15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Retinal-Diseases

The retinal blood flow depends on the diameter of retinal arterioles, but diameter changes in these vessels have hitherto only been assessed in vessels larger than approximately 100 μm. Therefore, a new method was developed for studying diameter changes along the vascular tree of arterioles in whole perfused segments of porcine retinas, and the effect of known vasoconstrictors on the diameter of retinal arterioles at different branching levels were studied.. Thirty-four whole-mounted porcine retinas were placed in a specially designed tissue chamber. On the basis of video recordings through an inverted microscope, the diameter of retinal arterioles was measured at five different branching levels before and after addition of a high potassium concentration, or increasing concentrations of endothelin-1, the prostaglandin analogue U46619, noradrenaline or none (time controls).. The baseline diameter ranged from 136 μm (95% CI 132-140 μm) for 1st order arterioles to 33 μm (95% CI 21-44 μm) for 5th order arterioles. In 1st order arterioles, endothelin produced 56.6% (95% CI 47.6-64.0) and U46619 14.6% (95% CI 5.7-22.6) relative constriction compared with baseline, which for both compounds decreased significantly with increasing branching level (p<0.0001 and p<0.0001, respectively). The change in diameter during addition of noradrenaline did not differ significantly from the time controls (p=0.07).. The effect of retinal vasoconstrictors differs among larger and smaller arterioles. The study highlights the need for investigating diameter regulation in smaller retinal arterioles as a basis for understanding normal and pathological changes in retinal blood flow.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterioles; Disease Models, Animal; Endothelin-1; Regional Blood Flow; Retinal Artery; Retinal Diseases; Swine; Vasoconstriction; Vasoconstrictor Agents; Video Recording

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2 (TxA2), we tested whether TxA2 plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2 exposure from postnatal days 5-14) was associated with increased TxB2 generation and was significantly prevented by TxA2 synthase inhibitor CGS-12970 (10 mg x kg(-1) x day(-1)) or TxA2-receptor antagonist CGS-22652 (10 mg x kg(-1) x day(-1)). TxA2 mimetics U-46619 (EC50 50 nM) and I-BOP (EC50 5 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2 formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2 in vasoobliteration of OIR and unveil a so far unknown function for TxA2 in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2 might participate in other ischemic neurovascular injuries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Capillaries; Cell Survival; Cells, Cultured; DNA Fragmentation; L-Lactate Dehydrogenase; Oxygen; Rats; Rats, Sprague-Dawley; Retinal Diseases; Retinal Vessels; Tetrazolium Salts; Thiazoles; Thromboxane A2