title: The novel analogue of hirsutine as an anti-hypertension and vasodilatary agent both in vitro and in vivo.
abstract: In this paper, an analogue of hirsutine (compound 1) has been synthesized and evaluated as an anti-hypertension agent, which exhibits extraordinary effects on the contractile response of thoracic aorta rings from male SD rats in vitro (IC50 = 1.129×10(-9)±0.5025) and the abilities of reducing the systolic blood pressure (SBP) and heart rate (HR) of SHR in vivo. The mechanism investigation reveals that the vasodilatation induced by compound 1 is mediated by both endothelium-dependent and -independent manners. The relaxation in endothelium-intact aortic rings induced by compound 1 can be inhibited by L-NAME (1×10(-6) mol•L(-1)) and ODQ (1×10(-6) mol•L(-1)). Moreover, compound 1 can also block Ca2+ influx through L-type Ca2+ channels and inhibit intracellular Ca2+ release while no effect on K+ channel has been observed. All these data demonstrated that the NO/cyclic GMP pathway can be involved in endothelium-dependent manner induced by compound 1. Meanwhile the mechanism on the vasodilatation of compound 1 probably also related to blockade of Ca2+ influx through L-type Ca2+ channels and inhibition of intracellular Ca2+ release may have no relationship with K+ channels.
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, 201203, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, 201203, China.
authors.forename: Su-Na
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, 201203, China.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Ma
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute Biomedical Sciences, Fudan University, Shanghai, 201203, China.
authors.forename: Xian-Feng
authors.initials: XF
authors.lastname: Gu
authors.affiliation: Departments of Physiology and Pathophysiology, Shanghai College of Medicine, Fudan University, Shanghai, 201203, China.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai, 201203, China; Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Yi-Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D045022:Lactate Dehydrogenases / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000959:Antihypertensive Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D009569:Nitric Oxide; D045022:Lactate Dehydrogenases; D006162:Guanylate Cyclase; D000109:Acetylcholine; D002118:Calcium; C038369:hirsutine