Role of calcium-activated potassium channels in acetylcholine-induced vasodilation of rat retinal arterioles in vivo.
The vascular endothelium plays an important role in regulating retinal blood flow via actions of several vasodilators, including nitric oxide (NO), prostaglandin I₂, and an endothelium-derived hyperpolarizing factor (EDHF). Our previous in vivo studies demonstrated that acetylcholine (ACh) dilates the rat retinal arteriole partly through NO- and prostaglandin-independent pathway, possibly the EDHF-mediated pathway, but the underlying mechanism(s) remains to be elucidated. It has been suggested that activation of Ca²+-activated K+ (K(Ca)) channels contributes to the EDHF-mediated responses; therefore, the roles of K(Ca) channels in ACh-induced vasodilation of retinal arterioles were examined in rats. The retinal vascular responses were assessed by determining changes in diameters of retinal arterioles in ocular fundus images that were captured with an original fundus camera system. Intravitreal injection of charybdotoxin, an inhibitor of intermediate- and large-conductance K(Ca) (I/BK(Ca)) channels, or iberiotoxin, an inhibitor of large-conductance K(Ca) (BK(Ca)) channels, significantly reduced the ACh-induced vasodilation of retinal arterioles, whereas neither apamin, an inhibitor of small-conductance K(Ca) (SK(Ca)) channels, nor TRAM-34, an inhibitor of intermediate-conductance K(Ca) (IK(Ca)) channels, altered the response. The vasodilator response to ACh observed under the combined blockade of NO synthase and cyclooxygenase with N(G)-nitro-L-arginine methyl ester plus indomethacin was also diminished by iberiotoxin. Iberiotoxin did not affect the NO donor NOR3-induced vasodilation of retinal arterioles, whereas it significantly reduced the BK(Ca) channel opener BMS-191011-induced responses. These results suggest that activation of BK(Ca) channels is involved in the EDHF-mediated component of the vasodilator response to ACh in the rat retinal arterioles in vivo.
Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Asami
A
Mori
Sachi
S
Suzuki
Kenji
K
Sakamoto
Tsutomu
T
Nakahara
Kunio
K
Ishii
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006898:Hydroxylamines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009574:Nitro Compounds; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012161:Retinal Artery / Q000187:drug effects / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C480883:3-((5-chloro-2-hydroxyphenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D006898:Hydroxylamines; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D010069:Oxadiazoles; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; C411671:TRAM 34; D018999:Charybdotoxin; D001030:Apamin; C064719:iberiotoxin; C061872:FK 409; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin