Acetaminophen treatment evokes anticontractile effects in rat aorta by blocking L-type calcium channels

Acetaminophen (APAP) is the most widely used analgesic and antipyretic in the world. However, in high or continuous doses, it can cause serious side effects including blood pressure variability and cardiovascular injuries, which are barely explored. This study aimed to evaluate the acute effect of APAP treatment on vascular tone focused on the blocking of Ca²⁺ channels.

Rats were treated with APAP orally by gavage (500 mg/kg/single dose). After 12 h, the aorta was isolated for vascular reactivity studies in an isolated organ bath. Vascular contraction and relaxation were measured after different stimuli. Moreover, molecular docking studies were performed to evaluate the action of NAPQI (APAP metabolite) on L-type calcium channels.

Phenylephrine-induced maximal vascular contraction was reduced in the APAP group (138.4 ± 9.2%) compared to the control group (172.2 ± 11.1%). APAP treatment significantly reduced contraction induced by Ca²⁺ influx stimulated with phenylephrine or KCl and reduced contraction mediated by Ca²⁺ released from the sarcoplasmic reticulum induced by caffeine. There was no difference in vascular relaxation induced by acetylcholine or sodium nitroprusside. Computational molecular docking demonstrated that NAPQI is capable of blocking L-type Ca²⁺ channels (Ca_v1.2), which would limit the influx of Ca²⁺.

These results suggest that APAP treatment causes an anticontractile effect in rat aorta, possibly by blocking the influx of Ca²⁺ through L-type channels (Ca_v1.2).