Functional K(ATP) channels in the rat retinal microvasculature: topographical distribution, redox regulation, spermine modulation and diabetic alteration.
The essential task of the circulatory system is to match blood flow to local metabolic demand. However, much remains to be learned about this process. To better understand how local perfusion is regulated, we focused on the functional organization of the retinal microvasculature, which is particularly well adapted for the local control of perfusion. Here, we assessed the distribution and regulation of functional K(ATP) channels whose activation mediates the hyperpolarization induced by adenosine. Using microvascular complexes freshly isolated from the rat retina, we found a topographical heterogeneity in the distribution of functional K(ATP) channels; capillaries generate most of the K(ATP) current. The initiation of K(ATP)-induced responses in the capillaries supports the concept that the regulation of retinal perfusion is highly decentralized. Additional study revealed that microvascular K(ATP) channels are redox sensitive, with oxidants increasing their activity. Furthermore, the oxidant-mediated activation of these channels is driven by the polyamine spermine, whose catabolism produces oxidants. In addition, our observation that spermine-dependent oxidation occurs predominately in the capillaries accounts for why they generate most of the K(ATP) current detected in retinal microvascular complexes. Here, we also analysed retinal microvessels of streptozotocin-injected rats. We found that soon after the onset of diabetes, an increase in spermine-dependent oxidation at proximal microvascular sites boosts their K(ATP) current and thereby virtually eliminates the topographical heterogeneity of functional K(ATP) channels. We conclude that spermine-dependent oxidation is a previously unrecognized mechanism by which this polyamine modulates ion channels; in addition to a physiological role, spermine-dependent oxidation may also contribute to microvascular dysfunction in the diabetic retina.
Ishizaki
Eisuke
E
Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Fukumoto
Masanori
M
Puro
Donald G
DG
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D002196:Capillaries / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D054086:KATP Channels / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D010477:Perfusion; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D013096:Spermine / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014699:Venules / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology
D054086:KATP Channels; D013096:Spermine; D020110:Pinacidil; D004228:Dithionitrobenzoic Acid; D006861:Hydrogen Peroxide; D000241:Adenosine; D011188:Potassium; D004229:Dithiothreitol; D000518:Eflornithine