Agents that modify EDRF formation alter antiplatelet properties of brain arteriolar endothelium in vivo.
In the presence of circulating Evans blue a helium-neon laser injures the endothelium of brain surface arterioles in situ. The injury is known to selectively eliminate endothelium-dependent responses. The present study documents in mice the fact that such endothelial sites become selectively attractive to passing platelets that have been activated as a result of more severe injury upstream. We then test the hypothesis that the "capture" of platelets at the downstream site is due to loss of "classical" endothelial-dependent relaxing factor of acetylcholine (EDRFACh) at that site. EDRFACh is known to inhibit platelet adhesion/aggregation and is synthesized from L-arginine. We show that agents that would either enhance or reduce the synthesis of local EDRFACh reduce or increase the incidence of capture as predicted by the hypothesis. Thus NG-monomethyl-L-arginine (L-NMMA) and arginase that would reduce synthesis of EDRFACh enhanced platelet capture. L-Arginine, which would enhance synthesis of EDRFACh, inhibited platelet capture. In addition, L-NMMA and arginase enhanced platelet aggregation over the more severely damaged site upstream from the site of capture. Ex vivo studies of platelets harvested from treated mice showed that the platelets themselves were unaffected by the treatments that, except for arginase given intravenously, all involved topical application of the tested drugs.
Nishimura
H
H
Department of Pathology (Neuropathology), Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0017.
Rosenblum
W I
WI
Nelson
G H
GH
Boynton
S
S
D000109:Acetylcholine / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D001119:Arginase / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001160:Arterioles / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology*; D002560:Cerebrovascular Circulation; D004730:Endothelium, Vascular / Q000502:physiology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019323:omega-N-Methylarginine
D010975:Platelet Aggregation Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase; D000109:Acetylcholine