Question:

The gaseous molecule nitric oxide (NO) is thought to be an endogenous mediator in the generation of primary headaches. NO donors like nitroglycerin can cause migraine-like headaches in migraineurs. In animal experiments, NO donors increase meningeal blood flow. We have recently shown that this vascular effect is mainly caused by nitroxyl (NO^- or HNO), the protonated one electron reduced form of NO, mediated by activation of transient receptor potential channels (TRPA1) and Ca²⁺-induced CGRP release from meningeal afferents. Since hydrogen sulfide (H₂S) has similar physiological effects as NO, we asked if H₂S interacts with NO to form the active redox molecule NO^- which increases meningeal blood flow.

Methods:

Isoflurane anesthetised male Wistar rats were trepanised exposing the parietal dura mater. Meningeal blood flow was recorded by laser Doppler flowmetry via needle-type probes positioned over branches of the middle meningeal artery in the cranial window. Na₂S (100 µM) as a progenitor of H₂S, the TRPA1 antagonist HC030031 (50 µM), L-NAME (1 mM) as a NO synthase inhibitor and glibenclamide (1 mM) as a K_ATP channel blocker were topically applied onto the dura mater in the cranial window. L-NAME (1.3 mg/kg) was also i.v. infused. Blood flow was measured in arbitrary units as mean value within 5 min of Na₂S application and compared to the pre-application baseline. Arterial pressure was monitored in parallel.

Results:

Na₂S caused an increase in blood flow within 5 min, which was partly inhibited by preadministration of HC030031 and topical as well as i.v. preapplication of L-NAME. The H₂S evoked blood flow increase was completely blocked by i.v. L-NAME when glibenclamide was preadministered. The arterial blood pressure did not significantly change after topical administrations but decreased upon L-NAME injection.

Conclusions:

We conclude that Na₂S converted to H₂S in the dura mater produces NO^- from NO, which in turn activates TRPA1 receptor channels followed via CGRP release by smooth vascular relaxation of dural arteries resulting in an increased meningeal blood flow. K_ATP channels seem to be independently involved in the vasodilatory effect of H₂S. Similar mechanisms may take place in the human meninges during NO donor induced and spontaneous headaches in migraineurs.