Two possible mechanisms underlying nitrate tolerance in monkey coronary arteries

Area of Science:

• Pharmacology
• Cardiovascular Physiology

Background:

• Nitric oxide (NO) donors like nitroglycerin (NTG) and sodium nitroprusside (SNP) exhibit cross-tolerance.
• The effect of atrial natriuretic peptide (ANP) on vasorelaxation in the context of NO donor tolerance is not well understood.

Purpose of the Study:

• To investigate cross-tolerance and interactions between NTG and ANP in coronary vasorelaxant responses.
• To elucidate the mechanisms underlying NTG tolerance in coronary arteries.

Main Methods:

• Utilized two models of isolated monkey coronary arterial strips (Macaca fuscata).
• Assessed vasorelaxant effects of NTG, ANP, and NO following different NTG pre-treatment protocols (with and without washout).
• Evaluated responses to 8-bromo-cGMP (8-Br-cGMP), papaverine, and forskolin to probe intracellular signaling pathways.

Main Results:

• NTG tolerance, induced with washout, attenuated subsequent NTG but not ANP or NO vasorelaxation, suggesting NO biotransformation is key.
• Without washout, NTG pre-treatment significantly attenuated vasorelaxant responses to ANP, NO, and SNP.
• The concentration-response curve for 8-Br-cGMP was shifted rightward, indicating impaired downstream signaling after cGMP synthesis.

Conclusions:

• NTG tolerance may involve impaired biotransformation of NTG to NO.
• An intracellular process occurring after cGMP synthesis is also implicated in NTG tolerance, affecting responses to ANP and other vasodilators.