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Atsuko Nakaizumi, Donald G. Puro; Vulnerability Of Retinal Capillaries To Hypoxia: Role Of Spermine And KAtp Channels. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5359.
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Although hypoxia occurs in many retinal vascular disorders, it is uncertain why the capillaries are particularly vulnerable to hypoxic damage. Here, we tested the hypothesis that spermine plays a role. This polyamine was of interest because of its recently revealed importance in capillary physiology(J Physiol 573:483, 2006 ; ibid 587:2233, 2009 ; IOVS 51:5979, 2010).
Antimycin A was used to induce chemical hypoxia in microvascular complexes freshly isolated from the adult rat retina. Cell viability, ionic currents, cell calcium and pericyte contractility were assayed by trypan blue dye exclusion, perforated-patch recordings, fura-2 fluorescence and time-lapse videos, respectively.
Consistent with capillaries being particularly vulnerable to hypoxia, a 20-h exposure of retinal microvascular complexes to 5 µM antimycin caused 28 ± 2% of the capillary cells to die while cell death in the proximal microvasculature was only 3 ± 1% (P < 0.001). Indicative of spermine’s importance, antimycin-induced cell death was reduced to 6 ± 2% (P < 0.001) in capillaries treated DFMO, a polyamine synthesis inhibitor. Knowing that capillary KATP channel activity is spermine-dependent (J Physiol 587:2233,2009), we assessed the role of these ion channels in hypoxic cell death. We observed a DFMO-sensitive KATP-mediated hyperpolarization during antimycin exposure and also found that the KATP channel blocker, glibenclamide, reduced antimycin-induced capillary cell death by 50% (P = 0.002). In addition, DFMO and glibenclamide diminished the hypoxia-induced rise in pericyte calcium. Furthermore, time-lapse experiments revealed that chemical hypoxia caused pericytes to contract by a DFMO- and glibenclamide-sensitive mechanism.
Endogenous spermine renders retinal capillaries particularly vulnerable to hypoxic cell death by a mechanism that, in part, involves KATP channel activation. We postulate the contraction of pericytes in hypoxic capillaries may diminish local perfusion and thereby, contribute to retinal damage. The previously unrecognized beneficial effect of inhibiting spermine synthesis suggests a new therapeutic strategy to minimize capillary cell death in a variety of retinal disorders.
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