Inhibitory effects of benzyl benzoate and its derivatives on angiotensin II-induced hypertension.
Hypertension is a lifestyle-related disease which often leads to serious conditions such as heart disease and cerebral hemorrhage. Angiotensin II (Ang II) plays an important role in regulating cardiovascular homeostasis. Consequently, antagonists that block the interaction of Ang II with its receptors are thought to be effective in the suppression of hypertension. In this study, we searched for plant compounds that had antagonist-like activity toward Ang II receptors. From among 435 plant samples, we found that EtOH extract from the resin of sweet gum Liquidambar styraciflua strongly inhibited Ang II signaling. We isolated benzyl benzoate and benzyl cinnamate from this extract and found that those compounds inhibited the function of Ang II in a dose-dependent manner without cytotoxicity. An in vivo study showed that benzyl benzoate significantly suppressed Ang II-induced hypertension in mice. In addition, we synthesized more than 40 derivatives of benzyl benzoate and found that the meta-methyl and 3-methylbenzyl 2'-nitrobenzoate derivatives showed about 10-fold higher activity than benzyl benzoate itself. Thus, benzyl benzoate, its derivatives, and benzyl cinnamate may be useful for reducing hypertension.
Ohno
Osamu
O
Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan.
Ye
Mao
M
Koyama
Tomoyuki
T
Yazawa
Kazunaga
K
Mura
Emi
E
Matsumoto
Hiroshi
H
Ichino
Takao
T
Yamada
Kaoru
K
Nakamura
Kazuhiko
K
Ohno
Tomohiro
T
Yamaguchi
Kohji
K
Ishida
Junji
J
Fukamizu
Akiyoshi
A
Uemura
Daisuke
D
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D031317:Liquidambar / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001565:Benzoates; D001593:Benzyl Compounds; D002934:Cinnamates; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C006723:benzyl benzoate; D002118:Calcium; C526327:benzyl cinnamate