Objective-Arginine used for nitric oxide formation can be from intracellular stores or transported into cells. The study evaluated the rapidity and primary site of NO and vascular resistance responses to arginine at near physiological concentrations (100-400 μM). Conclusions-This study demonstrated arterial resistance responses are as or more responsive to arginine induced NO formation as arterioles at near physiological concentrations of arginine. The vascular NO and resistance responses occurred rapidly at L-arginine concentrations at and below 400 μM, which predict arginine transport processes were involved. Methods-Arginine

ORIGINAL RESEARCH ARTICLEand low survival, lung cancer is the most common cause of death from cancer worldwide with 1.59 million deaths, more than 1 million in men and 491,000 in women (1). In Europe, it is the third most common cause of cancer, after breast and prostate cancer (1).The epidemiology of lung cancer is changing in many areas of the world in terms of incidence by gender, age class and histological type (3, 4). Different histological subtypes are linked to different risk factors; for example, outdoor particulate matter has been recognized as a stronger risk factor for adenocarcinoma of the lung than for other histologies, while smoking has been associated in the past mainly with squamous cell carcinoma. However, because of the dissemination of low-tar filter cigarettes, smoking has been hypothesized to be linked also with adenocarcinoma (3). Lung cancer appears to have biologically different characteristics in men and women. The histological distribution of lung cancer subtypes is distinctly different and female smokers are more likely to develop adenocarcinoma of the lung than squamous cell carcinoma, which is more common in men (4). However, the differences in incidence rates between men and women are mainly attributable to the different exposure to tobacco smoking (3).

Renal tubules process large amounts of NaCl that other investigators indicate increases tubular generation of nitric oxide. We questioned whether medullary or superficial cortical tubules would have the greater increase in nitric oxide concentration, [NO], when stressed by sodium and if the sodium/calcium exchanger was involved. Sodium stress in proximal tubules is due to the large amount of sodium absorbed and medullary tubules exist in a hypertonic sodium environment. To sodium stress the tissue, mouse kidney slices were exposed to monensin to allow passive entry of sodium ions from isotonic media and in separate studies, 400 and 600 mOsm NaCl was used. [NO] was measured with microelectrodes. Monensin (10 μM) caused a sustained increase in medullary and cortical [NO] to ∼180% of control and 400 mOsm NaCl caused a similar initial increase in [NO] that then subsided. 600 mOsm NaCl caused a more sustained increase in [NO] of >250% of control. L-NAME strongly attenuated the increased [NO] during sodium stress. The increase in [NO] during NaCl elevation was due to sodium ions because mannitol hyperosmolarity caused ∼20% of the increase in [NO]. Entry of sodium during NaCl hyperosmolarity was through bumetanide sensitive channels because the drug suppressed increased [NO]. Blockade of the sodium/calcium ion exchanger strongly suppressed the increased [NO] during monensin, to increase sodium entry into cells, and the elevated NaCl concentration. The data support a sodium -NO linkage that increased NO signaling in proportion to sodium stress by cortical tubules and was highly dependent upon sodium-calcium exchange.

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