L-NMMA in brain microcirculation of mice is inhibited by blockade of cyclooxygenase and by superoxide dismutase.
As previously reported, NG-monomethyl-L-arginine (L-NMMA) constricted pial arterioles, inhibited dilation of pial arterioles by acetylcholine (ACh) or L-arginine (L-Arg), and enhanced platelet adhesion/aggregation at sites of endothelial damage. However, all of these effects were inhibited by local application of 20 micrograms/ml indomethacin (Indo). When 100 micrograms/ml acetylsalicylic acid were used instead of Indo, the acid also blocked the effects of L-NMMA. Superoxide dismutase (SOD; 50 U/ml) blocked the constriction produced by L-NMMA and also blocked the constriction produced by N omega-nitro-L-arginine (NNA). SOD also prevented L-NMMA from blocking dilation by ACh. SOD itself had no effect on diameter or on the response to ACh, norepinephrine, or BaCl2. The effects of L-NMMA and of Indo were also selective. Thus L-NMMA did not inhibit dilation by prostacyclin or bradykinin, and Indo did not inhibit dilation by prostacyclin. Indo did not interfere with the ability of arginase to enhance platelet adhesion/aggregation or with the ability of ACh or L-Arg to inhibit adhesion/aggregation. We conclude that in mouse cerebral microcirculation the ability of L-NMMA and NNA to constrict arterioles, the ability of L-NMMA to inhibit dilation by ACh or L-Arg and the ability of L-NMMA to enhance platelet adhesion/aggregation are all related to interference with phenomena dependent on "classical" endothelium-derived relaxing factor (EDRFACh). However, in this preparation the action of L-NMMA or NNA may not be due to competitive inhibition of the enzyme producing EDRFACh from L-Arg. Rather, L-NMMA and NNA appear to activate cyclooxygenase with resultant production of superoxide, which inactivates EDRFACh.
Rosenblum
W I
WI
Department of Pathology (Neuropathology), Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0017.
Nishimura
H
H
Nelson
G H
GH
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016166:Free Radical Scavengers; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008833:Microcirculation / Q000187:drug effects; D019335:Nitroarginine; D010974:Platelet Aggregation / Q000187:drug effects; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine
D016861:Cyclooxygenase Inhibitors; D016166:Free Radical Scavengers; D014665:Vasodilator Agents; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D001120:Arginine; D013482:Superoxide Dismutase; D001241:Aspirin; D007213:Indomethacin