title: The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.
abstract: We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.
authors: Department of Anatomy, PTE-MTA "Lendület" PACAP Research Team, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary.
authors: E
authors: E
authors: Banki
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary.
authors: Zs
authors: Z
authors: Hajna
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary.
authors: A
authors: A
authors: Kemeny
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary.
authors: B
authors: B
authors: Botz
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary.
authors: P
authors: P
authors: Nagy
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary.
authors: K
authors: K
authors: Bolcskei
authors: Department of Medical Chemistry, University of Szeged, Dóm Square 8, Szeged H-6720, Hungary.
authors: G
authors: G
authors: Toth
authors: Department of Anatomy, PTE-MTA "Lendület" PACAP Research Team, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary.
authors: D
authors: D
authors: Reglodi
authors: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti Street 12, Pécs H-7624, Hungary; János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, Pécs H-7624, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
authors: Zs
authors: Z
authors: Helyes
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004423:Ear / Q000473:pathology / Q000503:physiopathology; D004487:Edema; D005260:Female; D019476:Insect Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009149:Mustard Plant; D009195:Peroxidase / Q000378:metabolism; D010938:Plant Oils; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000819:agonists* / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists / Q000378:metabolism; D012879:Skin Physiological Phenomena / Q000187:drug effects*; D013373:Substance P / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D019476:Insect Proteins; D010938:Plant Oils; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014662:Vasoconstrictor Agents; C069147:maxadilan protein, insect; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D009195:Peroxidase; C027793:mustard oil
keywords: Maxadilan; Neurogenic inflammation; PACAP; Plasma leakage; VIP; Vasodilation