Effects Of Angiotensin Receptor Blockers Research Articles

Irbesartan treatment does not influence plasma levels of the advanced glycation end products N (1-carboxymethyl)lysine and N (1-carboxyethyl)lysine in patients with type 2 diabetes and microalbuminuria. A randomized controlled trial

In vitro and animal experiments have shown inhibiting effects of angiotensin receptor blockers (ARBs) on the formation of advanced glycation end products (AGEs), which are known to be involved in the development of cardiovascular complications in diabetes. However, sufficient human data to confirm such beneficial effects of ARBs on AGEs are lacking. Therefore, we investigated the effects of irbesartan treatment on plasma levels of the AGEs N(ε)(1-carboxymethyl)lysine (CML) and N(ε)(1-carboxyethyl)lysine (CEL) in hypertensive patients with type 2 diabetes and microalbuminuria. We analysed data from a multicentre, double-blind, parallel, randomized controlled trial in patients with type 2 diabetes and microalbuminuria, the primary goal of which was to examine the renoprotective effects of irbesartan treatment (150 or 300 mg daily). Secondary end points included plasma CML and CEL in the treatment arm receiving 300 mg irbesartan (n = 139) and in the placebo group (n = 125). Effects of treatment at 1- and 2-year follow-up were analysed by means of generalized estimating equations according to an intention-to-treat principle. Levels of CML and CEL did not differ between groups at baseline. No significant changes were observed in CML and CEL over time in either group and there was no effect of treatment on CML and CEL at any time-point. Mean differences for the irbesartan versus placebo group over time were -0.96 μmol/mol lysine (95% confidence interval: -3.43 to 1.51) for CML and -0.10 μmol/mol lysine (-0.76 to 0.56) for CEL. Long-term irbesartan treatment does not influence plasma levels of the AGE CML and CEL in patients with type 2 diabetes and microalbuminuria.

Effects of Angiotensin Receptor Blocker on Phenotypic Alterations of Podocytes in Early Diabetic Nephropathy

BackgroundEmerging evidence suggests that podocyte injury is a crucial event in the stage of diabetic nephropathy (DN), a process in which angiotensin II is implicated. In this study, the authors investigated the influence of irbesartan, an angiotensin receptor blocker, on the phenotypic alterations of podocytes in experimental DN. MethodsDN was induced by combination of high-sucrose, high-fat diet and intraperitoneal injection of low dose of streptozotocin (35 mg/kg) in spontaneously hypertensive rats. Diabetic rats were treated with irbesartan (50 mg/kg/d) by gavage for 8 weeks. Nondiabetic normotensive Wistar-Kyoto rats, which have the same genetic background as spontaneously hypertensive rat, were used as controls. The renal histological changes were investigated by light and electron microscopy. The epithelial marker of nephrin and mesenchymal marker of desmin were detected by real-time reverse transcriptase-polymerase chain reaction and Western blotting. ResultsCompared with controls, diabetic rats were associated with mesangial matrix deposition, thickening of glomerular basement membrane, albuminuria, loss of podocytes and effacement of foot processes. Furthermore, the expression of nephrin was significantly reduced whereas desmin was increased. Irbesartan treatment not only lowered blood pressure and albuminuria but also attenuated podocyte loss, maintenance of nephrin expression and inhibition of desmin expression. ConclusionsThis study demonstrates that early irbesartan intervention attenuates the podocyte damage and ameliorates phenotypic alterations of podocytes, which provides a novel insight for the early application of angiotensin receptor blocker to prevent the development of DN.

Pleiotropic Effects of ARB in Diabetes Mellitus

Evidence accumulated to date indicates that inhibition of the rennin-angiotensin system with angiotensin receptor blockers (ARB) may prevent new-onset of diabetes. ARB is also used for the prevention of occurrence and progression of complications in diabetes and diabetic nephropathy. From the results of recent large-scale clinical studies, ARB is considered as a first choice drug in hypertensive patients with diabetes. In this review article, we focus on the effects of ARB on progression and prevention against diabetes as a metabolic-improving agent.

Atrial fibrillation and renin-angiotensin-aldosterone system: believe it or not

This editorial refers to ‘Association between angiotensin-converting enzyme insertion/deletion gene polymorphism and atrial fibrillation: a meta-analysis’ T. Liu et al ., on page 346. There is compelling evidence that the renin–angiotensin–aldosterone system (RAAS) is involved in the pathogenesis of atrial fibrillation (AF). Currently, it is recognized that there is a sustained reduction in new-onset AF in patients with significant underlying heart disease (e.g. left ventricular dysfunction and hypertrophy) treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs), but evidence is less convincing in patients with moderate structural heart disease and recurrent AF.1–3 Negative results have recently been reported in two large prospective studies with ARBs in patients with mild structural disease and this clearly raises the issue that these therapies may not offer the same benefit in all patients.4,5 Some probably assumed that since an ARB did not reduce the number of AF episodes in patients with paroxysmal AF without structural heart disease in the Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) study, RAAS blockade was not really effective in treating AF in general. Let us go back to basics. There is experimental evidence of antifibrillatory and antifibrotic effects of ACEIs and ARBs in various AF models. Their potential mechanisms of action include haemodynamic, antiproliferative, anti-inflammatory, and antioxidant effects that may prevent the development of left atrial stretch and enlargement, interstitial fibrosis, and adverse atrial electrical remodelling, which is manifested by shortened duration of the action potential, abnormalities of intracellular calcium handling, and alteration in cell-to-cell conduction.6,7 RAAS activation …

Reappraisal of role of angiotensin receptor blockers in cardiovascular protection

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND) trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT) and Olmesartan and Calcium Antagonists Randomized (OSCAR) studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.

Angiotensin receptor blockers and angiogenesis: clinical and experimental evidence

Angiotensin II type 1 receptor antagonists [ARBs (angiotensin receptor blockers)] are indicated for BP (blood pressure)-lowering, renal protection and cardioprotection in patients unable to tolerate ACEIs (angiotensin-converting enzyme inhibitors). A recent meta-analysis revealed an association between ARBs and tumour development, possibly due to enhancement of angiogenesis. However, published evidence is conflicting on the effects of ARBs on angiogenesis or the expansion of the existing vascular network. ARBs have been shown to exert primarily anti-angiogenic effects in basic science studies of cancer, retinopathy, peripheral artery disease and some models of cardiovascular disease. In animal and cellular models of myocardial infarction and stroke, however, ARB administration has been associated with robust increases in vascular density and improved recovery. The aim of the present review is to examine the angiogenic effects of ARBs in animal and cellular models of relevant disease states, including proposed molecular mechanisms of action of ARBs and the clinical consequences of ARB use.

Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy

Our recent in vitro study demonstrated peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist potentiated the anti-inflammatory effect of angiotensin receptor blocker (ARB) in tubular epithelial cell under milieu mimicking IgA nephropathy (IgAN). Here we studied the therapeutic effect of combining a PPAR-γ agonist, rosiglitazone (Ros), with an ARB, losartan (Los), in experimental IgAN induced in Lewis rats by oral and intravenous immunization with bovine gamma-globulin (BGG). The rats were randomly divided into six groups: control, IgAN, IgAN with unilateral nephrectomy (IgAN/1K), and IgAN/1K receiving Ros, Los, or Ros + Los. Medication was given 1 week after nephrectomy until killing. Rats developing IgAN had hematuria, mesangial hypercellularity with IgA deposition, glomerular damage, and tubulointerstitial infiltration of CD25+ leukocytes accompanied by increased renal expression of TGF-β, AngII receptor subtype-1 (ATR1) and ICAM-1. The renal histopathology, albuminuria, and renal expression of TGF-β, ATR1 and ICAM-1 worsened with unilateral nephrectomy. Ros or Los reduced the renal expression of PCNA, TGF-β, ATR1, and ICAM-1 in IgAN rats with nephrectomy. Despite no difference between rats treated with monotherapy, combined therapy offered additive effect with decreased renal expression of TGF-β, ATR1 and ICAM-1 and attenuation of renal injury. Our animal study suggests combined PPAR-γ agonist and ARB holds promise for future therapy for IgAN.

Pleiotropic Effects of Angiotensin Receptor Blockers: Addressing Comorbidities by Optimizing Hypertension Therapy

The efficacy of angiotensin receptor blockers (ARBs) in the management of hypertension is well established. Whether these agents induce pleiotropic effects that promote the amelioration of vascular disorders independent of blood pressure reduction remains controversial. This review examines preclinical and clinical data that highlight a potentially important role for ARBs in several common vascular disorders, including cardiovascular, cerebrovascular, renal, and metabolic disorders. The preponderance of evidence suggests that some of the benefits derived from ARBs might improve outcomes in these disorders by actions that extend beyond blood pressure reduction. This review also identifies some potentially important differences in the mechanism of action between ARBs and angiotensin-converting enzyme inhibitors that may have clinical significance in the management of vascular diseases.

Silent Cortical Neuronal Damage in Atherosclerotic Disease of the Major Cerebral Arteries

In atherosclerotic internal carotid artery (ICA) or middle cerebral artery (MCA) disease, hemodynamic compromise may cause selective neuronal damage manifested as loss of central benzodiazepine receptors (BZRs) in the normal-appearing cerebral cortex, without overt episode of stroke. To investigate the association of decreases in cortical BZRs with hemodynamic compromise and the effect of angiotensin receptor blockers (ARBs) on these receptors in patients whose atherosclerotic ICA or MCA disease is asymptomatic, we measured BZRs using positron emission tomography and 11C-flumazenil in 79 patients with asymptomatic atherosclerotic ICA or MCA disease and no cortical infarction. Three-dimensional stereotactic surface projections were used to calculate the BZR index, a measure of abnormally decreased BZRs in the cerebral cortex within the MCA distribution. Multiple regression analysis showed this index to be positively correlated with the value of oxygen extraction fraction, with the presence of silent subcortical infarcts, and with the presence of ischemic heart disease, whereas it was negatively correlated with the treatment of hypertension with ARBs. In asymptomatic atherosclerotic ICA or MCA disease, hemodynamic compromise is associated with selective neuronal damage manifested as decreases in cortical BZRs in the noninfarcted cerebral cortex, whereas ARBs are associated with preservation of cortical BZRs.

Comparison of the Long-term Effects of Losartan vs. Losartan/Hydrochlorothiazide in Patients With Hypertension

Background: Aldosterone (ALD) breakthrough generally occurs and is an important issue during long-term treatment with angiotensin receptor blockers (ARB). However, long-term effects of ARB with hydrochlorothiazide on plasma levels of ALD and left ventricular mass index (LVMI) remain unknown in patients with hypertension. Methods: Forty-eight stable outpatients with essential hypertension who had received amlodipine for more than one year were randomized to two groups [amlodipine was changed to losartan (L) (n=24) or losartan/hydrochlorothiazide (L/H) (n=24)].

Is the reno-protective effect of valsartan dose dependent? A comparative study of 80 and 160 mg day−1

Whether the reno-protective effect of angiotensin receptor blockers is dose dependent is unknown for the Japanese population. We sought to elucidate the dose-dependent reno-protective effects of valsartan in Japanese hypertensive patients with albuminuria. This was a multi-center, open-label, parallel-group trial. A total of 181 patients were randomized to receive either 80 (n=89) or 160 mg day(-1) (n=92) of valsartan for 24 weeks. Then, the effects on blood pressure, urinary albumin excretion (UAE), type IV collagen and beta(2)-microglobulin (beta2MG) were determined. Systolic and diastolic blood pressures decreased substantially by almost the same extent in the low-dose and high-dose groups, showing no inter-group difference during the treatment. The UAE value decreased significantly by 35% in both groups. Urinary excretion of beta2MG was significantly decreased in the high-dose group (17%), but not in the low-dose group (13%), although the decrease was not significantly different between the two groups (P=0.74). Urinary excretion of type IV collagen decreased non-significantly by 10% in the low-dose group and by 8% in the high-dose group, showing no significant inter-group difference (P=0.78). Low (80 mg day(-1)) and high (160 mg day(-1)) doses of valsartan showed a similar effect of lowering blood pressure. The high dose of valsartan resulted in a slightly greater decrease in urinary beta2MG, but it was inconclusive whether the high dose was more reno-protective as compared with the low dose.

BOTH ANGIOTENSIN RECEPTOR BLOCKER AND CALCIUM CHANNEL BLOCKER REDUCE THE EXPRESSION OF RECEPTOR FOR ADVANCED GLYCATION END-PRODUCTS IN THE AORTIC WALL OF TYPE 2 DIABETIC RATS: PP.17.137

Objectives: Receptor for advanced glycation end-product (RAGE) plays a key role in the development of vascular inflammation and acceleration of atherosclerosis in type 2 diabetics. Angiotensin receptor blocker (ARB) or calcium channel blocker (CCB) is commonly used in the treatment of diabetes-related hypertension. Thus we investigated the effect of ARB or CCB on the RAGE expression in the vessel walls of type 2 diabetic rats. Methods: Type 2 diabetic, 25-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomized to 8 weeks of gastric gavage of candersartan (CDRT; 3 mg/kg; n = 8), amlodipine orotate (AMDP; 3 mg/kg; n = 8) or saline (n = 8) after blood pressure (BP) measurement and intraperitoneal glucose tolerance tests (IP-GTT). After 8 weeks, all rats were sacrificed and their aortas underwent immunohistochemical (IHC) analyses for RAGE, dihydroethidium (DHE) staining for oxidative stress and immunoblotting for RAGE and ERK1/2. Results: Both CDRT and AMDP significantly lowered systolic BP than saline treatment (107±5 vs. 113±5 vs. 137±7 mmHg, p < 0.05) and postprandial 30-minute glucose levels (317±42 vs. 305±54 vs. 418±19 mg/dL, p < 0.05). An in vitro study showed that both CDRT and AMDP reduced AGE-stimulated RAGE expression in HUVECs. IHC analyses and immunoblots demonstrated reduced RAGE aortic signals in both CDRT- and AMDP-treated compared to saline-treated OLETF rats (p < 0.05, respectively). DHE staining revealed reduced reactive oxygen species (ROS) signals in CDRT- or AMDP-treated rats compared to saline-treated rats (p < 0.05). However, CDRT therapy significantly reduced phosphorylated-ERK 1/2 aortic signals compared to AMDP- or saline-treated rats (p < 0.05). Conclusion: Both ARB and CCB reduces aortic RAGE expression to the similar magnitude. ARB may reduce RAGE signals of aortic wall by suppressing aortic wall oxidative stress and ERK1/2 pathway. In contrast, CCB may reduce RAGE signals of aortic wall by suppressing oxidative stress, not by ERK1/2 pathway. These results suggest that both ARB and CCB have an anti-atherosclerotic agent by suppressing RAGE expression in type 2 diabetes.

Angiotensin receptor blocker-based therapy and cardiovascular events in hypertensive patients with coronary artery disease and impaired renal function

The aim of this study was to assess the effects of angiotensin receptor blocker (ARB)-based therapy on cardiovascular events in high-risk hypertensive patients with coronary artery disease (CAD) and impaired renal function in post hoc analysis of HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease). Patients (n=2049) were randomly assigned to candesartan-based or non-ARB treatment arms; 1022 patients (age 70±6 years, 28% female) with impaired renal function, defined as creatinine clearance <60 ml/min at baseline. There was no difference in major adverse cardiac event (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, unstable angina, heart failure, stroke and other cardiovascular events requiring hospitalization between the two arms in patients without impaired renal function. However, there was a lower incidence of MACE in the candesartan-based treatment arm than in the non-ARB treatment arm (HR=0.79, 95% CI 0.63–0.99, p=0.039) in patients with impaired renal function. Among the MACE, candesartan-based treatment reduced hospitalization for unstable angina (HR=0.71, 95% CI 0.52–0.96, p=0.028). Although candesartan-based treatment was not superior to non-ARB treatment in prevention of cardiac mortality, ARB-based therapy may be beneficial in reducing risk of coronary events in hypertensive patients with CAD and impaired renal function.

Involvement of the renin–angiotensin system in the development of vascular damage in a rat model of arthritis: Effect of angiotensin receptor blockers

To explore the involvement of the renin-angiotensin system (RAS) in the development of vascular damage in adjuvant-induced arthritis (AIA) in rats. Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II-induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT(1)R) and angiotensin-converting enzyme (ACE) in the aortas of rats with AIA were examined by real-time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT(1)R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real-time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT(1)R blockers was also determined. The Ang II-induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT(1)R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT(1)R blockers. The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.

Role of B1 and AT2 Receptors in Cardiac Remodeling and Dysfunction in B2 Receptor Knockout Mice with Myocardial Infarction

Activation of angiotensin II type 2 receptors (AT2R) contributes to cardioprotective effects of angiotensin receptor blockers, possibly via kinins acting on B1 and B2 receptors (B1R and B2R). Using B2R knockout mice (B2R−/− on B6;129SF2/J background, which have increased both B1R and AT2R expression), we tested the hypothesis that AT2R and B1R compensate for loss of B2R and that blockade of AT2R and/or B1R deteriorates cardiac remodeling and dysfunction in B2R−/− mice post myocardial infarction (MI). B2R−/− and wild-type controls (WT) were subjected to sham MI or MI and treated with either vehicle, B1R antagonist (B1R-ant, R892, 300 μg/kg/day), AT2R-ant (PD123319, 20 mg/kg/day) or B1R-ant + AT2R-ant for 4 weeks. We found that 1) B2R−/− with sham MI had greater LV mass and myocyte cross-sectional area (MCSA) than WT (Figure 2) after MI, the increase in MCSA and interstitial collagen fraction (ICF) was greater in B2R−/−, but ejection fraction (EF) did not differ from WT; 3) B1R-ant alone but not AT2R-ant further increased MCSA and ICF and decreased EF in B2R−/−; and 4) blockade of both B1R and AT2R increased LV mass, diastolic dimension, MCSA and ICF and decreased EF further. Our results suggest that B1R and AT2R may play an important role in preventing deterioration of cardiac function and remodeling post- MI when B2R are absent. This work was supported by NIH grants HL28982, HL078951.

Protective Effects of Intranasal Losartan in the APP/PS1 Transgenic Mouse Model of Alzheimer Disease

The local renin-angiotensin system (RAS) in the brain is a multitasking system controlling a plethora of essential functions such as neurogenic hypertension, baroreflexes, and sympathetic activity. Aside from its vasoactive actions, brain angiotensin II (AT-II) has also been implicated in the pathogenesis of cognitive decline, and beneficial effects of angiotensin receptor blockers (ARBs) in Alzheimer (AD) and Parkinson diseases (PD) are suggested. However, the use of ARBs at antihypertensive dosages would lead to unwanted hypotensive reactions in AD patients. Here we treated the APP/PS1 transgenic mouse model of AD with the ARB losartan (10 mg/kg body weight) to determine whether blockade of the AT-II receptor subtype 1 (AT1-R) with intranasal losartan, using at a dosage far below its systemic antihypertensive dose, could maintain its neuroprotective effects independent of its systemic vasoactive action. Intranasal losartan treatment (10 mg/kg every other day for 2 months) of APP/PS1 mice decreased amyloid beta (Abeta) plaques 3.7-fold. Blood serum levels of interleukin-12 (IL-12)p40/p70, IL-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in the vehicle-treated APP/PS1 mice. Intranasal losartan not only decreased IL-12p40/p70, IL-1beta, and GM-CSF, but also increased IL-10, which suppresses inflammation. Furthermore, losartan markedly increased tyrosine hydroxylase expression in the striatum and locus coeruleus. In conclusion, losartan exerts direct neuroprotective effects via its Abeta-reducing and antiinflammatory effects in the central nervous system (CNS). Therefore, intranasal losartan and potentially other ARBs, at concentrations below their threshold for altering systemic blood pressure, offer a new approach for the treatment of AD.

Response of cardiac sympathetic nerve activity to intravenous irbesartan in heart failure

To determine the effect of irbesartan treatment on resting levels and arterial baroreflex control of cardiac sympathetic nerve activity (CSNA) in heart failure (HF), we studied conscious normal sheep and sheep with HF induced by rapid ventricular pacing for 8-10 wk (n = 7 per group). In HF, there is a large increase in CSNA that is detrimental to outcome. The causes of this increase in CSNA and the effect of angiotensin receptor blockers on CSNA in HF are unclear. CSNA, arterial blood pressure, heart rate (HR), and arterial baroreflex curves were recorded during a resting period and after 90 min of irbesartan infusion (12 mg.kg(-1).h(-1) iv). This dose of irbesartan abolished the pressor response to intravenous ANG II infusion but caused only a slight decrease in the pressor response to centrally administered ANG II. In HF, there was a large increase in CSNA (from 44 +/- 3 to 87 +/- 3 bursts/100 heartbeats). Irbesartan reduced arterial pressure in the normal and HF groups, but the usual baroreflex-mediated increases in CSNA and HR were prevented. This resulted from a significant leftward shift in the CSNA and HR baroreflex curves in both groups. Irbesartan also decreased the sensitivity of the arterial baroreflex control of CSNA. Short-term treatment with an angiotensin receptor blocker, at a dose that abolished the response to circulating, but not central, ANG II, prevented the reflex increase in CSNA in response to the drug-induced fall in arterial pressure.

Effect of Renin-Angiotensin system blockade on insulin resistance and inflammatory parameters in patients with impaired glucose tolerance.

OBJECTIVEThe study investigated the effect of angiotensin receptor blockers (ARB) on glucose homeostasis and inflammatory parameters in patients with impaired glucose tolerance (IGT).RESEARCH DESIGN AND METHODSWe prospectively studied the insulin sensitivity index (ISI) and homeostasis model assessment–insulin resistance (HOMA-IR) in 13 obese males with IGT and in 13 matched control subjects with normal glucose tolerance (NGT) during hyperglycemic testing over 90 min. Adiponectin, retinol-binding protein 4 (RBP4), and high-sensitive C-reactive protein (hsCRP) were analyzed. Measurements were performed at baseline and after a 4-week treatment with 160 mg/day valsartan. The results of the IGT and NGT groups were compared.RESULTSAt baseline, HOMA-IR (IGT 4.1 ± 3 vs. NGT 2.3 ± 1.0, P < 0.01), hsCRP (IGT 3.9 ± 1.9 vs. NGT 1.8 ± 1 mg/l, P < 0.05), and RBP4 (IGT 27.1 ± 2.1 vs. NGT 24.0 ± 2.0 ng/ml, P < 0.05) were significantly higher, whereas ISI (IGT 1.5 ± 0.9 vs. NGT 1.8 ± 1.2, P < 0.05) and plasma adiponectin (IGT 3.2 ± 0.9, NGT 5.2 ± 2.4 μg/ml, P < 0.05) were significantly lower in the IGT group compared with the NGT group. Under ARB, there was an increase in both groups of adiponectin (IGT 4.1 ± 1.9 μg/ml, NGT 6.3 ± 2.9 μg/ml, P < 0.05) and an increase in ISI (IGT 1.5 ± 0.9 to 2.3 ± 1 μg/ml, NGT 1.8 ± 1 to 2.5 ± 2 μg/ml, P < 0.05). HOMA-IR (4.1 ± 3 to 2.6 ± 2; P < 0.01), hsCRP (3.9 ± 1.9 to 1.8 ± 1 mg/l, P < 0.05), and RBP4 (27.1 ± 2.1 to 22.1 ± 1.8 ng/ml, P < 0.01) decreased significantly in the IGT group.CONCLUSIONSInsulin sensitivity and associated inflammatory factors improve under ARB in IGT patients.

Abstract B93: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may decrease cancer-related mortality in patients with small-cell lung cancer

Abstract Introduction: Small-cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival at five years for patients with SCLC is estimated to be five to ten percent. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) have been reported to decrease the risk of lung cancer. The aim of this retrospective study was to investigate the association between ACE inhibitors and ARBs and cancerrelated mortality in patients with SCLC. Methods: In this study, we retrospectively reviewed the charts of 360 patients diagnosed with SCLC in our institution between 1995 and 2004. 199 patients with advanced SCLC, deceased at the time of this report, and for whom the cause of death was known, were identified. Within this group, cancer-related mortality in patients who were on ACE inhibitors and/or ARBs was compared to that of patients not on these medications. Results: Out of 199 patients, 58 (29%) were on ACE inhibitors and/or ARBs, 141 (71%) were not. In ACE inhibitor and/or ARB users, cancer was the cause of death in 34 patients. In patients not on ACE inhibitors and/or ARBs, 103 died from cancer. Patients on ACE inhibitors and/or ARBs had a 14% decrease in cancer-related mortality compared to patients who were not on these medications (59% versus 73% respectively, P= 0.046). Conclusion: Our data support the fact that ACE inhibitors and ARBs may be associated with a decrease in cancer-related mortality in patients with SCLC. This could be related to their inhibitory effects on angiogenesis and tumor growth, by blocking angiotensin II and increasing the levels of angiotensin (1–7). However, prospective studies are needed to establish the effect of ACE inhibitors and ARBs on cancer-related mortality in patients with SCLC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B93.

Olmesartan Inhibits Angiotensin II–Induced Migration of Vascular Smooth Muscle Cells Through Src and Mitogen-Activated Protein Kinase Pathways

Clinical studies have shown that angiotensin-receptor blockers (ARBs) reduce the risk of cardiovascular diseases in hypertensive patients. It is assumed that the reduction of the risk by ARBs may be attributed in part to the inhibition of angiotensin II (AII)-induced vascular smooth muscle cell (VSMC) migration associated with atherosclerosis. However, the effect of ARBs on AII-induced changes in intracellular signaling and resultant cell migration has not been well established. Here, we investigated the effect of olmesartan, an ARB, on AII-induced extracellular signal–regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation and rat aortic smooth muscle cell (RASMC) migration. Olmesartan inhibited AII-induced ERK1/2 and JNK activation at lower concentrations (10 nM). On the other hand, PP2, a Src tyrosine kinase inhibitor, also inhibited AII-induced ERK1/2 and JNK activation, but its effect on ERK1/2 was less pronounced than that of olmesartan. Olmesartan, U0126 (an ERK1/2 inhibitor), SP600125 (a JNK inhibitor), and PP2 potently inhibited AII-induced RASMC migration. From these findings, it was inferred that angiotensin-receptor blockade by olmesartan results in the inhibition of AII-induced activation of Src, ERK1/2, and JNK in RASMC. Olmesartan may be a potent inhibitor of AII-induced VSMC migration, which may be involved in the progression of atherosclerosis.