Mechanisms of Nitrate Tolerance

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults

“…However, tachyphylaxis to nitroglycerin may develop rather quickly and up to 20% of those with HF may develop resistance to even high doses. [605][606][607] Sodium nitroprusside is a balanced preload-reducing venodilator and afterload-reducing arteriodilator that also dilates the pulmonary vasculature. Data demonstrating efficacy are limited, and invasive hemodynamic blood pressure monitoring is typically required.…”

2013 ACCF/AHA Guideline for the Management of Heart Failure

“…However, tachyphylaxis to nitroglycerin may develop within 24 hours, and up to 20% of those with HF may develop resistance to even high doses. [766][767][768] Sodium nitroprusside is a balanced preload-reducing venodilator and afterload-reducing arteriodilator that also dilates the pulmonary vasculature. 769 Data demonstrating efficacy are limited, and invasive hemodynamic blood pressure monitoring (such as an arterial line) is typically required; in such cases, blood pressure and volume status should be monitored frequently.…”

Lack of nitrate tolerance in isosorbid dinitrate- and sodium nitroprusside-induced relaxation of rabbit internal anal sphincter

“…One of the major drawbacks of NO donating agent therapy in cardiovascular diseases is the rapid development of pharmacological tolerance. It develops shortly after the beginning of treatment and occurs both in vitro and in vivo conditions [32,33] . Both human and experimental studies showed that prolonged exposure to high levels of nitroglycerin and other organic nitroesters induce tolerance against the cardiovascular effects of the drugs [17][18][19][20] .…”

“…The mechanisms of nitrate tolerance are complex and multi-factorial, including processes such as decreased tissue sulphydryl availability, reduced bioactivation of the parent drug, physiological compensation and tissue oxidative stress [32,33,35] . Some investigators suggested that tolerance may arise from one or more steps involving the biotransformation process of organic nitrates prior to the formation of NO [21,22] .…”