title: Combination therapy of olmesartan and azelnidipine inhibits sympathetic activity associated with reducing oxidative stress in the brain of hypertensive rats.
abstract: It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg(-1) day(-1)), CAN/AM (4/2.5 mg kg(-1) day(-1)), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shinohara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Kishi
authors.forename: Keiji
authors.initials: K
authors.lastname: Yasukawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D000068557:Olmesartan Medoxomil; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; D001383:Azetidinecarboxylic Acid; D000068557:Olmesartan Medoxomil; C061679:azelnidipine; C081643:candesartan