What is the mechanism of nitrate tolerance?

Mechanism of Nitrate Tolerance

Nitrate tolerance develops through multiple interconnected mechanisms, primarily involving depletion of sulfhydryl groups in vascular smooth muscle, activation of counter-regulatory neurohormonal systems, and increased oxidative stress, which collectively attenuate the vasodilatory effects of organic nitrates during continuous exposure.

Primary Mechanisms

Sulfhydryl Group Depletion

• The leading mechanism involves depletion of reduced sulfhydryl (-SH) groups at vascular receptor and intracellular sites 1, 2.
• Nitrates require enzymatic biotransformation by mitochondrial aldehyde dehydrogenase to produce vasoactive nitric oxide, a process that depends on sulfhydryl cofactors 3.
• Continuous nitrate exposure depletes these essential sulfhydryl groups, reducing the conversion of nitrates to nitric oxide and diminishing vasodilatory effects 4, 2.

Neurohormonal Counter-Regulation

• Tolerance is associated with activation of compensatory vasoconstrictor mechanisms that oppose nitrate-induced vasodilation 5, 4.
• Elevated plasma catecholamines, arginine vasopressin, and plasma renin activity develop during continuous nitrate therapy 4.
• Activation of the renin-angiotensin system leads to sodium and water retention with plasma volume expansion, which modulates the effect of nitrate-induced vasodilation 4.

Additional Contributing Factors

• Oxygen free radical injury may contribute to tolerance development 5.
• Potential downregulation of membrane-bound enzymes or nitrate receptors has been proposed but remains incompletely understood 5.
• The shift of fluid from extravascular to intravascular compartments may attenuate hemodynamic effects 5.

Clinical Manifestations

Time Course and Characteristics

• Tolerance develops rapidly, often within 24 hours of continuous nitrate exposure 5, 2.
• Both in-vitro vascular strips exposed to millimolar concentrations and in-vivo continuous therapy demonstrate rapid tolerance development 5.
• Tolerance is dose- and time-dependent, with higher doses and longer exposure periods producing more pronounced effects 2.

Pattern of Tolerance

• Venous tolerance appears to develop more readily than arterial tolerance, which may explain the attenuation of nitrate effects during long-term therapy 5.
• In heart failure patients receiving isosorbide dinitrate 40 mg every 6 hours for 3 months, tolerance developed to systemic arterial-arteriolar effects while pulmonary vascular and venous dilative effects were maintained 1.

Prevention Strategies

Nitrate-Free Intervals

• The American College of Cardiology/American Heart Association guidelines recommend a nitrate-free interval of at least 10 hours to minimize tolerance development 3.
• Intermittent nitrate therapy prevents or minimizes both in-vitro and in-vivo tolerance 5, 6.
• Regimens should provide antianginal prophylaxis for 10-14 hours during daytime with overnight nitrate-free periods 5, 6.

Combination Therapy

• Combining nitrates with ACE inhibitors or hydralazine may help prevent tolerance development 3.
• The American Heart Association suggests that hydralazine may prevent nitrate tolerance through its potential antioxidative properties 7.
• Hydralazine may interfere with biochemical and molecular mechanisms responsible for tolerance development 3.

Sulfhydryl Donor Approach

• Repletion of sulfhydryl groups with sulfhydryl-containing drugs may help prevent tolerance 2.
• However, the efficacy and safety of this approach requires further evaluation, as studies using agents to counteract tolerance mechanisms have produced conflicting results 5, 2.

Important Clinical Caveats

Rebound Phenomena

• During nitrate-free periods, rebound phenomena can occur, including rest angina in patients with ischemic heart disease or deterioration in exercise performance 5, 6.
• Industrial workers with long-term nitrate exposure have experienced chest pain, acute myocardial infarction, and sudden death during temporary withdrawal, demonstrating true physical dependence 8, 9, 5.

Continuous Therapy Considerations

• For unstable angina, continuous intravenous nitroglycerin is recommended despite tolerance development, as tolerance can be overridden by dose escalation 5.
• Intermittent therapy cannot be recommended for unstable angina because rebound angina during nitrate-free periods complicates clinical decision-making 5.