Marc Maillard

Renal effects of selective cyclooxygenase‐2 inhibition in normotensive salt‐depleted subjects

To compare the renal hemodynamic and tubular effects of celecoxib, a selective inhibitor of cyclooxygenase‐2 (COX‐2) to those of naproxen, a nonselective inhibitor of cyclooxygenases in salt‐depleted subjects.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout.

Objective Losartan has been shown to increase urinary uric acid excretion and hence to lower serum uric acid levels. The purposes of the present study were: (1) to evaluate the effects of losartan on serum uric acid in hypertensive patients with hyperuricemia and gout, (2) to compare the effects of losartan with those of irbesartan, another angiotensin II receptor antagonist and (3) to evaluate whether losartan 50 mg b.i.d. has a greater impact on serum uric acid levels than losartan 50 mg once a day. Methods Thirteen hypertensive patients with hyperuricaemia and gout completed this prospective, randomized, double-blind, cross-over study. Uric acid-lowering drugs were stopped 3 weeks before the beginning of the study. Patients were randomized to receive either losartan 50 mg or irbesartan 150 mg once a day, for 4 weeks. During this phase, a placebo was given in the evening. After 4 weeks, the dose was increased to losartan 50 mg b.i.d., or irbesartan 150 mg b.i.d. for another 4 week period. Subsequently, the patients were switched to the alternative treatment modality. Enalapril (20 mg o.d.) was given during the run-in period and between the two treatment phases. Serum and urinary uric acid were measured at the beginning and at the end of each treatment phase. Results Our results show that losartan 50 mg once daily decreased serum uric acid levels from 538 ± 26 to 491 ± 20 μmol/l (P < 0.01). Irbesartan had no effect on serum uric acid. Increasing the dose of losartan from 50 mg o.d. to 50 mg twice a day, did not further decrease serum uric acid. This may in part be due to a low compliance to the evening dose as measured with an electronic device. Indeed, whatever the prescribed drug, the mean compliance of the evening dose was always significantly lower than that of the morning dose. The uricosuric effect of losartan appears to decrease with time when a new steady state of lower serum uric acid is reached. Conclusions In contrast to irbesartan, losartan was uricosuric and decreased serum uric acid levels. Losartan 50 mg b.i.d. did not produce a greater fall in serum uric acid than losartan once a day. Losartan might be a useful therapeutic tool to control blood pressure and reduce serum uric acid levels in hypertensive patients with hyperuricaemia and gout.

Nighttime Blood Pressure and Nocturnal Dipping Are Associated With Daytime Urinary Sodium Excretion in African Subjects

Blood pressure (BP) follows a circadian rhythm, with 10% to 15% lower values during nighttime than during daytime. The absence of a nocturnal BP decrease (dipping) is associated with target organ damage, but the determinants of dipping are poorly understood. We assessed whether the nighttime BP and the dipping are associated with the circadian pattern of sodium excretion. Ambulatory BP and daytime and nighttime urinary electrolyte excretion were measured simultaneously in 325 individuals of African descent from 73 families. When divided into sex-specific tertiles of day:night ratios of urinary sodium excretion rate, subjects in tertile 1 (with the lowest ratio) were 6.5 years older and had a 9.8-mm Hg higher nighttime systolic BP (SBP) and a 23% lower SBP dipping (expressed in percentage of day value) compared with subjects in tertile 3 (P for trend <0.01). After adjustment for age, the SBP difference across tertiles decreased to 5.4 mm Hg (P=0.002), and the SBP dipping difference decreased to 17% (P=0.05). A similar trend across tertiles was found with diastolic BP. In multivariate analyses, daytime urinary sodium and potassium concentrations were independently associated with nighttime SBP and SBP dipping (P<0.05 for each). These data, based on a large number of subjects, suggest that the capacity to excrete sodium during daytime is a significant determinant of nocturnal BP and dipping. This observation may help us to understand the pathophysiology and clinical consequences of nighttime BP and to develop therapeutic strategies to normalize the dipping profile in hypertensive patients.

Angiotensin II Receptor Blockade in Normotensive Subjects A Direct Comparison of Three AT1 Receptor Antagonists

Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects.

Angiotensin II receptor blockade: Is there truly a benefit of adding an ACE inhibitor?

Abstract—We assessed the blockade of the renin-angiotensin system (RAS) achieved with 2 angiotensin (Ang) antagonists given either alone at different doses or with an ACE inhibitor. First, 20 normotensive subjects were randomly assigned to 100 mg OD losartan (LOS) or 80 mg OD telmisartan (TEL) for 1 week; during another week, the same doses of LOS and TEL were combined with 20 mg OD lisinopril. Then, 10 subjects were randomly assigned to 200 mg OD LOS and 160 mg OD TEL for 1 week and 100 mg BID LOS and 80 mg BID TEL during the second week. Blockade of the RAS was evaluated with the inhibition of the pressor effect of exogenous Ang I, an ex vivo receptor assay, and the changes in plasma Ang II. Trough blood pressure response to Ang I was blocked by 35±16% (mean±SD) with 100 mg OD LOS and by 36±13% with 80 mg OD TEL. When combined with lisinopril, blockade was 76±7% with LOS and 79±9% with TEL. With 200 mg OD LOS, trough blockade was 54±14%, but with 100 mg BID it increased to 77±8% (P <0.01). Telmisartan (160 mg OD and 80 mg BID) produced a comparable effect. Thus, at their maximal recommended doses, neither LOS nor TEL blocks the RAS for 24 hours; hence, the addition of an ACE inhibitor provides an additional blockade. A 24-hour blockade can be achieved with an angiotensin antagonist alone, provided higher doses or a BID regimen is used.

ANTIMICROBIAL STEROIDS FROM THE FUNGUS FOMITOPSIS PINICOLA

Phytochemical examination of the dichloromethane extract of the European fungus Fomitopsis pinicola led to the isolation of a new lanostanoid derivative identified from spectral and chemical evidences as 3 alpha-(4-carboxymethyl-3-hydroxy-3-methylbutanoyloxy)-lanosta++ +-8,24-dien-21-oic acid. In addition, seven known triterpenes, polyporenic acid C, 3 alpha-acetyloxylanosta-8,24-dien-21-oic acid, ergosta-7,22-dien-3 beta-ol,21-hydroxylanosta-8,24-dien-3-one, pinicolic acid A, trametenolic acid B and pachymic acid, were also isolated. Antimicrobial activity against Bacillus subtilis in a TLC bioassay was observed for five of the isolated steroids.

Comparative angiotensin II receptor blockade in healthy volunteers: The importance of dosing

We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT1‐receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses.

Proximal Sodium Reabsorption An Independent Determinant of Blood Pressure Response to Salt

The purpose of this study was to evaluate the contribution of renal sodium handling by the proximal tubule as an independent determinant of blood pressure responsiveness to salt in hypertension. We measured blood pressure (BP), renal hemodynamics, and segmental renal sodium handling (with lithium used as a marker of proximal sodium reabsorption) in 38 hypertensive patients and 27 normotensive subjects (15 young and 12 age-matched) on a high and low sodium diet. In control subjects, changing the diet from a low to a high sodium content resulted in no change in BP and increases in glomerular filtration rate (P <0.05), renal plasma flow (P <0.05), and fractional excretion of lithium (FELi, P <0.01). In hypertensive patients, comparable variations of sodium intake induced an increase in BP with no change in renal hemodynamics and proximal sodium reabsorption. When analyzed by tertiles of their BP response to salt, salt-insensitive hypertensive patients of the first tertile disclosed a pattern of adaptation of proximal sodium reabsorption comparable to that of control subjects, whereas the most salt-sensitive patients of the third tertile had an inverse pattern with a high FELi on low salt and a lower FELi on high salt, suggesting an inappropriate modulation of proximal sodium reabsorption. The BP response to salt correlated positively with age (r =0.34, P =0.036) and negatively with the changes in FELi (r =−0.37, P =0.029). In a multivariate analysis, the changes in FELi were significantly and independently associated with the salt-induced changes in BP. These results suggest that proximal sodium reabsorption is an independent determinant of the BP response to salt in hypertension.

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.