Soluble guanylate cyclase induces cranial vasodilation and headache in adults: a randomized trial

The role of cranial vasodilation in headache pathogenesis sparks ongoing debate. Soluble guanylate cyclase is an enzyme that catalyses the conversion of guanosine triphosphate to cyclic guanosine monophosphate, leading to relaxation of vascular smooth muscle cells. Activation of this pathway might contribute to headache pathogenesis. We evaluated whether oral ingestion of riociguat, a stimulator of soluble guanylate cyclase, could elicit cranial vasodilation and headache in healthy adults. In this randomized, double-blind, placebo-controlled, two-way crossover study, we enrolled 12 healthy adults (nine females, three males; mean age 27.3 (SD 7.8) years). The participants attended two experimental sessions at a single site in Denmark (Danish Headache Center, Rigshospitalet, Denmark), receiving either a single oral dose riociguat 2.5 mg or placebo. The baseline measurements included the diameter of the superficial temporal artery and the blood flow velocity of the middle cerebral artery. These measurements were repeated over a 240-minute period after ingestion. The participants recorded headache occurrence and associated features in a diary for 12 h post-ingestion. For primary outcome (n = 12), results revealed no significant change in the diameter of the superficial temporal artery from baseline to 90 min post-ingestion between riociguat and placebo (P = 0.54). However, significant increases in the diameter were observed at 120 min (P = 0.02) and 240 min (P < 0.01) after riociguat ingestion compared with placebo. The blood flow velocity of the middle cerebral artery decreased significantly from baseline to 240 min post-riociguat ingestion, compared with placebo (P < 0.01). Headache was reported by 10 (83%) of 12 participants after riociguat ingestion, compared with three (25%) participants after placebo (P = 0.02). In conclusion, oral ingestion of riociguat, a stimulator of soluble guanylate cyclase, induces cranial vasodilation and headache. These findings support the hypothesis that cranial vasodilation mediated via direct soluble guanylate cyclase stimulation contributes to headache pathogenesis. Further research is warranted to delineate the relative contributions of nitric oxide-dependent versus nitric oxide-independent soluble guanylate cyclase activation, and to evaluate guanylate cyclase signalling as a potential therapeutic target in headache disorders.