Alpha-naphthoflavone induces vasorelaxation through the induction of extracellular calcium influx and NO formation in endothelium.
The effect of alpha-naphthoflavone (alpha-NF) on vascular function was studied in isolated ring segments of the rat thoracic aorta and in primary cultures of human umbilical vein endothelial cells (HUVECs). alpha-NF induced concentration-dependent relaxation of the phenylephrine-precontracted aorta endothelium-dependently and -independently at lower and higher concentrations, respectively. The cGMP, but not cAMP, content was increased significantly in alpha-NF-treated aorta. Pretreatment with N(omega)-nitro- l-arginine methyl ester (L-NAME) or methylene blue attenuated both alpha-NF induced vasorelaxation and the increase of cGMP content significantly. The increase of cGMP content induced by alpha-NF was also inhibited by chelating extracellular Ca(2+) with EGTA. These results suggest that the endothelium-dependent vasorelaxation induced by alpha-NF is mediated most probably through Ca(2+)-dependent activation of NO synthase and guanylyl cyclase. In HUVECs, alpha-NF induced concentration-dependent formation of NO and Ca(2+) influx. alpha-NF-induced NO formation was abolished by removal of extracellular Ca(2+) and by pretreatment with the Ca(2+) channel blockers SKF 96365 and Ni(2+), but not by the L-type Ca(2+) channel blocker verapamil. The Ca(2+) influx, as measured by (45)Ca(2+) uptake, induced by alpha-NF was also inhibited by SKF 96365 and Ni(2+). Our data imply that alpha-NF, at lower concentrations, induces endothelium-dependent vasorelaxation by promoting extracellular Ca(2+) influx in endothelium and the activation of the NO-cGMP pathway.
Cheng
Yu-Wen
YW
School of Pharmacy, Taipei Medical University, 250 Wu Hsing Street, Taipei, Taiwan.
Li
Ching-Hao
CH
Lee
Chen-Chen
CC
Kang
Jaw-Jou
JJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001571:Benzoflavones / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001571:Benzoflavones; D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D009569:Nitric Oxide; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester