thioinosine and Hyperoxia

Little is known regarding the status and implications of altered retinal blood flow (RBF) following a period of temporary retinal ischemia. We undertook studies to measure acute changes in RBF after ischemia, and the mechanisms responsible for mediating these changes.. Retinal ischemia was induced in anesthetized, mechanically ventilated newborn pigs by severe hypoxia, hypotension, and bradycardia secondary to 9 min of asphyxia by discontinued ventilation. Using fluorescein videoangiography, we calculated stimulus-induced changes in RBF by measuring changes in arteriovenous transit times and arteriolar and venular diameters from the angiogram videorecordings.. Asphyxia led to a progressive reduction in RBF during early reperfusion, with RBF decreasing 24 +/- 6% and 34 +/- 5% below baseline 1 h and 2 h, respectively, after asphyxia (n = 6). Intravitreal administration of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (25 nmol) at 15 min of postischemic reperfusion did not increase the magnitude of hypoperfusion (n = 6), and intravitreal acetylcholine (20 nmol) was no longer able to increase RBF at 1.5-2.0 h of postasphyxic reperfusion. The endothelin A receptor antagonist TBC 11251z attenuated the response by 53% at 2 h (n = 5). The adenosine transport inhibitor 4-nitrobenzyl-6-thioinosine reversed the hypoperfusion response (n = 5), whereas ventilating animals with 100% oxygen during reperfusion exacerbated the flow deficit, with RBF reduced to 49 +/- 5% below baseline at 2 h post-asphyxia (n = 6).. These findings indicate that (1) constriction by endothelin, together with a loss of nitric oxide's tonic dilatative effect, contributes importantly to mediating postischemic hypoperfusion in retina; (2) improvements in retinal perfusion can be realized with endothelin receptor blockade or potentiation of extracellular adenosine; and (3) additional reductions in postischemic RBF can occur in response to resuscitation with 100% oxygen because retinal microcirculatory reactivity to hyperoxia remains intact during the hypoperfusion period.

Topics: Acetylcholine; Adenosine; Animals; Animals, Newborn; Blood Flow Velocity; Endothelin Receptor Antagonists; Endothelium, Vascular; Enzyme Inhibitors; Fluorescein Angiography; Hyperoxia; Hypoxia; Ischemia; Isoxazoles; Nitric Oxide Synthase; omega-N-Methylarginine; Reperfusion; Retinal Vessels; Swine; Thioinosine; Thiophenes