title: Vasodilation and hypotension of a novel 3-benzylquinazolin- 4(3H)-one derivative via the inhibition of calcium flux.
abstract: A novel 3-benzylquinazolin-4(3H)-one derivative Z32, namely 6,7-dimethoxy-3-(3-chloro-4-(4-fluorobenzyloxy)benzyl)quinazolin-4(3H)-one was synthesized. The vasorelaxant and antihypertensive effects of Z32 and its underlying mechanisms were investigated. The following methods were used. The isometric tension of artery ring segments was recorded using an in vitro myography system. Changes in the calcium influx in mesenteric arteries were surveyed using a real-time confocal microscopy. The arterial pressure of spontaneously hypertensive rats was measured in vivo using a non-invasive tail cuff blood pressure system. The results showed that Z32 can relax rat mesenteric arteries pre-constricted by KCl or phenylephrine in a concentration-dependent manner. The vasorelaxant effects were not affected by the removal of the endothelium, blockade of potassium channels by tetraethylammonium chloride, or inhibition of either guanylate cyclase by ODQ, nitric oxide synthase by l-NAME, or cyclooxygenase by indomethacin. In Ca2+-free conditions, Z32 did not affect the constriction evoked by caffeine, however, significantly reduced the constrictions induced (1) by phenylephrine, (2) by CaCl2in either phenylephrine (in the presence of verapamil) or KCl stimulated arteries, (3) by extracellular Ca2+restoration in thapsigargin-treated mesenteric arteries, and (4) by the activator of protein kinase C phorbol-12, 13-dibutyrate, and the inhibitor of protein tyrosine phosphatase sodium orthovanadate. Further, Z32 decreased the systolic and diastolic arterial pressure of spontaneously hypertensive rats in a dose-dependent manner. In conclusion, Z32 lowers the arterial pressure and induces vasorelaxation through the inhibition of calcium flux, probably via a protein tyrosine phosphorylation-dependent way.
authors.affiliation: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.lastname: Sen Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Sai-Jie
authors.initials: SJ
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Dong-Zheng
authors.initials: DZ
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: San-Qi
authors.initials: SQ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: yxy@xjtu.edu.cn.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Cao
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000611336:3-benzyl-4(3H)quinazolinone; D000959:Antihypertensive Agents; D015221:Potassium Channels; D011453:Prostaglandins; D052999:Quinazolinones; D014665:Vasodilator Agents; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D000071756:Soluble Guanylyl Cyclase; D002118:Calcium
keywords: 3-benzylquinazolin-4(3H)-one; Calcium flux; Hypertensive rats; Hypotension; Mesenteric artery; Vasodilation