title: PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: possible involvement of mast cells.
abstract: BACKGROUND
  In healthy human volunteers and in migraineurs, pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) infusion caused sustained vasodilation of the middle meningeal artery (MMA) and an immediate as well as a delayed headache. All the study subjects experienced facial flushing. Mast cells (MCs) might have a role in the long-lasting effect of PACAP-38 infusion. We hypothesized that in mast cell-depleted (MCD) rats the vascular responses to PACAP-38 would be lesser than in control rats because of a lack of vasodilatory products released during MC degranulation.
  
  
  METHODS
  MCs were depleted by chronic treatment with compound 48/80. The effect of 20 minutes' intravenous (i.v.) infusion of calcitonin gene-related peptide (CGRP), PACAP-38, PACAP(6-38) (PAC-1 receptor antagonist) and PACAP-27 on the diameter of the MMA and on mean arterial blood pressure (MABP) in control and MCD rats was recorded by using the genuine closed-cranial window (CCW) model. Vasoactive intestinal polypeptide (VIP) infusion was given only in control rats. A combination of the histamine H1 receptor antagonist mepyramine (4 mg kg(-1) i.v.) and the H2 receptor antagonist famotidine (1 mg kg(-1) i.v.) was given 10 minutes prior to PACAP-38 infusion. Increasing doses of PACAP-38, PACAP-27 and VIP were infused through the intracarotid artery (i.c.) in control and MCD rats to see the direct effects of these peptides on MMA diameter change.
  
  
  RESULTS
  There was no significant change in CGRP-induced MMA diameter increase in control and MCD rats, and the dilated MMA immediately returned back to baseline after stopping the infusion. The delayed MMA dilation induced by PACAP-38 was abolished in MCD and antihistamine (AH)-pretreated rats. Compared to PACAP-38, the PACAP-27 i.v. infusion gave smaller peak dilation of MMA in control rats. In MCD rats, PACAP-27 did not induce any significant dilation. VIP i.v. infusion reduced MABP but did not dilate MMA significantly. PACAP(6-38), which is a potent MC degranulator, also gave a significant delayed dilation of MMA. PACAP-38 i.c. responses (direct receptor mediated response) were not affected by MC depletion. Only the maximum response (% E max) value of PACAP-27 (i.c.) was significantly lower in MCD rats compared to control rats.
  
  
  CONCLUSIONS
  The delayed MMA dilatory responses to PACAP-38 infusion were attenuated in MCD and AH-pretreated rats, indicating a role of the MC mediator-histamine in PACAP-38-induced delayed dilation of MA.
authors.affiliation: Danish Headache Center, Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Bhatt
authors.affiliation: Danish Headache Center, Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Danish Headache Center, Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.affiliation: Danish Headache Center, Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark inger.jansen.olesen@regionh.dk.
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
mesh_terms: D000818:Animals; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008576:Meningeal Arteries / Q000187:drug effects*; D008881:Migraine Disorders / Q000276:immunology / Q000503:physiopathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014665:Vasodilator Agents
keywords: CGRP; PACAP-27; PACAP-38; VIP; mast cells; migraine