DELAYED PLATELET-ADHESION AGGREGATION AT SITES OF ENDOTHELIAL INJURY IN MOUSE CEREBRAL ARTERIOLES AFTER TRANSIENT ELEVATIONS OF BLOOD-PRESSURE AND SHEAR

Background and Purpose Prior research showed that injection of angiote nsin II (Ang II) produces a transient elevation of blood pressure (BP) and shear in pial arterioles. This inhibited platelet adhesion/aggreg ation at a site of subsequently injured endothelium. The present study attempted to confirm the Ang II finding with a different method of en dothelial injury, to test the hypothesis that the effect on adhesion/a ggregation was a consequence of prolonged release of ''classic'' endot helium-derived relaxing factor (released by acetylcholine [Ach]; EDRF( ACh)) produced by the preceding transient elevation in shear, and to s how with the use of norepinephrine rather than Ang II that the effect of a preceding elevation of BP was independent of the presser agent us ed. Methods Focal platelet adhesion/aggregation was elicited in cerebr al surface (pial) arterioles by producing minimal endothelial damage w ith a helium-neon laser/Evans blue dye technique. Vessels were observe d by intravital microscopy. We recorded the time required for the lase r to elicit adhesion/aggregation in control mice and in mice given Ang II in a dose of 16 mu g/25 g IF. This dose produces an abrupt and sig nificant elevation of BP and shear, which return to baseline levels in less than 30 minutes. Laser/dye damage of endothelium and resultant a dhesion/aggregation of platelets were not induced until after BP and s hear returned to basal levels. The effect of topical Ang II on damage- induced adhesion/aggregation was also tested. In addition, mice inject ed with Ang II were treated with either topical indomethacin 40 mu g/m L or topical N-G-monomethyl L-arginine (L-NMMA; 10(-6) mol/L) in an ef fort to prevent the preceding increase in shear from inhibiting subseq uent adhesion/aggregation. Finally, norepinephrine instead of Ang II w as used to transiently raise BP (and shear) in an effort to delay subs equently induced adhesion/aggregation. Results Platelet adhesion/aggre gation at the injured site was significantly delayed by a prior transi ent rise in shear produced by either Ang II or norepinephrine. Locally applied Ang II failed to influence adhesion/aggregation, although a p revious study showed that such Ang II reaches the endothelium. Locally applied indomethacin had no effect on inhibition of platelet adhesion /aggregation, but locally applied L-NMMA prevented the prior transient elevation of shear from inhibiting adhesion/aggregation at a subseque ntly injured site. Conclusions Elevation of BP with consequent elevati on of shear inhibits local platelet adhesion/aggregation even when the latter is initiated by endothelial damage produced after return of sh ear to basal levels. The direct action of Ang II on endothelium is not responsible for the effect on adhesion/aggregation and indeed the eff ect is independent of the presser agent. The pharmacological data, tog ether with the literature, support the hypothesis that increased shear causes an increased release of EDRF(ACh), which may continue for at l east some minutes after return of shear to normal levels.