During the 1980s, the free radical, nitric oxide (NO), was discovered to be a crucial signalling molecule, with wide-ranging functions in the cardiovascular, nervous and immune systems. Aside from providing a credible explanation for the actions of organic nitrates and sodium nitroprusside that have long been used in the treatment of angina and hypertensive crises respectively, the discovery generated great hopes for new NO-based treatments for a wide variety of ailments. Decades later, however, we are still awaiting novel licensed agents in this arena, despite an enormous research effort to this end. This review explores some of the most promising recent advances in NO donor drug development and addresses the challenges associated with NO as a therapeutic agent.

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Recent developments in nitric oxide donor drugs

Nitric oxide and its role in the cardiovascular system.

Nitric oxide (NO) mediates multiple physiological and pathophysiological processes in the cardiovascular system. Pharmacological compounds that release NO have been useful tools for evaluating the pivotal role of NO in cardiovascular physiology and therapeutics. These agents constitute two broad classes of compounds, those that release NO or one of its redox congeners spontaneously and those that require enzymatic metabolism to generate NO. In addition, several commonly used cardiovascular drugs exert their beneficial action, in part, by modulating the NO pathway. Here, we review these classes of agents, summarizing their fundamental chemistry and pharmacology, and provide an overview of their cardiovascular mechanisms of action.

Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview.

Part I. Biology of Nitric Oxide. The Biological Chemistry of Nitric Oxide, Joseph Loscalzo. Cell and Molecular Biology of Nitric Oxide Synthases, Olivier Feron and Thomas Michel. Cellular Signal Transduction and Nitric Oxide, Stanley Heydrick. Regulation of Gene Expression by Nitric Oxide, Ami A. Deora and Harry M. Lander. Cytotoxicity, Apoptosis, and Nitric Oxide, Stefanie Dimmeler and Andreas M. Zeiher. Nitric Oxide and Ion Channels, Victoria M. Bolotina. Role of Nitric Oxide in Vasomotor Regulation, Richard A. Cohen. Nitric Oxide and Platelet-Mediated Hemostasis, Elisabeth M. Battinelli and Joseph Loscalzo. Nitric Oxide Modulates Leukocyte-Endothelial Cell Adhesion, Wolfgang Cerwinka and D. Neil Granger. Nitric Oxide and Cardiomyocyte Function, Jean-Luc Balligand and Paul J. Cannon. The Fibroblast and Nitric Oxide, Peter Brecher. Nitric Oxide in Cardiac Electrophysiology, Lu Fei and Douglas P. Zipes. Part II. Cardiovascular Pathophysiology of Nitric Oxide. Nitric Oxide and Endothelial Dysfunction, Gerard A. Dillon and Joseph A. Vita. Nitric Oxide and Hypertension, M. Audrey Rudd, Maria R. Trolliet, and Joseph Loscalzo. Nitric Oxide and Pulmonary Hypertension, John J. Leopore and Kenneth D. Bloch. Nitric Oxide in Atherosclerosis, Robert T. Eberhardt and Joseph Loscalzo. Thrombotic Disorders and Nitric Oxide Insufficiency, Jane E. Freedman and Joseph Loscalzo. Myocardial Nitric Oxide in Heart Failure, Douglas B. Sawyer and Wilson S. Colucci. Shock States and Nitric Oxide, Hartmut Ruetten and Christoph Thiemermann. Stroke and Nitric Oxide, Nancy E. Stagliano and Paul L. Huang. The Role of Nitric Oxide in Ischemia-Reperfusion, Allan M. Lefer and Reid Hayward. Part III. Nitric Oxide in Cardiovascular Therapeutics. Nitrovasodilators, John D. Horowitz. S-Nitrosothiols, Jane A. Leopold and Joseph Loscalzo. Diazeniumdiolates (Formerly NONOates) in Cardiovascular Research and Potential Clinical Applications, Joseph E. Saavedra, Anthony L. Fitzhugh, and Larry K. Keefer.Inhaled Nitric Oxide Therapy for Acute Respiratory Failure, William Hurford and Warren M. Zapol. Antioxidants and Endothelium-Derived Nitric Oxide Action, Annong Huang and John F. Keaney, Jr. Coating Arterial and Blood-Contacting Surfaces with NO*-Donating Compounds, John D. Folts and Joseph Loscalzo. Gene Therapy and Nitric Oxide, Heiko E. von der Leyen. Nitric Oxide and Tissue Preservation in Transplantation, David J. Pinsky and David M. Stern. L-Arginine: Its Role in Cardiovascular Therapy, Andrew J. Maxwell and John P. Cooke. Index.

Nitric Oxide and the Cardiovascular System

Increasing evidence suggests that organic nitrate action derives from their metabolic conversion to nitric oxide (NO) in the vascular smooth muscle cell. The primary catalytic activity of this process appears to reside at the cellular plasma membrane. There is no concrete evidence to indicate that NO formation is preceded by the production of inorganic nitrite ion or that the NO produced needs to form S-nitrosothiols before it can activate guanylate cyclase to produce cyclic guanosine 3′,5′-monophosphate (cGMP). Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon (by itself) is not sufficient to implicate intracellular sulfhydryl depletion as an operating mechanism of clinical nitrate tolerance. This is because sulfhydryl donors can react with nitroglycerin extracellularly to form S-nitrosothiols, and nonsulfhydryl compounds, such as enalapril and hydralazine, can prevent the development of in vivo nitrate tolerance. In addition to the cellular biochemical reactions, organic nitrates also produce systemic biochemical effects through altering neurohormonal status. These systemic effects may contribute significantly to the development of nitrate tolerance in therapeutic situations.

Biochemical mechanism of organic nitrate action.

We studied the effects of a unique vasoactive agent, S-nitrosocaptopril (SnoCap), in an anesthetized canine preparation. We have previously demonstrated that this agent manifests the properties of both a direct nitrovasodilator and an angiotensin-converting enzyme inhibitor in vitro. The present investigation was performed to evaluate the effects of SnoCap in vivo. Intravenous administration of SnoCap produced immediate reductions in blood pressure and significantly attenuated the pressor response to angiotensin I. Equieffective doses of SnoCap had a greater duration of action after intravenous bolus administration compared with nitroglycerin (15.3 +/- 2.6 min vs. 3.2 +/- 0.5 min, respectively; P less than .01); importantly, this effect was apparent despite the relatively short plasma half-life of the compound (T1/2 alpha = 0.48 min, T1/2 beta = 5.54 min) and did not appear to be the result of inhibition of angiotensin-converting enzyme. Another unexpected property of SnoCap was that its nitrovasodilator effect was 10- to 30-fold less potent than nitroglycerin when administered as a bolus, but more efficacious when given by continuous infusion. These data support the view that SnoCap is a vasoactive substance with the properties of a nitrovasodilator and an angiotensin-converting enzyme inhibitor, as well as the unique properties of an extended duration of action and greater potency when administered by continuous intravenous infusion than by bolus injection. The clinical utility of this compound in humans and in individuals with specific disease states remains to be demonstrated.

The hemodynamic effects of S-nitrosocaptopril in anesthetized dogs.

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The hemodynamic effects of S-nitrosocaptopril in anesthetized dogs.