Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress

Abstract

Organic nitrates, such as nitroglycerin (GTN), isosorbide-5-mononitrate and isosorbide dinitrate, and pentaerithrityl tetranitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of ^•NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of organic nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial dysfunction, which is in most cases linked to increased intracellular oxidative stress. Enzymatic sources of reactive oxygen species under nitrate therapy include mitochondria, NADPH oxidases, and an uncoupled ^•NO synthase. Acute high-dose challenges with organic nitrates cause a similar loss of potency (tachyphylaxis), but with distinct pathomechanism. The differences among organic nitrates are highlighted regarding their potency to induce oxidative stress and subsequent tolerance and endothelial dysfunction. We also address pleiotropic effects of organic nitrates, for example, their capacity to stimulate antioxidant pathways like those demonstrated for PETN, all of which may prevent adverse effects in response to long-term therapy. Based on these considerations, we will discuss and present some preclinical data on how the nitrate of the future should be designed. Antioxid. Redox Signal. 23, 899–942.

Abstract

• I. Introduction

  • A. Historical view

  • B. Hemodynamic effects of nitrates in patients with coronary artery disease and acute and chronic congestive heart failure

  • C. Cellular mechanisms of vasodilation by organic nitrates

  • D. No ^•NO from nitroglycerin?

  • E. Clinical uses/usefulness of organic nitrates

  • F. Do nitrates beneficially influence prognosis in patients with CAD?

  • G. Organic nitrate chemistry and pharmacokinetics

• II. Organic Nitrate Bioactivation

  • A. High-potency (affinity) pathway involving the ALDH-2 in GTN bioactivation

    • 1. ALDH-2 also involved in PETN bioactivation

    • 2. Impact of gene polymorphism on GTN bioactivation by ALDH-2

    • 3. Redox regulation of the ALDH-2

    • 4. Dihydrolipoic acid and thioredoxin as physiological reducing factors of ALDH-2

    • 5. Molecular mechanism of ALDH-2 bioactivation of organic nitrates via its reductase activity

    • 6. Impact of organic nitrate-induced ROS formation on ALDH-2 activity

    • 7. Purified ALDH-2 as a peroxynitrite synthase in the presence of GTN

  • B. The low-potency (affinity) pathway for bioactivation of GTN—low-molecular-weight systems and enzymatic systems of nitrate bioactivation besides ALDH-2

    • 1. Cytochrome P450 enzymes

    • 2. Xanthine oxidoreductase

    • 3. Glutathione-S-transferase

    • 4. Glyceraldehyde-3-phosphate dehydrogenase

    • 5. Other ALDH isoforms

• III. Side Effects of Chronic Nitroglycerin Therapy

  • A. Nitrate tolerance

    • 1. Pseudotolerance

    • 2. True vascular tolerance mechanisms

      • a. GTN increases oxidative stress and causes tolerance

      • b. Oxidative stress impairs GTN biotransformation

      • c. Desensitization of the sGC

      • d. Increased sensitivity to vasoconstrictors in response to GTN therapy

      • e. Increased sensitivity to vasoconstrictors in response to ISMN therapy

      • f. Epigenetic mechanisms of GTN-induced tolerance

  • B. Organic nitrates cause endothelial dysfunction in the clinical setting

    • 1. Molecular mechanisms underlying nitrate-induced endothelial dysfunction

      • a. BH4 deficiency

      • b. Changes in eNOS phosphorylation and S-glutathionylation

      • c. Increased NADPH oxidase activity

      • d. Nitration of prostacyclin synthase

• IV. Strategies to Prevent Development of Nitrate Tolerance and Nitrate-Induced Endothelial Dysfunction

  • A. Nitrate-free interval

  • B. Sulfhydryl group donors

  • C. Antioxidants

  • D. ACE inhibitors and angiotensin II type 1 receptor blockers

  • E. Hydralazine

  • F. Carvedilol

  • G. Statins

  • H. Endothelin receptor blockers

  • I. sGC stimulators and activators

  • J. PDE inhibitors

• V. Pleiotropic Effects of Organic Nitrates

  • A. Ischemic preconditioning

  • B. Antioxidant properties of PETN: Nrf2 and HO-1

  • C. Epigenetic pathways, microRNA, and gene regulation

  • D. The effect of organic nitrates on endothelial progenitor cells

• VI. Development of New Organic Nitrates Devoid of Side Effects

• VII. Summary and Future Perspectives for the Class of ^•NO Donors