Reproducibility and agreement of different non-invasive methods of endothelial function assessment.

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p < .001) and 65% (<0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p < .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p < .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable.

Blood Pressure in Patients With Migraine Treated With Monoclonal Anti-CGRP (Receptor) Antibodies: A Prospective Follow-up Study.

BACKGROUND AND OBJECTIVES: Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies are approved as preventive treatment for migraine. Recent concerns have been raised after a retrospective analysis of postmarketing case reports of elevated blood pressure (BP) associated with erenumab. In this prospective follow-up study, we aimed to assess the safety regarding BP in a real-world setting. METHODS: All people with migraine who were treated with erenumab and fremanezumab at the Leiden Headache Center between January 2019 and January 2021 were included. BP measurements were collected from baseline (T0) until 12 months of follow-up, with a 3-month interval (T1-T4). Mixed linear models were fitted with time as a fixed effect and the patient as a random effect. RESULTS: Both systolic and diastolic BP were increased at all time points T1-T4 compared with T0 (p < 0.001). The maximum estimated increase in the mean systolic BP was 5.2 mm Hg (95% CI 3.1-7.5). The maximum estimated increase in the mean diastolic BP was 3.5 mm Hg (95% CI 2.0-4.9). In the erenumab group (n = 109), both systolic and diastolic BP were increased at all time points compared with T0 (all p < 0.001). For fremanezumab (n = 87), systolic but not diastolic BP was increased compared with T0 at T1 (p = 0.006) and T2 (p = 0.004). Four patients (3.7%) with normal BP at T0 required antihypertensive treatment after erenumab was started. DISCUSSION: The mean systolic and diastolic BP increased after anti-CGRP (receptor) antibodies were started. The majority of patients remained within the normal BP limits, but some patients required antihypertensive treatment. Physicians should be aware that people with migraine may be at risk of developing hypertension when treated with anti-CGRP (receptor) antibodies, and this should be added to (inter)national treatment guidelines. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-CGRP (receptor) antibodies increase BP when used to treat patients with migraine.

Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs.

INTRODUCTION: The introduction of the triptans (5-hydroxytryptamine (5-HT)1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine. AREAS COVERED: In this review the different types of antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind α-adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT1D, 5-HT1F and 5-HT7 receptors have been explored for their antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection with the glutamatergic as well as the CGRP-ergic systems, which may open novel therapeutic avenues. EXPERT OPINION: Although the triptans are very effective in treating migraine attacks, their shortcomings have stimulated the search for novel drugs. Currently, the focus is on 5-HT1F receptor agonists, which seem devoid of vascular side effects. Moreover, novel compounds that affect multiple transmitter and/or neuropeptide systems that are involved in migraine could be of therapeutic relevance.

The 5-HT(1) receptors inhibiting the rat vasodepressor sensory CGRPergic outflow: further involvement of 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), subtypes.

We have previously shown that 5-HT(1B) receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT(1) receptors comprise 5-HT(1A), 5-HT(1B), 5-HT(1D) and 5-HT(1F) functional subtypes, this study has further investigated the role of 5-HT(1A), 5-HT(1D) and 5-HT(1F) receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT(1) receptor agonists. Then electrical spinal stimulation (T(9)-T(12)) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT(1A) receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT(1A/1B/1D/1F)), indorenate (5-HT(1A)), PNU-142633 (5-HT(1D)) or LY344864 (5-HT(1F)), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 µg/kg (but not 100 µg/kg) GR127935 (5-HT(1A/1B/1D/1F)) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 µg/kg SB224289 (5-HT(1B)) or BRL15572 (5-HT(1D)) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289+BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 µg/kg WAY100635 (5-HT(1A)) failed to block the inhibition to indorenate. These results suggest that 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT(1F) receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.