H1211–7. 24 Bolli R, Dawn B, Tang X-L, et al. The nitric oxide hypoth- Conclusion esis of late preconditioning. Basic Res Cardiol 1998;93:325– NO will remain one of nature’s fascinating 38. 25 Sasaaki N, Sato T, Ohler A, et al. Activation of mitochon- molecules and provide cardiovascular scientists drial ATP-dependent potassium channels by nitric oxide. with a tool to understand further the workings Circulation 2000;101:439–45.

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26 Ping P, Takano H, Zhang J, et al. Isoform-selective activation angiographic restenosis after coronary balloon angioplasty. of protein kinase C by nitric oxide in the heart of conscious The ACCORD Study. Angioplastic coronaire corvasal rabbits. Circ Res 1999;84:587–604. diltiazem. Circulation 1997;95:83–9.

27 Budinger GRS, Duranteau J, Chandel NS, et al. Hiberna- 42 Bertini G, Giglioli C, Biggeri A, et al. Intravenous nitrates in Heart: first published as 10.1136/heart.86.4.368 on 1 October 2001. Downloaded from tion during hypoxia in cardiomyocytes. J Biol Chem the prehospital management of acute pulmonary oedema. 1998;273:3320–6. Ann Emerg Med 1998;30:493–9. 28 Loke KE, McConnell PI, Tuzman JM, et al. Endogenous 43 Loeb HS, Johnson G, Henrick A, et al.EVect of enalapril, endothelial nitric oxide synthase-derived nitric oxide is a hydralazine plus and prazosin on physiological regulator of myocardial oxygen consumption. hospitalisation in patients with chronic congestive heart Circ Res 1999;84:840–5. failure. Circulation 1993;87:VI78–87. 29 Xu Z-L, Endoh H, Ishihata A, et al EVect of ischaemic pre- 44 Mandinov L, Eberli FR, Seiler C, et al. Diastolic heart fail- conditioning on myocardial oxygen consumption during ure. Cardiovasc Res 2000;45:813–25. ischemia. 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