title: Dilation of retinal arterioles in response to lactate: role of nitric oxide, guanylyl cyclase, and ATP-sensitive potassium channels.
abstract: OBJECTIVE
  Lactate, a key metabolite in the retinal tissue, has been implicated in regulating retinal blood flow to match retinal metabolic demand. However, the direct effect of lactate on retinal vascular tone and the possible underlying signaling mechanisms remain unknown. In the present study, the roles of endothelium-derived vasodilators, guanylyl cyclase, and potassium channels were examined in lactate-induced dilation of retinal arterioles in vitro.
  
  
  METHODS
  Porcine second-order retinal arterioles were isolated, cannulated, and pressurized to 55 cm H2O lumenal pressure without flow. Diameter changes in response to agonists were recorded with videomicroscopic techniques.
  
  
  RESULTS
  All vessels developed basal tone (approximately 70 microm in internal diameter) and dilated dose dependently in response to neutralized L-lactate (0.01-10 mM). Inhibition of cyclooxygenase by indomethacin only slightly reduced the vasodilatory response to lactate. In contrast, blockade of monocarboxylate transporters, nitric oxide (NO) synthase, soluble guanylyl cyclase, and ATP-sensitive potassium (KATP) channels nearly abolished lactate-induced vasodilation. The cGMP phosphodiesterase inhibitor zaprinast enhanced the vasodilation response to lactate. Similar to the lactate-induced response, the vasodilation elicited by S-nitroso-N-acetylpenicillamine, an NO donor that activates cGMP signaling, was also inhibited by the soluble guanylyl cyclase and KATP channel blockers.
  
  
  CONCLUSIONS
  These data suggest that uptake of lactate by vascular cells via monocarboxylate transporters causes retinal arteriolar dilation predominantly via stimulation of NO synthase and subsequent activation of guanylyl cyclase. The guanylyl cyclase/cGMP signaling triggers opening of KATP channels for vasodilation. A better understanding of the fundamental signaling pathways responsible for lactate-induced dilation of retinal arterioles may help shed light on the possible mechanisms contributing to the metabolic regulation of retinal blood flow under physiological and pathophysiological conditions.
authors.affiliation: Department of Surgery, Division of Ophthalmology, Scott & White Eye Institute, Texas A&M University System Health Science Center, Temple, Texas 76504, USA. thein@tamu.edu
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xu
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001160:Arterioles / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D027501:Monocarboxylic Acid Transporters; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D011688:Purinones / Q000494:pharmacology; D012161:Retinal Artery / Q000502:physiology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D027501:Monocarboxylic Acid Transporters; D015221:Potassium Channels; D011688:Purinones; D009569:Nitric Oxide; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; C011145:zaprinast; D007213:Indomethacin