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 failur e. 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 ad ministration of a combination of losartan (25 mg/kg, p.o.) and hydrochlorot hiazide (6.5 mg/kg, p.o.) over an 8-week period. Age-matched golden hamster s were used as healthy controls. The contractile response of aortic rings t o endothelin-l was significantly higher in cardiomyopathic hamsters than in control animals. Concentration-response curves for the endothelin- 1-induc ed contraction were displaced to the right after hydrochlorothiazide + losa rtan treatment (toward the curves for healthy controls); however, E-max fro m treated hamsters was significantly reduced when compared to E-max from un treated cardiomyopathic animals (1.016 +/- 0.073 vs. 1.336 +/- 0.153 g, P < 0.05, n = 6). No significant differences in the EC50 values from these cur ves were observed between hydrochlorothiazide + losartan treated and untrea ted cardiomyopathic animals (2.90 +/- 0.95 vs. 1.10 +/- 0.85 nM, P > 0.05). The acetylcholine-induced relaxation observed in cardiomyopathic animals w as not improved after treatment with hydrochlorothiazide + losartan or hydr ochlorothiazide alone, but the combination of these drugs increased signifi cantly the basal production of nitric oxide (NO). Angiotensin-converting en zyme activity increased in plasma (from 29.9 +/- 1.33 to 41.16 +/- 1.82 nmo l mg(-1) min(-1), n = 8. P < 0.05) but decreased in the aorta (from 0.33 +/ - 0.02 to 0.25 +/- 0.017 nmol mg(-1) min(-1) n = 6, P < 0.05) after treatme nt with hydrochlorothiazide + losartan. In addition, the combination of the se 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 thick ness of the aortic media (0.076 <plus/minus> 0.003 for treated vs. 0.149 +/ - 0.009 mm for untreated animals,,l = 8, P < 0.05). Although hydrochlorothi azide alone lowered systolic blood pressure to the same level achieved with both drugs in combination (from 166 <plus/minus> 10 for untreated cardiomy opathic animals to 84 +/- 1 mm Hg for hydrochlorothiazide + losartan, and 8 0 +/- 5 mm HE for hydrochlorothiazide alone. P < 0.05), no significant redu ction 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, c hronic hydrochlorothiazide + losartan administration normalizes the vascula r responses to endothelin-1, improves basal vascular tone, and prevents the development of cardiac and vascular hypertrophy. (C) 2001 Published by Els evier Science B.V.