Migraine induced by vascular K _ATP channel activation is independent of HCN channel activity: A randomised controlled trial with translational validation

Objective To investigate whether blockade of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels modifies migraine induced by activation of vascular ATP-sensitive potassium (K ATP ) channels. Methods We conducted a single-centre, randomised, double-blind, placebo-controlled, two-way crossover study in adults with migraine without aura. On two separate days, participants received intravenous levcromakalim followed immediately by either oral ivabradine or placebo in a balanced order. The primary endpoint was the 12-h incidence of levcromakalim-induced migraine. Secondary endpoints included the area under the curve (AUC) for headache intensity and haemodynamic responses. Parallel preclinical experiments were performed in a validated mouse model using von Frey-based tactile sensitivity to assess whether ivabradine, given as pretreatment or as rescue medication, alters levcromakalim-induced hypersensitivity. Results Twenty seven of 31 individuals completed the human study and provided data for the final analysis. Ivabradine did not modify the incidence of levcromakalim-induced migraine (22 of 27 after ivabradine and 22 of 27 after placebo; P > 0.99) or the AUC for headache intensity ( P = 0.11). Haemodynamic responses did not differ between study days. In mice, ivabradine at multiple doses neither prevented nor reversed tactile hypersensitivity induced by repeated levcromakalim administration. Conclusions HCN channel blockade does not influence migraine or nociceptive behaviour provoked by vascular K ATP channel activation. These convergent human and preclinical findings indicate that HCN channels are not essential for the downstream transformation of vascular K ATP channel activation into migraine pain and support a model in which migraine initiation arises from signalling at the vessel-to-neuron interface. Trial registration ClinicalTrials.gov; NCT04853797; Registered: 16-03-2021. Preclinical experiments were not preregistered beyond the animal ethical license (2017-15-0201-01358) from the Danish Animal Experiments Inspectorate.