Continuous infusion of glyceryl trinitrate for more than 24 to 48 hours leads to loss of antianginal effect. The mechanism of nitrate tolerance is best explained by:
- A Downregulation of soluble guanylate cyclase in vascular smooth muscle
- B Depletion of tissue sulfhydryl groups with reduced bioactivation of nitrate to nitric oxide ✓
- C Induction of hepatic cytochrome enzymes accelerating nitrate clearance
- D Compensatory activation of the renin-angiotensin system causing receptor resistance
Correct answer: B. Depletion of tissue sulfhydryl groups with reduced bioactivation of nitrate to nitric oxide
Explanation
Tolerance develops because organic nitrates require bioconversion by mitochondrial aldehyde dehydrogenase and related enzymes that consume free sulfhydryl groups. Depletion of these groups impairs generation of nitric oxide and S-nitrosothiols, reducing cGMP formation. B nitrate-free interval of 10 to 12 hours restores responsiveness, which is why asymmetric dosing is recommended. Soluble guanylate cyclase is not downregulated, and hepatic induction does not explain the phenomenon.
Reference: Katzung Basic and Clinical Pharmacology, 16th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.