Pioglitazone enhances the blood pressure-lowering effect of losartan via synergistic attenuation of angiotensin II-induced vasoconstriction

Abstract

Introduction: This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats. Materials and methods: An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT 1 ), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47 phox , level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected. Results: After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47 phox and AT 1 , NADPH oxidase activity, and nitrotyrosine level. Conclusions: Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.

Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

“…The combination of a PPAR-γ agonist with an AT 1 R blocker results in a facilitated effect on blood pressure, greater than seen with either agent alone. 47, 48 Although these effects were attributed to peripheral renal and vascular mechanisms, similar synergistic interactions between the PPAR-γ and AT 1 R have been suggested to occur in the brain. 49 The present results support the general concept that PPAR-γ agonists may provide a significant additional benefit as adjunctive therapy for patients with hypertension.…”

Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats

“…Accordingly, pioglitazone also reduced the increased mRNA levels of NOX-1, NOX-4, and p47 phox , NOX activity, and vascular O 2 •Ϫ production. These effects of pioglitazone could contribute to explain the improvement of endothelium-dependent relaxation induced by glitazones in different pathologies (15,22,28,35).…”

“…Surprisingly, increased COX-2 expression was observed in rat mesenteric resistance arteries after pioglitazone treatment (22); we do not have explanation for such contradictory results, but differences in the compensatory mechanisms occurring in resistance versus conductance arteries could explain them. Furthermore, PPAR-␥ agonists inhibit the expression of several components of NOX and the subsequent ROS production, therefore contributing to the anti-inflammatory and vascular protective effects of these drugs (22,28,32,34). Accordingly, pioglitazone also reduced the increased mRNA levels of NOX-1, NOX-4, and p47 phox , NOX activity, and vascular O 2 •Ϫ production.…”

“…Nevertheless, despite the above-mentioned effects of pioglitazone on COX-2, ET-1, and oxidative stress, no changes were observed in blood pressure in SHRs. Glitazones have proven blood pressure-lowering effects in patients or animal models of diabetes and/or metabolic syndrome; however, in those conditions in which hypertension is not associated with diabetes or with other factors of metabolic syndrome, no changes in blood pressure have been generally described unless long-term treatment (28,58) or high doses of PPAR-␥ agonists (9, 17, 28) were used. It is possible that, although in our model of well-established hypertension pioglitazone did reduce some proinflammatory markers, these mechanisms are before the blood pressurelowering effect, which is likely to occur with long-term treatment.…”

Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats

“…It is evident that PPAR-γ agonists, including pioglitazone, are known to counteract the characteristics of diabetes and hypertension, activating via production of adiponectin which is mediator moderating oxidative stress through activation of signaling cascades, such as cAMP-PKA and AMPK-eNOS component (39) and reduction in sensitivity to Ang II (11) respectively. However, the extent of reduction of SBP & MAP in pioglitazone treated groups was lower as compared to adiponectin treated groups, which possibly could be due to enhanced production of nitric oxide (NO), stimulated by adiponectin (7), whereas, regulation of MAP and vascular tone depends upon nitric oxide, which acts as endothelium-derived molecule (40). The secretion of renin from kidneys mediates production of angiotensin II, which inhibits the adiponectin production, thus offsetting the dilator action of NO reflecting an important interaction with RAAS in regulating B.P through NO production (12), and thus impacts on B.P control.…”