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Nitric Oxide Therapeutics and the Management
of Endothelial Dysfunction

David W. Laight, PhD

School of Pharmacy & Biomedical Sciences, University of Portsmouth, UK

INTRODUCTION
   The purpose of this short lecture is to outline a rationale for nitric oxide (NO) therapy in cardiovascular disease and develop an awareness of current and potential NO therapeutics and their extant and prospective clinical indications. These tasks will naturally be facilitated by a brief consideration of the NO signalling pathway in the vascular wall, its regulation and its roles in health and disease.

BACKGROUND ON THE VASCULAR PHYSIOLOGY OF NO
   NO is a reactive nitrogen species derived from L-arginine by the action of one of three major isoforms of NO synthase (NOS). The most relevant physiological vascular source of NO is constitutive endothelial NOS (type III NOS); but constitutive neuronal NOS (type I NOS) and an inducible form (type II NOS) expressed by inflammatory cells can also provide vasoactive NO. Once synthesised in the endothelium, a single monolayer of cells covering the surface of the vascular tree, NO may freely diffuse to the underlying vascular smooth muscle or out into the vascular lumen, where it has the potential to interact with cellular formed elements such as thrombocytes and leuckocytes. Alternatively, NO may act in an autocrine or paracrine manner within the endothelium. On the other hand, NO may simply be sequestered by binding to albumin or erythrocyte-associated haemoglobin in the vascular lumen; or may face inactivation following oxidation or reaction with reactive oxygen species such as superoxide anion. The non-degradative interactions of NO represent physiological signalling events which, depending on the target cell, mediate: vasodilation, antivasoconstriction and antiproliferation (vascular smooth muscle); reduced permeability (endothelium); antiaggregation (thrombocytes); and antiadhesion (leukocytes). These intracellular actions of NO predominantly arise from the activation of soluble guanylyl cyclase (the intracellular 'receptor' for NO) and subsequent generation of the second messenger cGMP, intracellular levels of which are strictly regulated by phosphodiesterase type V (PDE V) activity.

   It is these multiple vascular activities which commend NO as a principal pleiotropic mediator of cardiovascular homeostasis, a deficiency in which has now been recognised as a major factor in the development of atherosclerosis, vasospasm, thrombosis, restenosis, essential hypertension and organic erectile dysfunction. Such deficiencies may most obviously result from decreased type III NOS activity or expression; but reduced NO bioavailability, in particular mediated by destruction by superoxide anion, is thought to be a leading cause of impaired NO signalling and subsequent endothelial dysfunction in both diabetic and cardiovascular disease and also the iatrogenic state of organic nitrate tolerance.

CURRENT AND FUTURE INDICATIONS FOR NO THERAPEUTICS
   The major clinical requirement for NO therapy is currently in the prevention and management of ischaemic heart disease, acute myocardial infarction, congestive heart failure, portal hypertension and hypertensive crises. This NO therapy is provided in the form of nitrovasodilators, of which the organic nitrates such as glyceryl trinitrate and isosorbide mononitrate represent the dominant therapeutic category. Other therapeutically valuable nitrosovasodilators include sodium nitroprusside, nicorandil (which also activates potassium channels) and S-nitrosothiols such as S-nitrosoglutathione, which interestingly display an antiplatelet selectivity. Another more recently developed area of NO therapy concerns the treatment of erectile dysfunction with the PDE V inhibitor sildenafil, which effectively amplifies the NO-mediated vasodilator signal in the corpus cavernosum.

   Other potential therapeutic areas of promise according to recent clinical trials include: hypoxic respiratory failure and pulmonary hypertension (treated with authentic inhaled NO); thrombotic disorders and restenosis (treated with S-nitrosothiols); and peripheral vascular disease such as Raynaud's Phenomenon (treated with a transdermal NO delivery system). Another theoretical prospect is that NO therapeutics could be employed in more general terms to restore a failing systemic endothelial function, in the style of an NO 'replacement' therapy. Given the importance of the endothelium in regulating blood pressure, lipid profiles and in vivo insulin sensitivity in addition to preventing atherogenesis, such a treatment paradigm would see the administration of NO therapeutics in cardiovascular and dysmetabolic disease with the clinical goals of alleviating hypertension, atherosclerosis, dyslipidaemia, thrombosis and even insulin resistance and dysglycaemia.

FUTURE PROSPECTS FOR NO THERAPEUTICS
   In addition to established NO therapeutics such as nitrovasodilators and selective PDE V inhibitors, there exist several other potential NO treatment modalities. These include: authentic NO itself; the precursor of NO, L-arginine; cGMP analogues; activators of soluble guanylyl cyclase; transfectable NOS genes; antioxidants which can protect NO from inactivation by superoxide anion; and other existing pharmacotherapies which favour NO synthesis/release and benefit endothelial function such as angiotensin converting enzyme inhibitors, statins and oestrogen receptor modulators. A novel recent development has been a recognition of the need to deliver therapeutic NO while preserving it from inactivation at sites of oxidant stress, which of course paves the way for hybrid antioxidant nitrovasodilator compounds. This 'smart' nitrosovasodilator approach, which represents 'added value' NO therapy, could prove particularly valuable in overcoming primary NO resistance due to established oxidant stress endemic in cardiovascular disease and diabetes as well as limiting the potential for secondary NO resistance attendant on de novo superoxide anion generation following prolonged nitrovasodilator use (nitrate tolerance). Another likely benefit of combination antioxidant nitrovasodilator therapy is a reduction in the risk of generating the powerful proatherogenic oxidising reaction product of NO and superoxide anion, peroxynitrite. Of course, the avoidance of delivering NO altogether, e.g. by substituting NO mimetics such as activators of soluble guanylyl cyclase, would be expected to circumvent NO tolerance development and peroxynitrite formation.

CONCLUSIONS
   Recent advances in our understanding and appreciation of vascular NO as a guardian of cardiovascular and also metabolic homeostasis have ushered in a renaissance in NO therapeutics, pioneered by organic nitrates over a century ago. Whether NO is specifically therapeutically exploited as a vasodilator agent, as with the organic nitrates, or as an antiplatelet agent, as with S-nitrosothiols, or applied as an endothelial panacea, this renaissance promises rational refinements in existing NO therapies as well as offering exciting new opportunities for addressing endothelial dysfunction in cardiovascular and dysmetabolic disease.

REFERENCES

1. Laight, D.W. (2001). Nitric oxide therapy for cardiovascular disease. Expert Opin. Ther. Patents 11: 999-1005.

2. Laight, D.W. (2000). The emerging therapeutic potential of nitric oxide. Future Prescriber 4: 22-25.

3. Laight, D.W., Carrier, M.J., Änggård, E.E. (2000). Antioxidants, diabetes and endothelial dysfunction. Cardiovasc. Res. 47: 457-464.

4. Laight, D.W., Carrier, M.J., Änggård, E.E. (1999). Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy. Diabetes Metab. Res. Rev. 15: 274-282.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
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apacher@fac.org.ar
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