Chronic administration of losartan plus hydrochlorothiazide improves vascular status in young cardiomyopathic hamsters.
The combination of an angiotensin II receptor antagonist and a thiazide has been used extensively in the treatment of patients with overt heart failure. The effect of this combination on the vascular wall early in the disease, however, has not been investigated. To evaluate this effect, the vascular status of 3-month-old cardiomyopathic hamsters was assessed after daily administration of a combination of losartan (25 mg/kg, p.o.) and hydrochlorothiazide (6.5 mg/kg, p.o.) over an 8-week period. Age-matched golden hamsters were used as healthy controls. The contractile response of aortic rings to endothelin-1 was significantly higher in cardiomyopathic hamsters than in control animals. Concentration-response curves for the endothelin-1-induced contraction were displaced to the right after hydrochlorothiazide+losartan treatment (toward the curves for healthy controls); however, E(max) from treated hamsters was significantly reduced when compared to E(max) from untreated cardiomyopathic animals (1.016+/-0.073 vs. 1.346+/-0.153 g, P<0.05, n=6). No significant differences in the EC50 values from these curves were observed between hydrochlorothiazide+losartan treated and untreated cardiomyopathic animals (2.90+/-0.95 vs. 1.10+/-0.85 nM, P>0.05). The acetylcholine-induced relaxation observed in cardiomyopathic animals was not improved after treatment with hydrochlorothiazide+losartan or hydrochlorothiazide alone, but the combination of these drugs increased significantly the basal production of nitric oxide (NO). Angiotensin-converting enzyme activity increased in plasma (from 29.9+/-1.23 to 41.16+/-1.82 nmol x mg(-1) x min(-1), n=8, P<0.05) but decreased in the aorta (from 0.33+/-0.02 to 0.25+/-0.017 nmol x mg(-1) x min(-1), n=6, P<0.05) after treatment with hydrochlorothiazide+losartan. In addition, the combination of these drugs reduced the heart-to-body mass ratio (3.96+/-0.07 for treated vs. 5.01+/-0.20 mg/g for untreated animals, n=7, P<0.05), and the thickness of the aortic media (0.076+/-0.003 for treated vs. 0.149+/-0.009 mm for untreated animals, n=8, P<0.05). Although hydrochlorothiazide alone lowered systolic blood pressure to the same level achieved with both drugs in combination (from 166+/-10 for untreated cardiomyopathic animals to 84+/-1 mm Hg for hydrochlorothiazide+losartan, and 80+/-5 mm Hg for hydrochlorothiazide alone, P<0.05), no significant reduction in heart-to-body mass ratio was observed in animals treated with the diuretic alone (P>0.05). In conclusion, in this model of heart failure, chronic hydrochlorothiazide+losartan administration normalizes the vascular responses to endothelin-1, improves basal vascular tone, and prevents the development of cardiac and vascular hypertrophy.
Crespo
M J
MJ
Department of Pharmacology, University of Puerto Rico-School of Medicine, GPO Box 365067, San Juan, Puerto Rico 00936-5067, USA. mcrespo@rcm.upr.edu
De Mello
W C
WC
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D014665:Vasodilator Agents; D006852:Hydrochlorothiazide; D009569:Nitric Oxide; D007703:Peptidyl-Dipeptidase A; D019808:Losartan; D000109:Acetylcholine