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pu12en12g · #1 04-08-2006, 08:03 AM

Nobel committee says yes to 'NO'

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The 1998 Nobel Prize in Physiology and Medicine

The Nobel Foundation recently announced its winner for the 1998 Nobel Prize in Physiology and Medicine. The prestigious honor goes this year to three Americans who independently made important contributions to the discovery that the gas nitric oxide (chemical formula NO) can act as a signaling molecule. Since its discovery, it has been found to play important roles in a variety physiological systems, including the nervous system where it can act as a second messenger, and as a neurotransmitter.

There is a bit of irony in the topic of the award this year. The Nobel Prize was created by Alfred Nobel who invented a process to stabilize nitroglycerine to form dynamite. Even in his day, it was known that small amounts of nitroglycerin would relieve angina heart pain through some undetermined mechanism. And, Nobel was himself treated with this compound for his heart condition. Now, about one century later, the award is being given for work that elucidated the mechanism by which nitroglycerine can relieve angina.

The discovery of NO as a signaling molecule

The work that eventually lead to the discovery of NO as a signaling molecule began with an investigation of drugs that caused relaxation or contraction of vascular smooth muscle. Initial experiments showed that acetylcholine caused a contraction of an isolated smooth muscle preparation made from aorta, the large artery that caries blood away from the heart. This was somewhat of a paradox since cholinergic drugs that act the same way as acetylcholine cause vasodilation (relaxation of the vascular smooth muscle) when given systemically.

Later experiments gave contradictory results, and further investigation led to the finding that if the epithelium associated with the vascular smooth muscle were intact, cholinergic drugs would cause relaxation of the smooth muscle, while in preparations where the epithelial cells were removed, it would cause contraction. This led to the conclusion that the epithelial cells released some chemical that caused the smooth muscle to relax and the search was on for this new compound, then called endothelium-derived relaxing factor (EDRF).

Around the same time, work was being done to determine how certain nitrogenous compounds, like nitroglycerine could affect vascular smooth muscle. This work showed that these compounds released NO, and that it was the NO that was effecting the relaxation of smooth muscle. This led to the hypothesis that EDRF could be NO, a hypothesis that was shortly confirmed. Later work found the synthetic enzyme that makes NO (nitric oxide synthase, or NOS) and its distribution throughout many tissues, including in the peripheral and central nervous systems.

NO in the brain

As a signaling molecule, NO is very unique. It is the first gas that has ever been shown to act as a signaling molecule. Furthermore, NO is a caustic component of diesel exhaust that is highly reactive (for example, white blood cells also create NO as one of the weapons they use to kill bacteria.) But NO was soon found to be involved in may physiological process, including penile erection; the drug Viagra works by exploiting a signaling pathway that uses NO.

To add to the surprise, an isoform of NOS that makes NO was found to be widely, but selectively distributed in the brain. This led to the idea that NO was acting as a neurotransmitter in the brain. Since then, scientists have learned that NO is involved in a number of neuronal functions including long-term potentiation (a cellular basis for learning), synapse formation, drug tolerance and dependence, modulation of sensory and motor pathways, local regulation of cerebral blood flow, neuroendocrine regulation, learning, and feeding and sexual behavior. I will deal more with the mechanism of NO action in the brain in a later feature article.

The Prize Recipients

Dr. Robert F. Furchgott
Ph.D. Biochemistry, Northwestern University,
Department of Pharmacology, SUNY Health Science Center

Dr. Furchgott studied the effects of various drugs on blood vessels. He found that in some cases, the same drug caused contradictory results. Work in his lab demonstrated that the different results depended on whether the epithelial lining of the blood vessels was intact and from this concluded the epithelial cells released some chemical that caused relaxation of the blood vessels. Much of his research efforts in the 1970's and 1980's were directed toward elucidating the nature of this compound, that he called endothelium-derived relaxing factor (EDRF), and that he later concluded was NO.

Dr. Louis J. Ignarro
Ph.D. Pharmacology, University of Minnesota
Department of Molecular and Medical Pharmacology, UCLA School of Medicine

Dr. Ignarro was also on the quest for the identity of ENDF. His laboratory independently, and simultaneously with Dr. Furchgott's demonstrated that ENDF was NO. Results from both labs were presented at the same scientific conference in July, 1986.

Dr. Freid Murad
M.D./Ph.D. Pharmacology, Western Reserve University
Department of Integritive Biology, Pharmacology, and Physiology, University of Texas Medical School at Huston.

Dr. Murad investigated the way that compounds like nitroglycerine cause vasodilation. In 1977, he discovered that these compounds release NO, and that this in turn was the factor that caused relaxation of the vascular smooth muscle. In 1977, he hypothesized that endogenous factors may also work through NO, and it was his work that paved the way for the research of Drs. Furchgott and Ignarro that demonstrated that endogenously released NO from epiltheial cells can effect vasodilation.

pu12en12g · #2 04-08-2006, 08:04 AM

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Dietary L-Arginine Supplementation Improves the Glomerular Filtration Rate and Renal Blood Flow After 24 Hours of Unilateral Ureteral Obstruction in Rats.

Ito K, Chen J, Vaughan ED Jr, Seshan SV, Poppas DP, Felsen D.

SUMMARY: PURPOSE Unilateral ureteral obstruction (UUO) results in a significant change in renal blood flow (RBF) and glomerular filtration rate (GFR) by 24 hours. The intake of L-arginine, a substrate of nitric oxide (NO) synthase (NOS), can augment NO production. NO can maintain renal function through its vasodilatory action. Therefore, we examined the effect of dietary arginine supplementation on renal function in UUO.

MATERIALS AND METHODS GFR and RBF were measured by inulin and para-aminohippurate clearance, respectively, in control rats and in rats 24 hours after UUO. Rats were given arginine with or without the concomitant administration of N-nitro-L-arginine methyl ester. Urinary nitrate/nitrite (NO2/NO3) was measured by the Griess reaction and urinary cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. The expression of renal inducible NOS was determined by immunohistochemistry.

RESULTS Urinary NO2/NO3 was significantly increased after 2 weeks of arginine, confirming increased NO production. In control rats GFR and RBF were not significantly different in untreated vs arginine treated groups. In contrast, arginine treatment significantly increased GFR in the obstructed kidney (0.06 +/- 0.01 to 0.14 +/- 0.02 ml per minute per 100 gm) and the contralateral kidney compared with control UUO. RBF was also significantly increased by arginine. The increases in renal function with arginine were blunted by a NOS inhibitor in obstructed and contralateral kidneys. Inducible NOS expression was increased in obstructed and contralateral kidneys.

CONCLUSIONS This study demonstrates that L-arginine supplementation can improve renal function in acute UUO. This finding suggests that NO system may be a future site of pharmacological intervention for UUO.

FYI

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