ROLE OF L-ARGININE IN CONTROL OF BRAIN MICROCIRCULATION

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We postulate 2 roles for L-Arginine in the control of brain microcirculation. Both roles are endothelium dependent and depend on the production of an endothelium derived relaxing factor ("EDRF") from L-Arginine. The "EDRF" relaxes the vessels and opposes platelet adhesion and aggregation. These hypotheses are based on a variety of published data, most of it in vitro. Tests of the hypotheses will be performed on mouse pial arterioles in vivo. Diameter will be monitored by TV microscopy. We will test the ability of L-Arg to dilate the arterioles and the ability of L-NMMA to block this dilation and to constrict the arterioles. L-NMMA is the putative inhibitor of the L-Arg to "EDRF" pathway. We will compare the activities of L-Arg with other amino acids (controls). We will injure the endothelium with a laser/Evans blue technique. This eliminates "EDRF". If the actions of L-Arg or LNMMA on diameter are endothelium dependent and mediated by "EDRF", these actions should be lost. A greater injury by laser/Evans blue will induce platelet aggregation at the damaged site. We monitor onset of aggregation via intravital microscopy. We will test the capacity of L-Arg or L-NMMA to influence the onset of aggregation. Platelet aggregation is inhibited during and after periods of high shear. We will see if this is due to increased release of "EDRF" by attempting to alter the effects of high shear with agents known to alter "EDRF" release and with L-Arg and LNMMA. Zones of very minimal endothelial injury eliminate local "EDRF" without inducing platelet aggregation. Such zones will now "capture" passing platelet emboli or platelets activated by an upstream stimulus. We will attempt to alter the increased "stickiness" of such "capture" sites by treating the vessels with substances known to alter production or release of "EDRF", and with L-Arg and LNMMA. A role of L-Arg in control of local platelet aggregation/adhesion via EDRF will be supported if: (a) enhancers of EDRF production/release inhibit aggregation/adhesion - (b) L-Arg and LNMMA respectively inhibit and enhance local aggregation/adhesion.