title: Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.
abstract: While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yahiro
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Suematsu
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Arimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D018929:Cell Culture Techniques; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D007295:Inositol Phosphates; D020030:Nitric Oxide Donors; D013777:Tetrazoles; D009569:Nitric Oxide; C437965:olmesartan