Superiority of combination of thiazide with angiotensin-converting enzyme inhibitor or AT₁-receptor blocker over thiazide alone on renoprotection inl-NAME/SHR

Abstract

The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg x kg(-1) x day(-1)) alone or in combination with enalapril (30 mg x kg(-1) x day(-1)) or losartan (30 mg x kg(-1) x day(-1)) or enalapril (15 mg.kg(-1).day(-1)) plus losartan (15 mg x kg(-1) x day(-1)) was administered to l-NAME/SHR (5.0 +/- 0.10 mg x kg(-1) x day(-1)) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances (P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

“…These results are consistent with the fact that the combination of thiazide diuretics and RAS inhibitors has been used to lower blood pressure and limit target-organ damage. 43,44 We acknowledge a limitation that the indirect tail-cuff method used to determine SBP is not adequate for ruling out the possibility that the results could be attributable to differences in blood pressure between the different treatment groups. 45 We also acknowledge that the use of anesthetics ketamine and xylazine may have affected some of our results including measurements of the RAS, because those agents may stimulate sympathetic nervous system in the rats.…”

Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model

“…Accordingly, the association between thiazides and either ARBs or ACEI has been used to lower blood pressure and limit proteinuria (21,24,36,40). However, the long-term effects of this association on CKD progression had not been systematically examined.…”

“…In CKD patients, Dussol and co-workers (5) obtained comparable antihypertensive and better natriuretic effect with chlorthalidone than with furosemide. In addition, the antihypertensive effect and cardiovascular risk reduction provided by ACEI or ARB are strongly reinforced by concomitant administration of thiazides (21,33,36,40). However, systematic clinical or experimental studies of the longterm renoprotective effect of these associations have not been performed.…”

The Salt Conundrum

“…69 Consequently, we further hypothesize that the reason for the dissociation of the stroke and coronary heart disease benefits from those potential benefits preventing cardiac and renal failure increases with diuretic-based antihypertensive therapy was not solely related to the hypotensive action of diuretics. We suggest that the inability of the many reports and guidelines published over the years demonstrating the ever-increasing cardiac and renal failure end points 7,8 was not because the trialists had not yet had the opportunities to analyze and these outcomes, but because the diuretic (by itself or with inadequate doses of angiotensin-inhibiting drugs) stimulated local cardiac, vascular, or renal RAAS.…”