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.

Effects of FTO RS9939906 and MC4R RS17782313 on obesity, type 2 diabetes mellitus and blood pressure in patients with hypertension

“…It has been widely demonstrated in animal models the contribution of melanocortin system on cardiovascular function [43], and, in human beings, it has been shown how centrally expressed melanocortin 4 receptor ( MC4R ) not only conveys hypothalamic signals suppressing food intake, but it is also involved in blood pressure control [21]. Common variants near MC4R could reflect the same effect, but is unknown if anti-hypertensive drugs or changes in lifestyle could modify the expression of these genes or the effects of both polymorphisms on blood pressure, as it has been shown [44]. Among different model species, it has been demonstrated signaling cascades and transcription factors for several obesity genes that could be useful for development of new drugs and for translational research [45].…”

Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis

“…Twenty-four rats were maintained on 0.3% NaCl (DSN) as a normal control group. HCTZ (10 mg/kg/d) was orally administered to another 24 rats as previously reported43 when they were switched to the 8% NaCl diet (DSH+HCTZ), which was continued until the time of sacrifice. The rats in these three groups were sacrificed at weeks 3, 6, 9, and 12 (n = 6 per time point).…”

Losartan/hydrochlorothiazide combination vs. high-dose losartan in patients with morning hypertension—a prospective, randomized, open-labeled, parallel-group, multicenter trial

“…First, the combination of ARB and thiazide diuretic exerts a synergistic BP-lowering effect through complementary mechanisms of action whereas the antihypertensive effect of ARBs is not dose dependent. 10,11,23 Second, 50 mg of losartan combined with 12.5 mg of HCTZ has a longer duration and a greater trough-to-peak ratio of BP-lowering effect than once daily 100 mg losartan. 24 Next, increased salt sensitivity is associated with a non-dipper pattern of circadian BP rhythm.…”

“…8,9 Among various combinations, an angiotensin II type-1 receptor blocker (ARB) combined with a small dose of thiazide diuretic is desirable because the two drugs have complementary mechanisms of action, effectively reduce BP, and are generally well tolerated. 10,11 A high-dose regimen of ARB is another treatment option. At present, however, little or no information is available on the efficacy of the ARB/ thiazide diuretic combination for controlling morning hypertension.…”