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 (% Emax) 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.