Involvement of Gap Junctions in Acetylcholine-Induced Endothelium-Derived Hyperpolarization-Type Dilation of Retinal Arterioles in Rats

• Published in: Biological & pharmaceutical bulletin 2021/12/01, Vol.44(12), pp.1860-1865
• Main Authors: Mori, Asami, Namekawa, Ryo, Sakamoto, Kenji, Ishii, Kunio, Nakahara, Tsutomu
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine - pharmacology; Acids; Animals; Arginine; Arterioles; Arterioles - drug effects; Calcium channels; Calcium conductance; Cell interactions; Dilatation; Endothelium; Endothelium, Vascular - drug effects; endothelium-dependent hyperpolarization; Endothelium-Dependent Relaxing Factors; gap junction; Gap Junctions; Hyperpolarization; Indomethacin; Injection; Male; Muscle, Smooth, Vascular; NG-Nitroarginine methyl ester; Nitric oxide; Nitric Oxide - metabolism; Potassium channels (calcium-gated); Potassium conductance; prostaglandin; Prostaglandin endoperoxide synthase; Rats; Rats, Wistar; Retina; Retina - drug effects; Retinal Vessels - drug effects; Signal Transduction; Smooth muscle; Vasodilation; Vasodilator Agents - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b21-00547

An electrical communication between the endothelial and smooth muscle cells via gap junctions, which provides the signaling pathway known as endothelium-dependent hyperpolarization (EDH), plays a crucial role in controlling the vascular tone. In this study, we investigated the role of gap junctions in the acetylcholine (ACh)-induced EDH-type dilation of rat retinal arterioles in vivo. The dilator response was evaluated by measuring the diameter of retinal arterioles. Intravitreal injection of gap junction blockers (18β-glycyrrhetinic acid and carbenoxolone) reduced the ACh-induced dilation of retinal arterioles. Moreover, the retinal arteriolar response to ACh was attenuated by 18β-glycyrrhetinic acid under treatment with a combination of NG-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor; 30 mg/kg) and indomethacin (a cyclooxygenase inhibitor; 5 mg/kg). The NO- and prostaglandin-independent, EDH-related component of ACh-induced dilation of retinal arterioles was prevented by intravitreal injection of iberiotoxin, which inhibits large-conductance Ca2+-activated K+ channels. Furthermore, the combination of 18β-glycyrrhetinic acid and iberiotoxin produced greater attenuation in the EDH-related response than that by the individual agent. Treatment with 18β-glycyrrhetinic acid revealed no significant effect on NOR3 (an NO donor)-induced retinal vasodilator response. These results suggest that gap junctions contribute to the ACh-induced, EDH-type dilation of rat retinal arterioles in vivo.