Comparison of effects of chronic and acute administration of NG‐nitro‐L‐arginine methyl ester to the rat on inhibition of nitric oxide‐mediated responses
Authors: Bryant Clare E. , Allcock Graham H. , Warner Timothy D. 
Published: July 2012

Vascular responses to acetylcholine and sodium nitroprusside in vivo and in vitro, in the isolated perfused kidney and in rings of rat thoracic aorta, were measured in rats treated chronically with NG‐nitro‐L‐arginine methyl ester (l‐NAME; approx, 70 mg kg−1) and compared to responses in age‐ matched control animals, and age‐matched animals after the acute administration of L‐NAME (3–100 μmol kg−1). Parallel experiments examined alterations in responsiveness in rings of trachea and anococcygeus muscles taken from the same animals.
Chronic oral administration of L‐NAME elevated the blood pressure in anaesthetized animals from 114 ± 5mmHg to 153 ± 11mmHg (n = 5). The hypotensive responses to both acetylcholine (1 nmol kg−1) and sodium nitroprusside (10 nmol kg−1) were enhanced by chronic L‐NAME treatment (n = 5–7) whereas acute L‐NAME administration enhanced only the response to sodium nitroprusside (n = 5).
After chronic treatment with L‐NAME, the basal perfusion pressure in the isolated perfused kidney was elevated. However, vasodilator responses to either acetylcholine (1 nmol) or sodium nitroprusside (3 nmol) were unaltered (n = 5–7). The vasodilatation induced by acetylcholine was inhibited in a concentration‐dependent manner by the administration of acute L‐NAME (0.1–100 μm; n = 5), such that significant inhibition was seen at 10 μm L‐NAME. The response to sodium nitroprusside was unaffected by L‐NAME.
The relaxations of isolated rings of rat thoracic aorta induced by acetylcholine were inhibited in tissues prepared from rats treated chronically with L‐NAME (n = 5–7). Acute administration of L‐NAME (0.1–100 μm) concentration‐dependently inhibited the relaxations induced by acetylcholine in this preparation, with significant inhibition occurring at 1 μm L‐NAME (n = 5). Responses to sodium nitroprusside were unaffected by either chronic or acute exposure to L‐NAME (n = 5–7).
Relaxations of precontracted anococcygeus muscles induced by electrical field stimulation, or contractions of rings of trachea induced by carbachol or endothelin‐1, were unaffected by chronic oral administration of L‐NAME (n = 4–6). Acute addition of L‐NAME (0.1–100 μm) to the organ baths inhibited in a concentration‐dependent manner the relaxations of anococcygeus muscles taken from control animals, with a significant effect being seen at a concentration of 10 μm (n = 4–6).
Our cardiovascular data are consistent with chronic oral administration of L‐NAME inhibiting the production of nitric oxide (NO) within the vasculature, although the pattern of inhibition is not uniform between different tissues. Despite the inhibition of endothelial NO production, chronic L‐NAME does not alter the vasodepressor activity of acetylcholine in vivo or in the isolated perfused kidney. This may be explained by an enhanced responsiveness of guanylyl cyclase pathways, the increased release of vasodilators other than nitric oxide or a decreased importance of nitric oxide in resistance vessels compared with conductance vessels. The resistance of peripheral neuronal NO responses to chronic treatment with L‐NAME indicates that selective inhibition of different isoforms of NOS may be achieved in vivo.