Patient adherence and the choice of antihypertensive drugs: focus on lercanidipine

Despite the development of many effective antihypertensive drugs, target blood pressures are reached in only a minority of patients in clinical practice. Poor adherence to drug therapy and the occurrence of side effects are among the main reasons commonly reported by patients and physicians to explain the poor results of actual antihypertensive therapies. The development of new effective antihypertensive agents with an improved tolerability profile might help to partly overcome these problems. Lercanidipine is an effective dihydropyridine calcium channel blocker of the third generation characterized by a long half-life and its lipophylicity. In contrast to first-generation dihydropyridines, lercanidipine does not induce reflex tachycardia and induces peripheral edema with a lower incidence. Recent data suggest that in addition to lowering blood pressure, lercanidipine might have some renal protective properties. In this review we shall discuss the problems of drug adherence in the management of hypertension with a special emphasis on lercanidipine

P-621: Metabolic determinants of proximal sodium reabsorption in healthy women

Increased reabsorption of sodium (Na) in the proximal segments of the nephron is present in hypertensive patients. Studies performed in men reported an association between proximal Na reabsorption and features of the metabolic syndrome. This study explores the relationship between metabolic variables and proximal Na reabsorption in healthy women. This study is population-based and cross-sectional examining 661 healthy women aged 40-75y. After 15 minutes rest, blood pressure was measured 3 times, blood was drawn and urine was collected. Fractional excretion of endogenous lithium (FELi) was used as an indirect marker of proximal sodium reabsorption, lithium being only reabsorbed in the proximal tubule. All women receiving blood pressure, blood glucose or lipid lowering therapy were excluded. Correlations: FELi was positively correlated with the fractional excretion of sodium (FENa, r=0.3, p<0.001). FELi was negatively associated with total cholesterol (r=-0.14, P<0.0001), LDL-cholesterol (r=-0.16, P<0.0001), BMI (r=-0.08, P<0.05) and weight (r=-0.09, P<0.05). Menopausal status or a family history of hypertension did not affect the associations. Simple linear regression analysis: age, waist circumference, waist/hip ratio, systolic blood pressure, diastolic blood pressure, Hdl cholesterol, triglycerides, serum uric acid or a family history of hypertension were not significant predictors of FELi. BMI was a significant predictor but the strongest relationships were found between FELi and total cholesterol, LDL-cholesterol and FENa. Multivariate linear regression model: When significant predictors of FELi were examined in a multivariate linear regression model also controlling for age, weight, systolic blood pressure and FENa, total cholesterol (p=0.003) or LDL-cholesterol (p=0.001) significantly and independently predicted FELi. In conclusion, these data suggest that metabolic parameters, in particular total cholesterol and LDL-cholesterol and to a lesser extent weight and BMI, are associated with increased proximal Na reabsorption in a healthy untreated women population. Considering the possible link between increased reabsorption of sodium and the development of hypertension, a major cardiovascular risk factor, this association may provide an additional hypothesis for the increased cardiovascular risk of subjects with the metabolic syndrom

The effect of pH-neutral peritoneal dialysis fluids on adipokine secretion from cultured adipocytes

Background. Adipokines are a group of fat-secreted hormones and cytokines, including leptin and adiponectin, with important functions in humans. Peritoneal dialysis (PD) is associated with markedly raised plasma adipokines, suggesting increased production in this setting. We have shown that low pH down-regulates leptin production. The current study was designed to test if novel pH-neutral PD fluids may regulate leptin and adiponectin secretion in vitro. Methods. We exposed 3T3-L1 adipocytes to a 50 : 50 mixture of dialysate and M199 containing 10% serum for upto 48 h. Dialysates were commercial PD fluids, i.e. conventional acidic, lactate-buffered solutions (PD-acid) and pH-neutral lactate-buffered (PD-Bal) or bicarbonate-buffered solutions (PD-Bic). Leptin and adiponectin concentrations in culture-cell media were measured by ELISA. Results. Compared with PD-acid, PD-Bal and PD-Bic produced a 25 and 43% increase, respectively, in leptin secretion at 48 h (P < 0.05). In contrast, adiponectin secretion was not affected. High glucose PD fluids (4.25%) specifically inhibited leptin secretion vs 1.5% glucose, buffer-matched solutions (P < 0.05). However, differences in leptin secretion due to pH and type of buffer remained significant. In further experiments, the pH of test media were extensively varied without the presence of dialysates. Leptin secretion was shown to increase in a parallel to pH, whereas large changes in pH did not affect adiponectin secretion. Conclusion. The pH-neutral PD solutions specifically induce leptin, but not adiponectin secretion from 3T3-L1 adipocytes. PD-Bic produced a greater leptin stimulation than PD-Bal, but this difference was attributable to pH per se, rather than the type of buffe

Root presence modifies the long-term decomposition dynamics of fungal necromass and the associated microbial communities in a boreal forest

Recent studies have highlighted that dead fungal mycelium represents an important fraction of soil carbon (C) and nitrogen (N) inputs and stocks. Consequently, identifying the microbial communities and the ecological factors that govern the decomposition of fungal necromass will provide critical insight into how fungal organic matter (OM) affects forest soil C and nutrient cycles. Here, we examined the microbial communities colonising fungal necromass during a multiyear decomposition experiment in a boreal forest, which included incubation bags with different mesh sizes to manipulate both plant root and microbial decomposer group access. Necromass-associated bacterial and fungal communities were taxonomically and functionally rich throughout the 30 months of incubation, with increasing abundances of oligotrophic bacteria and root-associated fungi (i.e., ectomycorrhizal, ericoid mycorrhizal and endophytic fungi) in the late stages of decomposition in the mesh bags to which they had access. Necromass-associated beta-glucosidase activity was highest at 6 months, while leucine aminopeptidase peptidase was highest at 18 months. Based on an asymptotic decomposition model, root presence was associated with an initial faster rate of fungal necromass decomposition, but resulted in higher amounts of fungal necromass retained at later sampling times. Collectively, these results indicate that microbial community composition and enzyme activities on decomposing fungal necromass remain dynamic years after initial input, and that roots and their associated fungal symbionts result in the slowing of microbial necromass turnover with time.Peer reviewe

O-28: Molecular basis for the insurmountable AT-1 receptor antagonism of telmisartan

In vitro studies have shown that telmisartan is an insurmountable angiotensin II AT-1 receptor antagonist. In this study we have investigated the molecular basis of this insurmountable antagonism. The association and dissociation kinetics of telmisartan to angiotensin AT-1 receptors were measured using an in vitro radio-receptor binding assay. These radioligand binding studies were conducted either directly on rat vascular (aorta) smooth muscle cells (RVSMC) expressing solely the AT-1 receptor or on membrane preparation obtained from the same cells. The specific binding of3H-telmisartan to the surface of living RVSMC or membranes was saturable. From these data, a Kd value of 1.7 nM was estimated. Scatchard analysis of the3H-telmisartan binding on RVSMC indicated the existence of a single class of binding sites. The affinity of telmisartan for AT-1 receptor is only poorly affected by the presence of proteins (0.4% of rat plasma proteins) in the binding buffer, indicating that no great competition between telmisartan binding to its specific AT-1 receptor and to non-specific proteins binding sites occurs. In association experiments, the specific binding of3H-telmisartan increases quickly and reaches equilibrium within less than 1 hour, with an association rate constant calculated to be 0.006 min-1nM-1. Telmisartan dissociates very slowly from the AT-1 receptor, either in RVSMC membrane preparation or in living cells with a dissociation rate constant of ca. 0.01 min-1 resulting in a dissociation half-life (t1/2) of about 60 min, which is comparable to the previously published data for candesartan in bovine adrenal cortical membranes and almost 5 times slower than that of 125I-angiotensin II binding (t1/2=12 min). In contrast to candesartan that has been shown to re-associate with the AT-1 receptor, telmisartan does not appear to re-associate. Indeed, when the dissociation of labeled-telmisartan from AT-1 receptors was induced by washing the cells with cold-binding buffer, followed by addition of fresh binding buffer containing either cold telmisartan, Ang II or losartan, or nothing, no difference were observed in the dissociation rate constants measured with telmisartan whatever the composition of the binding buffer after removal of labeled-telmisartan. In conclusion, these results suggest that the insurmountable antagonism of telmisartan is due mainly to its very slow dissociation from angiotensin AT-1 receptor

P-440: Losartan but not irbesartan reduces serum uric acid in hypertensive patients with hyperuricemia and/or gout

Losartan has unique uricosuric properties and has been shown to decrease serum uric acid (SUA) levels in normal subjects as well as in hypertensive patients. The purpose of the present study was to compare the effects of losartan and irbesartan on serum uric acid in hypertensive hyperuricemic patients with or without gout. Twelve hyperuricemic (SUA>420mmol/L), hypertensive patients (mean age: 58 yr) participated in this randomized, double-blind, crossover study. After a 3-week run-in period during which patients received enalapril 20 mg o.d, patients were randomized to receive either losartan 50 mg o.d for 4 weeks followed by losartan 50 mg bid for another 4 week period or irbesartan 150 mg o.d followed by irbesartan 150 mg bid for 4 weeks. The losartan and irbesartan phases were separated by 3 weeks of the ACE inhibitor. All drugs were provided in an electronic pill container allowing to monitor compliance (MEMS system). Losartan decreased SUA significantly from 539±28 mmol/L to 490±22 mmol/L (p1 month). Hence, the uricosuric effect tends to decrease with time as SUA is reduced. Increasing the dose of losartan to 50 mg bid does not appear to induce a further decrease in serum uric aci

P-537: Pioglitazone blunts the blood pressure response to angiotensin II in insulin-resistant zucker rats

Thiazolidinediones are high-affinity agonists of peroxisome proliferator-activated receptors (PPAR)-γ which have been found to lower blood pressure (BP) in animal models of diabetes and reno-vascular hypertension. The mechanisms leading to this decrease in blood pressure are still unclear. Since the renin-angiotensin system is a main regulator of blood pressure, we investigated the effects of pioglitazone on blood pressure, plasma renin activity and on the blood pressure response to exogenous angiotensin II in insulin-resistant Zucker rats. Pioglitazone 20mg/kg/d or vehicle were administered for 4 weeks to 8-weeks old fa/fa Zucker rats. Pioglitazone-treated rats were heavier than vehicle-treated rats (respectively 481g±8g vs 437±5g, p=0.0002, mean±SEM) and ate more (35.6±0.5g/d vs 28.9±0.3, p<0.0001). The increase in blood sugar after an intra-venous glucose tolerance test was significantly attenuated in the pioglitazone treated rats at 10,15 and 30 minutes. Systolic (SBP), diastolic (DBP) blood pressure and heart rate (HR) were lower in pioglitazone-treated rats: SBP: 124±3 mmHg vs 144±3, p<0.001; DBP: 80±2 vs 94±2, p<0.001; HR: 369±6 vs 397±8, p<0.01. The BP response to exogenous angiotensin II was significantly attenuated in pioglitazone treated rats. With the 25 ng/kg Ang II dose the increase in BP was 27.8±2.4 mmHg with pioglitazone and 37.5±3.3 with the vehicle (p=0.04) and with the Ang II 100 ng/kg dose the increase in BP was respectively 36.1±2.7 mmHg and 49.2±2.3 (p=0.003). Plasma renin activity was comparable in both groups. In conclusion, these results show that pioglitazone blunts the BP response to angiotensin II in insulin-resistant Zucker rats. This effect may partially explain the blood pressure lowering effect of PPAR-γ agonist

P-620: Pioglitazone stimulates renin and favors sodium retention and weight gain in healthy subjects

Glitazones induce peripheral edema through an unknown mechanism in up to 20% of cases. This study examines the effects of pioglitazone (PIO) on renal sodium handling and renal hemodynamics in healthy male volunteers (HV) exposed to a high (HS) and low (LS) sodium diet. The influence of PIO on plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP) was examined. Nine HV aged 22-28 y were enrolled. BMI, blood pressure and glucose tolerance were normal. The study had a double-blind, randomized, placebo controlled, twofold cross-over design. Each subject received either PIO 45 mg qd or placebo qd, for 6 weeks, with 2 weeks wash-out. From weeks 1-4, subjects were on their usual diet. During weeks 5 and 6, subjects were either on a LS or a HS diet for a week which was followed by ambulatory blood pressure measurements, hormonal measurements and renal function studies. The differences between PIO and placebo effects were examined (median, range among all subjects). No subject developed edema. Insulin sensitivity, systolic and diastolic blood pressure, glomerular filtration rate, renal plasma flow or filtration fraction did not change significantly with PIO. Weight increased with PIO in 7/9 subjects while on a LS diet (0.7kg; -1-2.9) and in 6/9 while on a HS diet (1.1kg; -1.5-3.4). Median sodium (Na) excretion with placebo was of 21.2mmol/24h and 239.7mmol/24h respectively while on a LS and HS diet. Urinary Na excretion decreased with PIO in 6/9 subjects on a LS diet (-12.2mmol/24h; -21-8.7, p=0.05), and in 5/9 subjects on a HS diet (-30mmol/24h; -344-69). Na clearance decreased in 6/9 subjects on a LS diet (-0.05 ml/min; -0.11-0.05) and in 6/9 subjects on a HS diet (-0.15 mmol/ml; -2.7-0.4). Na clearance at the proximal level decreased with PIO in 8/9 subjects on a LS diet (-4.9 ml/min; -14.4-1.5, p=0.01) and in 5/9 subjects on a HS diet (-2 ml/min; -43-8.5). PRA increased with PIO in 8/9 subjects on a LS diet (0.16 ng/ml/h; -0.07-0.8, p=0.02) and on a HS diet (0.09 ng/ml/h; -0.1-0.21, p=0.03). Aldosterone increased in 5/9 subjects on a LS diet (6 pg/ml; -19-144) and in 6/9 subjects on a HS diet (5 pg/ml; -20-74). ANP levels did not change. In conclusion, pioglitazone increases PRA, independently from Na intake and favors Na retention in healthy volunteers. This mechanism could contribute to the development of edema in subjects treated with glitazone