title: Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension.
abstract: Although thiazide diuretics are commonly used to supplement angiotensin receptor blockers for treatment of hypertension, the mechanism underlying the therapeutic effects of this drug combination remains unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy with losartan (LOS) and hydrochlorothiazide (HCTZ), in comparison with those of either drug alone, in Dahl salt-sensitive hypertensive rats. Rats fed a high-salt diet from 6 weeks of age were treated with LOS, HCTZ, both drugs (COMB) and vehicle from 6 to 11 weeks. The salt-induced increase in systolic blood pressure was attenuated moderately by LOS and to a greater extent by HCTZ and COMB. Left ventricular (LV) hypertrophy and fibrosis, diastolic dysfunction, as well as angiotensin-converting enzyme and angiotensin II type 1A (AT(1A)) receptor gene expression were attenuated similarly by LOS and HCTZ and more so by COMB. LOS downregulated expression of the AT(1A) receptor gene, without affecting that of the AT(2) receptor gene, in the aorta. In contrast, neither HCTZ nor COMB affected aortic expression of the AT(1A) receptor gene, but both markedly upregulated that of the AT(2) receptor gene. The salt-induced decrease in the plasma concentration of nitric oxide metabolites was attenuated substantially by LOS and abolished by both HCTZ and COMB. In conclusion, the combination of LOS and HCTZ attenuated hypertension, as well as LV remodeling and diastolic dysfunction, more effectively than did LOS or HCTZ alone in rats with salt-sensitive hypertension. Modulation of the cardiac and vascular renin-angiotensin system may have contributed to these beneficial effects of the drug combination.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Takuya
authors.initials: T
authors.lastname: Hattori
authors.forename: Tamayo
authors.initials: T
authors.lastname: Murase
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ohtake
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furukawa
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D006852:Hydrochlorothiazide; D007703:Peptidyl-Dipeptidase A; D019808:Losartan