Mechanisms of glyceryl trinitrate provoked mast cell degranulation

• Published in: Cephalalgia 2015-12, Vol.35 (14), p.1287-1297
• Main Authors: Pedersen, Sara Hougaard, Ramachandran, Roshni, Amrutkar, Dipak Vasantrao, Petersen, Steffen, Olesen, Jes, Jansen-Olesen, Inger
• Format: Article
• Language: English
• Subjects: Animals; Cell Degranulation - drug effects; Cell Degranulation - physiology; Headache - chemically induced; Headache - metabolism; Male; Mast Cells - drug effects; Mast Cells - metabolism; Mast Cells - physiology; Nitric Oxide Donors - toxicity; Nitroglycerin - toxicity; Rats; Rats, Sprague-Dawley
• ISSN: 0333-1024; 1468-2982
• DOI: 10.1177/0333102415574846

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.