Mechanisms of hyperoxia-induced reductions in retinal blood flow in newborn pig.
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.
Department of Neurological Surgery, Washington University School of Medicine, and St. Louis Children's Hospital, St. Louis, MO, USA.
Y
Y
Zhu
T S
TS
Park
J M
JM
Gidday
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002210:Caprylates / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005451:Fluorescein Angiography; D018496:Hyperoxia / Q000503:physiopathology*; D007267:Injections; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D014741:Video Recording
D002210:Caprylates; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; C078274:CGS 22652