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.