Mikaelle C Correia1, Eder S A Santos2, Bruno J Neves2, Matheus L Rocha3. 1. Laboratory of Pharmacology, UFG, Faculty of Pharmacy, Federal University of Goias, Setor Leste Universitário, CEP, Rua 240, esquina com 5ª Avenida, s/n, Goiânia, GO, 74605-170, Brazil. 2. LabMol-Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, Rua 240, esquina com 5ª Avenida, s/n, Setor Leste Universitário, Goiânia, GO, 74605-170, Brazil. 3. Laboratory of Pharmacology, UFG, Faculty of Pharmacy, Federal University of Goias, Setor Leste Universitário, CEP, Rua 240, esquina com 5ª Avenida, s/n, Goiânia, GO, 74605-170, Brazil. rochaml@ufg.br.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 (Cav1.2), which would limit the influx of Ca2+. CONCLUSION: These results suggest that APAP treatment causes an anticontractile effect in rat aorta, possibly by blocking the influx of Ca2+ through L-type channels (Cav1.2).
BACKGROUND: 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. METHODS: 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. RESULTS: 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 (Cav1.2), which would limit the influx of Ca2+. CONCLUSION: These results suggest that APAP treatment causes an anticontractile effect in rat aorta, possibly by blocking the influx of Ca2+ through L-type channels (Cav1.2).
Authors: Andrew T Chan; JoAnn E Manson; Christine M Albert; Claudia U Chae; Kathryn M Rexrode; Gary C Curhan; Eric B Rimm; Walter C Willett; Charles S Fuchs Journal: Circulation Date: 2006-03-13 Impact factor: 29.690