Mechanisms of glyceryl trinitrate provoked mast cell degranulation. (December 2015)

• Record Type: Journal Article
• Authors: Pedersen, Sara Hougaard; Ramachandran, Roshni; Amrutkar, Dipak Vasantrao; Petersen, Steffen; Olesen, Jes; Jansen-Olesen, Inger
• Is Part Of: Cephalalgia. Volume 35:Number 14(2015)
• Page Start: 1287
• Page End: 1297
• Publication Date: 2015-12
• Subjects: Dural mast cell -- migraine -- nitric oxide -- rat glyceryl trinitrate infusion model -- sumatriptan -- L-nitro-arginine methyl ester; Headache -- Periodicals; 616.8491
• DOI: 10.1177/0333102415574846
• Languages: English
• ISSNs: 0333-1024

Abstract

Background: Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache. Methods: Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate. Results: A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre-treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733, 060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo . Conclusions: Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulation ex vivo . In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists.