Organic Nitrates: Observations That Will Surprise You

TMED Blog

| 1 December 2023

Written by Kana Ogawa, MSc25’ (Candidate)

On Thursday, November 23^rd, 2023, the Medical Grand Rounds coordinated by the Department of Medicine had the privilege of listening to Dr. John D. Parker provide his expertise on the therapeutics of organic nitrates, revealing its role in cardiovascular medicine.

Organic nitrates—including glyceryl trinitrate (GTN), are common drugs used to treat cardiovascular diseases such as angina. Instead of receptor engagement, GTN undergoes biotransformation in which enzymes such as aldehyde dehydrogenase 2 (ALDH2) mediates GTN conversion into moieties that lead to vasodilation.¹ GTN, when administered acutely via sublingual, transdermal, or intravenous routes, produces potent effects on blood pressure, filling pressures, exercise tolerance, and relieve acute attacks of angina.²

Central to Dr. Parker's research is the phenomenon of nitrate tolerance. Although the etiology remains uncertain, chronic nitrate administration is associated with tolerance and diminution of therapeutic efficacy. Specifically, nitrates lose hemodynamic and clinical effectiveness when given continuously for more than 24 hours.³ Moreover, continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion, highlighting its role in the attenuation of nitrate effects.⁴

Initial studies on intermittent transdermal nitrate therapy showed promise in forestalling tolerance onset and improving exercise ability,⁵ however, subsequent research indicated that patients with angina experienced a reduction in exercise capacity over time following nitrate withdrawal.⁶ The developing body of literature suggests that intermittent therapy is not without limitations. Specifically, it has been associated with rebound phenomena, in which there is a development of unstable angina or myocardial infarction during the nitrate-free interval.^7,8

Data concerning chronic therapy revealed that nitrates cause endothelial dysfunction.⁹ Moreover, rodent studies showed that GTN tolerance is endothelium dependent, and that the endothelium produce free radicals in response to GTN exposure.¹⁰ Similarly, this is evident in humans; Dr. Parker discovered that both continuous and intermittent GTN therapy led to abnormal coronary artery responses to the endothelium-dependent vasodilator acetylcholine, characterized by a significant constriction in the mean luminal diameter of the left anterior descending (LAD) coronary artery.^{11, 12}

Finally, Dr. Parker's work has shed light on the genetic factors that influence the body's response to nitrates. In 2002, it was determined that ALDH2, which also metabolizes alcohol, acts as the key enzyme in nitrate biotransformation.¹³ALDH2 features a common polymorphism prevalent in individuals of East Asian descent,¹⁴ which can significantly reduce its enzymatic activity. To investigate ALDH2’s role in nitrate mechanisms, Dr. Parker examined the hemodynamic response to sublingual and intravenous GTN in the East Asian population carrying the polymorphisms. His findings revealed that individuals developed nitrate tolerance and endothelial dysfunction at similar rates, regardless of ALDH2 activity levels.¹⁵

In Dr. Parker's post-lecture discussion with the Translational Medicine graduate students, he offered an overview of how his research findings could be applied in patient care, emphasizing the critical importance of understanding the underlying drug mechanisms for enhancing clinical outcomes. He observed that, despite the long-standing use of nitrates, there is a paucity of evidence supporting their safety and efficacy in improving outcomes in heart failure beyond mere symptom relief. Dr. Parker advocates against the use of intermittent transdermal GTN for stable angina due to a lack of evidence for long-term benefits and the existence of superior therapeutic options. Interestingly, while nitrates have been helpful in chronic heart failure when combined with hydralazine,¹⁶ their effects when used alone in heart failure have not been well-studied. The conversation then turned to Dr. Parker's career path, from his educational roots at Queen's University to his collaborative work with his father, the renowned Dr. John O. Parker, highlighting the impact of mentorship and legacy on scientific inquiry.

In summary, Dr. Parker's body of work underscores the critical importance of understanding drug mechanisms in the pursuit of clinical excellence. His contributions to the field of nitrate pharmacology serve as a testament to the value of translational research in transforming patient care. As emerging healthcare professionals, we are reminded of the imperative to ground clinical practices in research, ensuring that strategies and interventions are effective and sustainable. Dr. Parker's commitment to elucidating the complex mechanisms of organic nitrates and his dedication to translating these findings into practical treatment modalities, exemplify the core of translational medicine. It is a reminder that at the heart of medical advancement lies a dedication to the meticulous study of the interactions between drugs and the body. As we navigate our paths in the healthcare field, we carry forward the lessons learned from Dr. Parker, striving to integrate research and clinical practice for the betterment of healthcare advancements.

References:

Ignarro LJ. After 130 years, the molecular mechanism of action of nitroglycerin is revealed. Proc Natl Acad Sci U S A. 2002;99(12):7816-7817. doi:10.1073/pnas.132271799.

Boden WE, Padala SK, Cabral KP, Buschmann IR, Sidhu MS. Role of short-acting nitroglycerin in the management of ischemic heart disease. Drug Des Devel Ther. 2015;9:4793-4805. doi:10.2147/DDDT.S79116.

Steering Committee of the Transdermal Nitroglycerin Cooperative Study. Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin. Am J Cardiol. 1991;68(13):1263-1273. doi:10.1016/0002-9149(91)90229-E.

Parker JD, Farrell B, Fenton T, Cohanim M, Parker JO. Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation. 1991;84(6):2336-2345. doi:10.1161/01.cir.84.6.2336.

Parker JO, Amies MH, Hawkinson RW, et al. Intermittent transdermal nitroglycerin therapy in angina pectoris. Circulation. 1995;91(5):1368-1374. doi:10.1161/01.cir.91.5.1368.

Parker JD, Parker AB, Farrell B, Parker JO. Intermittent transdermal nitroglycerin therapy. Circulation. 1995;91(4):973-978. doi:10.1161/01.cir.91.4.973.

Demots H, Glasser SP. Intermittent transdermal nitroglycerin therapy in the treatment of chronic stable angina. J Am Coll Cardiol. 1989;13(4):786-793. doi:10.1016/0735-1097(89)90216-7.

Ferratini M, Pirelli S, Merlini P, Silva P, Pollavini G. Intermittent transdermal nitroglycerin monotherapy in stable exercise-induced angina. Eur Heart J. 1989;10(11):998-1002. doi:10.1093/oxfordjournals.eurheartj.a059425.

Fayers KE, Cummings MH, Shaw KM, Laight DW. Nitrate tolerance and the links with endothelial dysfunction and oxidative stress. Br J Clin Pharmacol. 2003;56(6):620-628. doi:10.1046/j.1365-2125.2003.01946.x.

Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. J Clin Invest. 1995;95(1):187-194. doi:10.1172/JCI117637.

Caramori PR, Adelman AG, Azevedo ER, et al. Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine. J Am Coll Cardiol. 1998;32(7):1969-1974. doi:10.1016/s0735-1097(98)00456-2.

Azevedo E, Schofield A, Kelly S, et al. Nitroglycerin withdrawal increases endothelium-dependent vasomotor response to acetylcholine. J Am Coll Cardiol. 2001;37(2):505-509. doi:10.1016/S0735-1097(00)01140-2.

Chen Z, Zhang J, Stamler JS. Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci U S A. 2002;99(12):8306-8311. doi:10.1073/pnas.122225199.

Li H, Borinskaya S, Yoshimura K, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet. 2009;73(Pt 3):335-345. doi:10.1111/j.1469-1809.2009.00517.x.

Zhou K, Parker JD. Manuscript submitted for publication. University of Toronto, Department of Pharmacology and Toxicology; 2023.

Al-Mohammad A. Hydralazine and nitrates in the treatment of heart failure with reduced ejection fraction. ESC Heart Fail. 2019;6(4):878-883. doi:10.1002/ehf2.12459.

Organic Nitrates: Observations That Will Surprise You

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Organic Nitrates: Observations That Will Surprise You

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