Headache-type adverse effects of NO donors: vasodilation and beyond

Abstract

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side-effects, mainly headaches, the summaries of product characteristics of nitrate-containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate-induced migraine. Two different types of nitrate-induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine-type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3-6 h after the intake of nitrates, with debilitating, long-lasting symptoms including nausea, vomiting, photo- and/or phono-phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene-related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S-nitrosylation. Migraines usually need anti-attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti-migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.

Figure 1

Headache intensity (0–10 verbal scale) after sublingual nitroglycerin (GTN, 0.5 mg) administration in controls (CO; n= 11), in controls with risk factor for migraine (CO+; n= 2), in migraineurs who did not develop delayed migraine type headache (M−; n= 8) and in migraineurs who developed typical delayed migraine without aura (M+; n= 20). (Combined data from Juhasz et al., 2003b; ;.)

Figure 3

Nitrate derived NO actions relevant to nitroglycerin (GTN)-induced immediate and delayed (migraine-type) headaches. The NO donor GTN activates the NO-cGMP pathway via the soluble guanylate cyclase enzyme (sGC). Through protein kinase G the NO-cGMP pathway is able to control the function of various ion channels, including the calcium-activated potassium channels K_Ca1.1 (also known as BK or Slo1) that modify smooth muscle contractility and may play an important role in immediate headaches. The NO-cGMP pathway also increases calcitonin gene-related peptide (CGRP) release mainly by activation of Ca_v2.1 (P/Q-type) voltage-gated calcium channels. CGRP can cause vasodilation via K_IR6 channels (also known as K_ATP) and can cause delayed migraine-type headaches via mechanisms which are not fully understood yet. The CB1 receptor is able to inhibit both CGRP- and NO-induced dural vessel dilation. It is possible that this is partially due to the inhibition of Ca_v2.1 (P/Q-type) voltage-gated calcium channels but the mechanism is still unclear. The trigeminovascular activation, both vasodilation and CGRP release, can be blocked via the activation of 5-HT_1B/1D/1F receptors. In chronic migraine patients up-regulation of 5-HT₂ receptors due to the low baseline 5-HT level may occur, and an increase in nNOS activity and elevated NO release due to an acute increase in 5-HT release could be expected. The NO-cGMP pathway also increases the release of glutamate that has major role in central sensitization and can lead to migraine attacks. Dopamine, prostaglandins and sodium channels also play a role in NO-induced migraine-type headaches but further studies are needed to elucidate the exact mechanism. Red box: different type of headaches, green boxes: ion channels, orange boxes: neurotransmitters, brown boxes: neurotransmitters and modulators, blue boxes: GTN-NO-cGMP pathway, arrows: activation lines: blockade of action, thick lines: evidence based pathways, thin lines: hypothesized pathways.

Figure 2

Effects of nitroglycerin (GTN, 0.5 mg sublingual) on plasma calcitonin gene-related peptide (CGRP) and platelet 5-HT concentrations in controls without delayed migraine attack (n= 10; A) and in migraineurs with delayed migraine attack (n= 19; B). We calculated z scores for plasma CGRP and platelet 5-HT concentrations [(subgroup mean − grand mean)/subgroup SD] to compare their changes during the GTN challenge. Baseline blood samples were collected at 7.00 a.m. (−1). A secondary blood sample was taken 1 h after sublingual application of GTN, at 9.00 a.m. (1). The next three blood samples were taken 60 min (M1), 120 min (M2) and 180 min (M3) after the beginning of the migraine attack. In controls, similar time schedules were used based on preliminary data (M1: 5 h, M2: 6 h and M3: 7 h after GTN respectively). Migraine patients took 20 mg sumatriptan nasal spray immediately after the M2 blood sampling. *Significant changes after sublingual GTN compared with baseline (P < 0.05). (Combined data from Juhasz et al., 2003b; ;.)