Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease

Kraehling, Jan R.; Sessa, William C.

doi:10.1161/circresaha.117.303776

Cited by 82 publications

(64 citation statements)

References 107 publications

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“…Although many of the organic nitrates have been used clinically for decades, there are several new drugs and drug classes that have been approved recently or are currently being studied that have the potential to add to the list of modulators of the NO-sGC-cGMP pathway (174). Their methods of modulation of this pathway are summarized in Figure 5.…”

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

“…Caveolin-1 (CAV1) is the main coat protein of caveolae, invaginations in the plasma membrane implicated in several biological processes, including signaling, in endothelial cells (174–178). eNOS activity is decreased when bound to CAV1 (179,180).…”

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

“…In the microcirculation, hemoglobin α forms a macromolecular complex with eNOS and controls the flux of bioavailable NO (174,182). The reduced Fe 2+ -O 2 -hemoglobin-α reacts with NO rapidly and generates nitrate and the oxidized Fe 3+ -hemoglobin-α.…”

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

“…The reduced Fe 2+ -O 2 -hemoglobin-α reacts with NO rapidly and generates nitrate and the oxidized Fe 3+ -hemoglobin-α. This oxidized form of hemoglobin-α has a much lower affinity for NO than the reduced form, and, therefore, allows eNOS-generated NO to diffuse to underlying vascular smooth muscle cells (174,183). Nicotinamide adenine dinucleotide (NADH)-cytrochrome b 5 reductase 3 reduces Fe 3+ -hemoglobin-α to Fe 2+ -hemoglobin-α.…”

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

“…Two small molecules, AVE3085 and AVE9488, have been identified as transcriptional enhancers of eNOS that bind its promoter (174,185). In apolipoprotein E-knockout mice, 12 weeks of treatment with AVE9488 or AVE3085 reduced atherosclerotic plaque formation.…”

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

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The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

Divakaran

Loscalzo

2017

Journal of the American College of Cardiology

142

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The use of nitroglycerin in the treatment of angina pectoris began not long after its original synthesis in 1847. Since then, the discovery of nitric oxide as a biological effector and better understanding of its roles in vasodilation, cell permeability, platelet function, inflammation, and other vascular processes have advanced our knowledge of the hemodynamic (mostly mediated through vasodilation of capacitance and conductance arteries) and non-hemodynamic effects of organic nitrate therapy, via both nitric oxide-dependent and independent mechanisms. Nitrates are rapidly absorbed from mucous membranes, the gastrointestinal tract, and the skin, and, thus, nitroglycerin is available in several preparations for delivery via several routes: oral tablets, sublingual tablets, buccal tablets, sublingual spray, transdermal ointment, and transdermal patch; it is also available in intravenous formulations. The organic nitrates are commonly used in the treatment of cardiovascular disease, but clinical data limit their use mostly to the treatment of angina. They are also used in the treatment of subsets of patients with heart failure and pulmonary hypertension. One major problem with the use of nitrates is the development of tolerance. Although several agents have been studied for use in the prevention of nitrate tolerance, none are currently recommended owing to a paucity of supportive clinical data. Only one method of preventing nitrate tolerance remains widely accepted: the use of a dosing strategy that provides an interval of no or low nitrate exposure during each 24-hour period. Nitric oxide’s important role in several cardiovascular disease mechanisms continues to drive research toward finding novel ways to affect both endogenous and exogenous sources of this key molecular mediator.

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Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

Section: Novel Modulators Of the Nosgc-cgmp Pathwaymentioning

confidence: 99%

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The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

Divakaran

Loscalzo

2017

Journal of the American College of Cardiology

142

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Nitric Oxide: Synthesis and Action

Childers

Garcin

2017

Encyclopedia of Life Sciences

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Nitric oxide (NO) is a diatomic radical implicated in a variety of pathways including vascular homeostasis, neurotransmission and immune defence. NO is produced endogenously by three nitric oxide synthases (NOS) and can also be formed from nitrates and nitrites. Several mechanisms regulate NOS function, including protein–protein interactions, posttranslational modifications, cell localization, calcium levels, substrate availability, and the cell redox status. Picomolar NO concentrations activate guanylyl cyclase to increase cGMP levels and lead to vasodilation and memory formation. Excess NO concentrations cause posttranslational modifications of cellular components and formation of peroxynitrite leading to inflammation and cell death. Due to its involvement in multiple pathways and high reactivity with a myriad of downstream targets, tight regulation of NO production is crucial to maintain cellular function. Major advancements in understanding NO chemistry, production and downstream signalling have provided new avenues to target this pathway for the treatment of cardiovascular, neurodegenerative and autoimmune diseases. Key Concepts Nitric oxide is produced endogenously by three nitric oxide synthase (NOS) isozymes. Low NO levels mediate cell signalling, while high NO levels mediate the immune response and defence against pathogens. A tight regulation of NO production is necessary to maintain cellular function. The guanylyl cyclase enzyme (GC1) is the primary receptor of NO in smooth muscle cells and mediates vasorelaxation. Better understanding of NO/GC1 signalling will lead to novel drugs targeting this pathway for improved cardiovascular health. Nitrite, a product of nitrate reduction via oral bacteria, is a biologically relevant source of NO under hypoxic and acidic conditions. Dysfunction in NO synthesis due to oxidative damage leads to NOS uncoupling and increased output of ROS, a well‐known trait of cardiovascular disease (CVD).

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Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

Fricker¹

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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The discovery of nitrogen monoxide (nitric oxide, NO) as the vasodilator molecule endothelium‐derived relaxing factor revealed a major physiological role for this simple diatomic molecule. We now know that NO regulates cardiovascular function, is a neurotransmitter, and is a component of the innate immune response to infection and cancer. The physiological effects of NO are mediated by its varied chemistry which includes redox chemistry and interaction with transition metals. NO can interact with iron‐heme‐containing proteins including hemoglobin and cytochrome c oxidase, and nonheme iron proteins such as aconitase and bacterial transcription regulatory proteins. NO reacts with superoxide to form the highly reactive peroxynitrite which decomposes to give the hydroxyl radical. Nitrosothiols, thiol adducts of NO, act to control NO release, and to shuttle NO between proteins and transport NO across cell membranes. NO is produced by one of three nitric oxide synthase (NOS) enzymes, endothelial NOS, neuronal NOS, and inducible NOS. Signaling functions are mediated via interaction with the heme‐containing protein soluble guanylate cyclase (GC), which produces the cell signaling molecule cyclic guanosine monophosphate (cGMP). This, in turn, is hydrolyzed by phosphodiesterase 5 (PDE5), which turns off NO signaling. Perturbation in NO function contributes to the pathophysiology of many disease states. Endothelial dysfunction and subsequent reduced NO production contribute to hypertension and atherosclerosis. Excess NO is a mediator of inflammatory disease, and neurodegenerative disease, due in part to the production of peroxynitrite. The cardiovascular collapse observed in septic shock is caused by the vasodilator action of NO. Targeting the NO pathway theoretically provides many opportunities for therapeutic intervention. The NO donor drugs glyceryl trinitrate, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate are used to treat acute angina; and inhaled NO is used to treat persistent pulmonary hypertension in new born infants. Conversely, NOS inhibitors and NO scavengers have been explored to counteract NO as a mediator of disease. Though promising results have been obtained in animal models of disease these latter approaches have had little clinical success. However, targeting downstream of NO has been more successful with new clinically approved classes of drugs such as the inhibitors of PDE5 sildenafil, tadalafil, and vardenafil; and the stimulator of the NO receptor soluble GC, riociguat. It has become apparent that the biological actions, and biological chemistry, of NO are very complex. New opportunities for drug discovery could result from an improved understanding of the biology of NO.

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Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease

Cited by 82 publications

References 107 publications

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

Nitric Oxide: Synthesis and Action

Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

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