Abstract 4395: Combined Effects of Losartan and Hydrochlorothiazide on Cardiac Remodeling and Function in Dahl Salt-Sensitive Hypertensive Rats
A combination therapy of two or more antihypertensives is recommended for treatment of hypertension where monotherapy is ineffective. Although low doses of thiazide diuretics are commonly used as add-ons to angiotensin receptor blockers (ARB), the basic rationale for such efficacy is unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy of losartan (LOS) and hydrochlorothiazide (HCTZ) in comparison with those of LOS alone or HCTZ alone, in Dahl salt-sensitive (DS) hypertensive rats. DS rats fed a high-salt diet from 6 weeks of age were treated with LOS (30 mg/kg/day, n=6), HCTZ (75 mg/L/day, n=6), combination of LOS and HCTZ (L+H, same doses, n=6) or vehicle (n=6) from 6 to 11 weeks. The vehicle group progressively developed severe hypertension and marked left ventricular (LV) hypertrophy and fibrosis were apparent in these animals at 11 weeks in comparison with age-matched controls (n=6). Systolic blood pressure (SBP) was significantly reduced in the LOS, HCTZ, and L+H groups compared with the vehicle group from 7 to 11 weeks. Although the degree of SBP reduction at 11 weeks was greater in HCTZ (−66.4 mmHg) and L+H (−82.1 mmHg) than that of LOS (−28.9 mmHg), there was no significant difference in reducing SBP between HCTZ and L+H. Treatment with HCTZ markedly attenuated LV hypertrophy but it did not significantly reduce LV fibrosis. In contrast, treatment with LOS attenuated LV hypertrophy less than that of HCTZ but LOS monotherapy completely prevented LV interstitial and coronary perivascular fibrosis. The combination therapy with LOS plus HCTZ attenuated LV hypertrophy to the same extent as that of HCTZ and the combination completely inhibited LV fibrosis. In addition, the prolongation in LV isovolumic relaxation time apparent in the vehicle group was attenuated by treatment with both LOS and HCTZ and was further improved in the L+H group. LV systolic function was not affected by either treatment. The present results demonstrate that the combination therapy of LOS and HCTZ improves LV diastolic function as well as strongly attenuates blood pressure elevation and LV hypertrophy and fibrosis by making up the deficit of each monotherapy in DS hypertensive rats.