title: The anti-diabetic drug repaglinide induces vasorelaxation via activation of PKA and PKG in aortic smooth muscle.
abstract: We investigated the vasorelaxant effect of repaglinide and its related signaling pathways using phenylephrine (Phe)-induced pre-contracted aortic rings. Repaglinide induced vasorelaxation in a concentration-dependent manner. The repaglinide-induced vasorelaxation was not affected by removal of the endothelium. In addition, application of a nitric oxide synthase inhibitor (L-NAME) and a small-conductance Ca(2+)-activated K(+) (SKCa) channel inhibitor (apamin) did not alter the vasorelaxant effect of repaglinide on endothelium-intact arteries. Pretreatment with an adenylyl cyclase inhibitor (SQ 22536) or a PKA inhibitor (KT 5720) effectively reduced repaglinide-induced vasorelaxation. Also, pretreatment with a guanylyl cyclase inhibitor (ODQ) or a PKG inhibitor (KT 5823) inhibited repaglinide-induced vasorelaxation. However, pretreatment with a voltage-dependent K(+) (Kv) channel inhibitor (4-AP), ATP-sensitive K(+) (KATP) channel inhibitor (glibenclamide), large-conductance Ca(2+)-activated K(+) (BKCa) channel inhibitor (paxilline), or the inwardly rectifying K(+) (Kir) channel inhibitor (Ba(2+)) did not affect the vasorelaxant effect of repaglinide. Furthermore, pretreatment with a Ca(2+) inhibitor (nifedipine) and a sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor (thapsigargin) did not affect the vasorelaxant effect of repaglinide. The vasorelaxant effect of repaglinide was not affected by elevated glucose (50mM). Based on these results, we conclude that repaglinide induces vasorelaxation via activation of adenylyl cyclase/PKA and guanylyl cyclase/PKG signaling pathways independently of the endothelium, K(+) channels, Ca(2+) channels, and intracellular Ca(2+) ([Ca(2+)]i).
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Han Sol
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Shin
authors.affiliation: Department of Biomedical Engineering, Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan 608-737, South Korea.
authors.forename: Won-Kyo
authors.initials: WK
authors.lastname: Jung
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Eun-Taek
authors.initials: ET
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Microbiology, Inje University College of Medicine, Busan 614-735, South Korea.
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.affiliation: Department of Pulmonary, Critical Care and Sleep Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Firth
authors.affiliation: Department of Physiology, College of Medicine, Chung-Ang University, Seoul 06974, South Korea.
authors.forename: Hyoweon
authors.initials: H
authors.lastname: Bang
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea. Electronic address: parkws@kangwon.ac.kr.
authors.forename: Won Sun
authors.initials: WS
authors.lastname: Park
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; D014665:Vasodilator Agents; D010656:Phenylephrine; C072379:repaglinide; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D005947:Glucose
keywords: Aortic smooth muscle; Protein kinase A; Protein kinase G; Repaglinide