Comparison between the effects of torsemide and furosemide on the renin-angiotensin-aldosterone system of normal dogs.

INTRODUCTION/OBJECTIVES: We hypothesized that torsemide and furosemide, at approximately equipotent dosages (similar diuresis), would have comparable effects on the circulating renin-angiotensin-aldosterone system. ANIMALS, MATERIALS AND METHODS: Six, healthy, middle-aged, male Beagles were randomized to receive torsemide (0.1 mg/kg PO q 12 h), furosemide (2.0 mg/kg PO q 12 h), or placebo for 10 days during three separate periods, separated by a 10-day washout period, in a crossover design. Blood was collected on days 1, 5, and 9 and 24-h urine collection ended on days 2, 6, and 10. After repeated measures analysis and Bonferonni correction, variables with an adjusted p<0.05 were investigated further, using Tukey's method. RESULTS: Twenty-four-hour urine production differed significantly between the diuretics only on day 10, with torsemide causing a 38% greater diuresis than furosemide. There was, however, no significant difference in average 3-day diuresis. There were no significant differences between diuretics in the 24-h urinary excretion of sodium, chloride, or potassium, though furosemide caused less kaliuresis than torsemide. Serum renin, angiotensin II, and aldosterone and the urine aldosterone-to-creatinine ratio were significantly increased in the diuretic groups, as compared to placebo on days 5/6 and 9/10. There were no significant differences in these values between diuretics. Creatinine and blood urea nitrogen concentrations rose comparably in the diuretic groups, remaining within reference intervals in all dogs. CONCLUSIONS: At approximately equipotent dosages (20:1), torsemide and furosemide produced comparable renin-angiotensin-aldosterone system activation. Torsemide's similar potassium excretion profile to furosemide decreases support for a hypothesized mineralocorticoid-receptor blocking capability.

Quantification of systemic renin-angiotensin system peptides of hypertensive black and white African men established from the RAS-Fingerprint®.

OBJECTIVE: The objective of this study was to make use of a quantitative and qualitative approach comparing the systemic renin-angiotensin system (RAS) of hypertensive black and white African men by using RAS equilibrium analysis. MATERIALS AND METHODS: This sub-study involved 23 black (n = 15) and white (n = 8) hypertensive men aged 39.5-41 years, living in the North West Province of South Africa. The RAS-Fingerprinting was determined with LC-MS/MS quantification of angiotensin peptides. Blood pressure and other variables were determined with known methods. RESULTS: The main finding of this study was the significant lower Ang I (<5.0 and 45.1 pg/ml; p = 0.005) and Ang II (15.6 and 123.9 pg/ml; p ⩽ 0.001) encountered in the hypertensive black African men compared to their white counterparts. Levels of Ang 1-5 (downstream metabolite of Ang 1-7) (1.8 and 3.0 pg/ml), were detected in black and white hypertensive men, respectively. CONCLUSIONS: The observed differences between circulating RAS components, which are reflected via equilibrium angiotensin levels, point to a distinctive molecular regulation of the RAAS in the two study cohorts. The increased peripheral resistance observed in hypertensive black individuals might take over a dominant role in control of blood pressure in this study population. A novel highly sensitive LC-MS/MS method resolved the issue of peptide recovery variations during sample preparation by using internal standards for each individual angiotensin metabolite.

Weight loss and weight regain-5-year follow-up for circular- vs. linear-stapled gastrojejunostomy in laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Weight regain (WR) occurs in some patients after laparoscopic Roux-en-Y gastric bypass (LRYGBP). Loss of restriction due to dilation of the gastrojejunostomy (GJS) or the gastric pouch might be the main cause for WR. With different techniques available for the establishment of the GJS, the surgical technique might influence long-term success. METHODS: We present a 5-year follow-up for weight loss and WR of a matched-pair study comparing circular stapled (CSA) to linear stapled (LSA) GJS in a series of 150 patients who underwent primary antecolic antegastric LRYGBP. Complete 5-year follow-up was obtained for 79 % of the patients. RESULTS: Excess BMI loss (EBL) at 3 months was better with the CSA (p = 0.02) and comparable thereafter. The 5-year %EBL was 67.3 ± 23.2 vs. 73.3 ± 24.3 % (CSA vs. LSA, p = 0.19) WR of > 10 kg from nadir was found in 24 patients (16 %) with higher incidence in CSA than in LSA patients (20 % vs. 12 %). The %WR was comparable for both groups, 16 ± 13 vs. 15 ± 19 % (CSA vs. LSA, p = 0.345). Eleven patients underwent surgical re-intervention for WR by placement of a non-adjustable band (n = 2), adjustable band (n = 7) and conversion to distal gastric bypass (n = 2). CONCLUSIONS: CSA and LSA lead to comparable weight loss in this 5-year follow-up. More patients in the CSA group had WR. Weight regain of more than 10 kg was found in one out of seven patients within 5 years postoperatively.

CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages.

Human cytomegalovirus (CMV) remains one of the most important pathogens following solid-organ transplantation. Mounting evidence indicates that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of CMV infection in solid-organ recipients. Here we aimed at elucidating the molecular mechanisms of this effect by employing a human CMV (HCMV) infection model in human macrophages, since myeloid cells are the principal in vivo targets of HCMV. We demonstrate a highly divergent host cell permissiveness for HCMV with optimal infection susceptibility in M2 but not M1 polarized macrophages. Employing an ultrahigh purified HCMV stock we observed rapamycin-independent viral entry and induction of IFN-ß transcripts, but no proinflammatory cytokines or mitogen-activated protein kinases and mTOR activation early after infection. However, in the late infection phase, sustained mTOR activation was observed in HCMV-infected cells and was required for efficient viral protein synthesis including the viral late phase proteins pUL-44 and pp65. Accordingly, rapamycin strongly suppressed CMV replication 3 and 5 days postinfection in macrophages. In conclusion, these data indicate that mTOR is essential for virus replication during late phases of the viral cycle in myeloid cells and might explain the potent anti-CMV effects of mTOR inhibitors after organ transplantation.

The novel immunosuppressant FK778 inhibits formation of the immunologic Synapse.

The malononitrilamide FK778 is a derivative of A77 1726, the active metabolite of the antirheumatic drug leflunomide. A77 1726 inhibits de novo pyrimidine synthesis and activity of Src-family kinases; thus, it may interfere with T-cell proliferation as well as with early T-cell signaling. Formation of a stable interaction between T cells and antigen-presenting cells (APC)--the immunologic synapse--has emerged to be of crucial importance for T-cell activation. Here in we show that FK778 inhibits formation of the immunologic synapse by blocking superantigen-stimulated relocalization of adhesion (LFA-1), and signaling molecules (CD3) to the T-cell/APC contact site. These data show that FK778 affects T-cell/APC interactions, particularly events crucial for T-cell adhesion and formation of stable conjugates underlying sustained and effective T-cell activation. Thus, in this model system close to physiologic T-cell stimulation, FK778 affects critical events in the course of T-cell-mediated immune responses earlier than T-cell proliferation, which may contribute to its immunosuppressive potential.