N-Acetyl Cysteine Found to Trigger Pulmonary Arterial Hypertension in Mice

Researchers have found that the antioxidant N-acetyl cysteine (NAC) can interfere with the nitric oxide (NO) signaling system with serious physiological ramifications such as the development of pulmonary arterial hypertension (PAH).

Nitric oxide is a key biological messenger, playing a role in a variety of biological processes. Known as the endothelium-derived relaxing factor (EDRF), nitric oxide is biosynthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by reduction of inorganic nitrate. The endothelium of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. The production of nitric oxide is elevated in populations living at high-altitudes, which helps these people avoid hypoxia. Nitric oxide is also generated by macrophages and neutrophils as part of the human immune response. Nitric oxide is toxic to bacteria and other human pathogens, however many bacterial pathogens have evolved mechanisms for nitric oxide resistance.

Investigators at the University of Virginia Health System (Charlottesville, USA) used NAC as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo. Results of their studies published in the September 2007 issue of the Journal of Clinical Investigation revealed that NAC was converted to S-nitroso-N-acetylcysteine (SNOAC), decreasing red blood cell S-nitrosothiol content, both during whole-blood deoxygenation in vitro and during a three-week protocol in which mice received a high-dose of NAC in vivo. The NAC-treated mice developed pulmonary arterial hypertension (PAH). PAH results in thickening of the pulmonary arteries and narrowing of these blood vessels. In response, the right side of the heart works harder to move the blood through these arteries, and it becomes enlarged. Eventually overworking the right side of the heart may lead to right-sided heart failure, resulting in death.

"NAC fools the body into thinking that it has an oxygen shortage,” said senior author Dr. Ben Gaston, professor of pediatrics at the University of Virginia Health System. "We found that an NAC product formed by red blood cells, know as a nitrosothiol, bypasses the normal regulation of oxygen sensing. It tells the arteries in the lung to ‘remodel'; they become narrow, increasing the blood pressure in the lungs and causing the right side of the heart to swell.”


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