CGS-22652

Although reductions in retinal blood flow (RBF) in response to acute hyperoxia are well described, the mechanistic basis of this response has yet to be clarified. The present study was undertaken in order to determine the possible involvement of two arachidonic acid-derived vasoconstrictors, the cyclooxygenase metabolite thromboxane and the cytochrome P450 metabolite 20-HETE, as well as the involvement of the peptide endothelin and superoxide free radical. Fluorescein videoangiography was performed on the intact eyes of isoflurane-anesthetized newborn piglets. RBF responses to 20 min of hyperoxia were calculated from the angiograms off-line, using changes in mean arteriovenous transit times and arteriolar and venular diameters. The effect of hyperoxia (PaO2=351+/-9 mmHg; n=39) on RBF was examined in each animal under control conditions and again after intravitreal perivascular administration of drugs that block the synthesis or receptors of known vasoconstrictors. Estimated RBF decreased by a maximum of 42+/-3% in the 7 animal groups in response to 20 min of hyperoxia. The magnitude and time course of the change in RBF resulting from two successive hyperoxic challenges did not differ, and were unaffected by intravitreal administration of vehicle. The response to hyperoxia was attenuated 46+/-6 (n=6; P=0.001) after intravitreal CGS 22652 (2 nmol), a combined thromboxane synthesis inhibitor and receptor antagonist. DDMS (12.5 nmol), a competitive inhibitor of the P450 enzyme omega-hydroxylase that forms 20-HETE, blocked hyperoxic constriction by 23+/-7% (n=6; P=0.01). Intravitreal pretreatment with TBC 1241z (2 nmol), a receptor antagonist of the peptide endothelin, blocked the hyperoxic response by 26+/-5% (n=6; P=0.01). A combination of CGS 22652 (2 nmol), DDMS (12.5 nmol), and TBC 1241z (2 nmol), blocked the hyperoxic flow response by 51+/-3% (n=5; P=0.003). Administration of a combination of superoxide dismutase (10 U intravitreally, 10000 U kg-1 of the polyethylene glycol-conjugate intravenously) and catalase (10 U intravitreally, 10000 U kg-1 intravenously) was without effect on hyperoxia-induced reductions in RBF (n=5). The present results indicate that the arachidonic acid metabolites thromboxane and 20-HETE, and the peptide endothelin, participate in mediating the acute reduction in RBF in response to hyperoxia.

The goal of the study was to determine the role of cyclooxygenase metabolites in mediating platelet-induced suppression of baroreceptor activity. Exposure of the isolated carotid sinus of rabbits to thrombin-activated rabbit platelets (3 x 10(8) cells/ml Krebs buffer) decreased baroreceptor activity (P < 0.05) without significantly altering the slope of the pressure-activity relation (gain). The platelet-induced suppression of activity was not blocked but instead was even more pronounced after inhibition of cyclooxygenase with indomethacin; both maximum baroreceptor activity and gain were decreased markedly. The exacerbation of platelet-induced baroreceptor dysfunction contrasted with equivalent carotid vasoconstrictor responses to platelets before and after indomethacin. Furthermore, the stable thromboxane (TxA2) mimetic U-46619 caused similar vasoconstriction as platelets but did not influence baroreceptor gain or maximum activity. In contrast to indomethacin, the selective TxA2 synthesis inhibitor and receptor blocker CGS-22652 failed to influence platelet-induced suppression of activity. In summary, 1) rabbit platelet aggregating in carotid sinus suppress baroreceptor activity, which cannot be explained by the vasoconstriction, and 2) the suppression of activity is not mediated by TxA2 from platelets and is opposed by prostacyclin (PGI2) or other prostanoids produced in carotid sinus. The combination of impaired formation of PGI2 and platelet activation in atherosclerotic and thrombotic states may lead to profound baroreceptor dysfunction.