Vulnerability of the retinal microvasculature to hypoxia: role of polyamine-regulated K(ATP) channels.

Abstract

PURPOSE:

It is uncertain why retinal capillaries are particularly vulnerable to hypoxia. In this study, it was hypothesized that their specialized physiology, which includes being the predominant microvascular location of functional adenosine triphosphate-sensitive potassium (K(ATP)) channels, boosts their susceptibility to hypoxia-induced cell death.

METHODS:

Cell viability, ionic currents, intracellular calcium, and pericyte contractility in microvascular complexes freshly isolated from the rat retina were assessed using trypan blue dye exclusion, perforated-patch recordings, fura-2 fluorescence, and time-lapse videos. Chemical hypoxia was induced by antimycin, an oxidative phosphorylation inhibitor.

RESULTS:

In freshly isolated retinal microvascular complexes, chemical hypoxia caused more cell death in capillaries than in arterioles. Indicative of the role of polyamine-dependent K(ATP) channels, antimycin-induced capillary cell death was markedly decreased in microvessels treated with the polyamine synthesis inhibitor, difluoromethylornithine, or the K(ATP) channel inhibitor, glibenclamide. These inhibitors also diminished the antimycin-induced hyperpolarization, as well as the antimycin-induced intracellular calcium increase, which was significantly dependent on extracellular calcium and was diminished by the inhibitor of calcium-induced calcium release (CICR), dantrolene. Consistent with the importance of the CICR-dependent increase in capillary cell calcium, dantrolene significantly decreased hypoxia-induced capillary cell death. We also found that activation of the polyamine/K(ATP) channel/Ca(2+) influx/CICR pathway not only boosted the vulnerability of retinal capillaries to hypoxia, but also caused the contraction of capillary pericytes, whose vasoconstrictive effect may exacerbate hypoxia.

CONCLUSIONS:

The vulnerability of retinal capillaries to hypoxia is boosted by a mechanism involving the polyamine/K(ATP) channel/Ca(2+) influx/CICR pathway. Discovery of this pathway should provide new targets for pharmacological interventions to minimize hypoxia-induced damage in retinal capillaries.

• Authors: Atsuko Nakaizumi, Donald G Puro
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 13 Pg. 9345-52 (Dec 09 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 22039232 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• KATP Channels
• Glyburide
• Eflornithine

Topics

• Animals
• Apoptosis
• Disease Models, Animal
• Eflornithine (pharmacology)
• Glyburide (pharmacology)
• Hypoxia (metabolism, pathology)
• Ion Transport
• KATP Channels (metabolism)
• Membrane Potentials
• Microvessels (physiopathology)
• Patch-Clamp Techniques
• Rats
• Rats, Long-Evans
• Retina (drug effects, metabolism, pathology)
• Retinal Diseases (drug therapy, metabolism, physiopathology)
• Retinal Vessels (drug effects, metabolism, pathology)