S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators

Area of Science:

• Pharmacology
• Cardiovascular Research
• Nitric Oxide Signaling

Background:

• N-acetylcysteine (NAC) has been observed to enhance the effects of glyceryl trinitrate (GTN).
• The formation of S-nitrosothiol compounds, such as S-nitroso-N-acetylcysteine (SNAC), is proposed to mediate these effects.

Purpose of the Study:

• To investigate the effects of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO) on isolated coronary arteries.
• To understand the role of SNAC formation in vasodilation and tolerance development.

Main Methods:

• Isolated bovine coronary artery rings were used to study responses to NO, SNAC, and S-nitroso-N-acetyl-penicillamine (SNAP).
• Experiments involved acute and prolonged superfusion with vasodilators and assessment of relaxation responses.
• High-performance liquid chromatography (HPLC) was used to confirm SNAC formation.

Main Results:

• SNAC, SNAP, and NO induced rapid but transient relaxations. SNAC's duration of action was longer than SNAP and NO.
• N-acetylcysteine significantly increased the duration of SNAP and NO-induced relaxations by converting them to SNAC.
• Prolonged exposure to SNAC or NO led to tolerance, distinct from GTN-induced tolerance, potentially involving impaired guanylate cyclase activity.

Conclusions:

• SNAC is a more stable vasodilator formed from NAC, SNAP, or NO.
• SNAC formation can acutely circumvent GTN-induced tolerance.
• Prolonged exposure to SNAC or NO can induce tolerance to a range of vasodilators, including GTN, but not endothelium-dependent agents like A23187.