Effects of diazepam on contractility in a human umbilical artery model: Underlying mechanisms of vasoactivity

The increasing recognition of peripheral GABAergic signaling has renewed interest in the vascular effects of benzodiazepines (BDZs), particularly in light of their frequent use during pregnancy. Although BDZs have been studied in various vascular beds, their exact vasorelaxant mechanisms are still unclear. This study aimed to investigate the mechanisms underlying diazepam-induced vasodilation in human umbilical arteries (HUAs).

Isolated endothelium-intact HUA rings were pre-contracted with serotonin, and concentration-response curves for diazepam (0.01-100 μM) were obtained using the tissue bath method. The roles of the endothelium, potassium and calcium channels, and TSPO were assessed using specific inhibitors or blockers: L-NAME, indomethacin, sildenafil, ODQ, glibenclamide, 4-aminopyridine, tetraethylammonium, and PK11195. The effects of diazepam pre-treatment on BaCl₂-and serotonin-induced contractions were also investigated.

Diazepam induced a time- and concentration-dependent relaxation of HUA, with ⁓ 96% of the maximal effect being achieved at 100 μM. This response was endothelium-independent, as it was unaffected by eNOS or COX inhibition, but included an ODQ-sensitive component compatible with involvement of the soluble guanylate cyclase (sGC)-cGMP pathway. Potassium channel involvement was confirmed, and diazepam significantly suppressed BaCl₂-and serotonin-induced contractions, suggesting calcium channel antagonism. PK11195 significantly attenuated diazepam-induced relaxation, implying involvement of TSPO.

Diazepam elicits near-complete relaxation in serotonin-precontracted HUA through endothelium-independent mechanisms that likely involve potassium channel activation, calcium channel inhibition, a component sensitive to ODQ suggesting possible involvement of the sGC-cGMP pathway, and interaction with TSPO. These results emphasize the remarkable vasoactivity of diazepam and its importance in the regulation of umbilical vascular tone.