Furosemide Enhances the Release of Endothelial Kinsis, Nitric Oxide and Prostacyclin

Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time- dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation

Optimization of PET protocol and interrater reliability of 18F-PSMA-11 imaging of prostate cancer

Background Several scan parameters for PET imaging with F-18-PSMA-11 such as dosage, acquisition time and scan duration were evaluated to determine the most appropriate scan protocol, as well as the effect of furosemide administration on lesion visualization. Forty-four patients were randomly assigned to a dosage group (2.0 +/- 0.2 or 4.0 +/- 0.4 MBq/kg F-18-PSMA-11). All patients received a full-body PET/CT 1 h and 3 h after radiotracer injection with a scan duration of 3 min/bed position. For comparison of the scan duration, images were reconstructed for 1.5 and 3 min/bed position. Patients were intravenously administered 0.5 mg/kg furosemide with a maximum dose of 40 mg. To evaluate the furosemide effect, 22 additional patients were recruited and received one full-body PET/CT 1 h after administration of 2.0 +/- 0.2 MBq/kg F-18-PSMA-11 with a scan duration of 3 min/bed position. To this group, no furosemide was administered. Images were scored on image quality using a 7-point scale and each suspicious lesion was described. To assess interrater reliability, two nuclear physicians scored all scans independently and described all observed suspicious lesions. Results The 4 MBq/kg group received for all reconstructed images (60 min p.i., 1.5 and 3 min/bed position and 180 min p.i., 1.5 and 3 min/bed position) the highest median image quality score compared to the 2 MBq/kg group (p values < 0.01). When comparing all reconstructed images, the highest image quality score was given to images at 60 min p.i., 3 min/bed position for both dosage groups (score 5 and 6 for 2 and 4 MBq/kg, respectively). The addition of furosemide administration decreased the interference score with one point (p = 0.01106) and facilitated the evaluation of lesions in proximity to the ureters. The interrater reliability for the comparison of each lesion separately after more than 40 F-18-PSMA-11 scan readings showed an increasing kappa value from 0.78 (95% CI, 0.65-0.92) to 0.94 (95% CI, 0.87-1). Conclusion Although the results indicate an administered activity of 4.0 +/- 0.4 MBq/kg, preference will be given to 2.0 +/- 0.2 MBq/kg due to the small difference in absolute score (max 1 point) and the ALARA principle. For evaluation of lesions in proximity to the ureters, the co-administration of a diuretic can be useful. The increase of the kappa value from 0.78 to 0.94 suggests a learning curve in the interpretation of F-18-PSMA-11 images

NaCl transport stimulates prostaglandin release in cultured renal epithelial (MDCK) cells

Prostaglandins (PGs) can modulate a variety of renal functions, including Na+ and Cl- reabsorption. However, it is not known if a direct interdependence exists between PG synthesis and transport activity. The present study was done to find out whether or not the rate of NaCl transport has an influence on PG synthesis in renal tubular cells. For our studies we used cultures of so-called high-resistance MDCK cells, which were originally derived from canine kidney. This cell type has a loop diuretic- and ouabain-sensitive NaCl transport that can be enhanced by activation of the adenylate cyclase (AC). In MDCK cell cultures we found that each state of increased NaCl transport during stimulation of AC by either epinephrine (10(-6) M), isoprenaline (10(-5) M), or forskolin (10(-5) M) was accompanied by a twofold increase in PG release. During inhibition of NaCl transport by furosemide (10(-4) M) or ouabain (2 X 10(-4) M), stimulation of AC failed to increase PGE2 release, whereas basal PG production was not inhibited by either furosemide or ouabain. Furthermore, PG formation during activation of AC was dependent on the concentration of extracellular Na+, whereas PG formation in the absence of activators of AC was independent of extracellular Na+. These results suggest that increased NaCl transport stimulates PG formation in cultures of high-resistance MDCK cells

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users

Sodium chloride transport of normal and dietary enlarged rat cecum in vitro

Sodium chloride transport across isolated cecum mucosa was investigated in normal rats and rats with adaptive cecum growth induced by dietary polyethylene glycol (PEG). The normal cecum absorbed CI in excess of Na with a small short-circuit current (Isc). Dietary adaptation led to large equivalent increments of Na and Cl net absorption without adequate Ise change. Inhibitor studies (mucosal amiloride 10(-3) and 10(-4) M; mucosal 4,4-diisolhiocyanatostilbene-2,2-disulfonic acid 5 x 10(-5) M;serosal furosemide 10(-3) M;serosal ouabain 10(-3) M) suggested that normal cecal NaCl absorption involves electroneutral Na/N and Cl/HCO3 exchange at the apical and Na-K-ATPase-mediated exit across the basolateral cell membrane. Dietary adaptation stimulates the loosely coupled antiports and possibly activates a small serosally located NaCl cotransport. Comparative histology showed flattening of all tissue layers and widening of crypts in PEG animals. Crypt widening may facilitate ion access to underutilized transport sites and, at least in part, explain the increased absorption of the enlarged cecum

Advantages of the new loop diuretic torasemide over furosemide in patients with cirrhosis and ascites

Torasemide is a new loop diuretic with a longer half-life and longer action than furosemide in healthy subjects. In order to evaluate the pharmacodynamic effects, single oral doses of furosemide (80 mg) and torasemide (20 mg), which were equipotent in healthy subjects, were given to 14 patients with cirrhosis and ascites. Before the study patients underwent an equilibration period of 4 days without diuretics. The drugs were alternated following a randomized double-blind cross-over design after a wash-out period of at least 2 days. Urine was collected at defined intervals for 24 h after drug administration and blood samples were taken before, 6 h and 24 h after medication. Torasemide induced greater cumulative 24 h diuresis (2863 ± 343 vs. 2111 ± 184 ml, p < 0.01) than furosemide. Torasemide did not differ from furosemide for cumulative 0–6 h sodium excretion (96 ± 17 vs. 92 ± 23 mmol sodium) but caused a more pronounced cumulative 6–24 h natriuresis (38 ± 11 vs. 17 ± 4 mmol, p < 0.05). Five patients exhibited a weak response to furosemide (0–36 mmol sodium/24 h, median 24 mmol; 690–1460 ml urinary volume/24 h, median 1325 ml). These patients showed significantly higher natriuresis and diuresis following torasemide (26–136 mmol sodium/24 h, median 78 mmol, p < 0.05; 1670–3610 ml urinary volume/24 h, median 2200 ml, p < 0.05). Twenty-four hours after administration of both drugs there were no significant changes in hemodynamic, renal or hormonal parameters. No adverse effects were noted with either treatment. These findings suggest that torasemide might be more advantageous than furosemide in the treatment of ascites due to cirrhosis

Targeted monitoring for human pharmaceuticals in vulnerable source and final waters

A range of pharmaceuticals has been detected in soils, surface waters and groundwaters across the world. While the reported concentrations are generally low (i.e. sub μg l-1 in surface waters), the substances have been observed throughout the year across a variety of hydrological, climatic and land-use settings. As a result, questions have been raised over the potential for pharmaceuticals in surface waters to enter drinking water supplies and to affect consumers. In a previous Drinking Water Inspectorate (DWI) funded study, results from a simple exposure model were used alongside information on therapeutic doses of pharmaceuticals to identify pharmaceuticals that are likely to be of most concern in UK drinking water sources. However, this previous study was entirely desk-based and did not involve any experimental measurements of pharmaceutical concentrations. The current study was therefore performed to generate actual measurements on the occurrence of pharmaceuticals in source and treated waters in England. The study considered a range of pharmaceutical compounds and their metabolites that have either a) high predicted exposure concentrations; b) toxicological concerns; or c) a low predicted exposure to therapeutic dose ratio. An illicit drug and its major metabolite were also investigated. The study compounds (in total 17) covered a range of chemical classes and varied in terms of their physico-chemical properties. The study was done at four sites where concentrations in source water at the drinking water treatment abstraction point were predicted to be some of the greatest in England. The study therefore is likely to provide a ‘worst case’ assessment of potential human exposure to pharmaceuticals in drinking water in England and Wales. Ten of the 17 study compounds were detected in untreated source waters at sub-μg/l concentrations. Six of these compounds (namely, benzoylecgonine (a metabolite of cocaine), caffeine, carbamazepine (an antiepileptic medicine), carbamazepine epoxide (a metabolite of carbamazepine), ibuprofen and naproxen (both non-steroidal anti-inflammatory drugs) were also detected in treated drinking water. With the exception of carbamazepine epoxide, concentrations in treated drinking water were generally significantly lower than in source water. Even though England is a densely populated country and in some regions there is limited dilution of wastewater effluents, these observations, made at sites that were predicted to have some of the highest concentrations of pharmaceuticals in England and Wales, are in line with results from similar studies performed in other countries. Comparison of measured concentrations of the study compounds in drinking waters with information on therapeutic doses demonstrated that levels of these compounds in drinking water in England are many orders of magnitude lower than levels that are given to patients therapeutically. It would therefore appear that the low or non-detectable levels of pharmaceuticals and illicit drugs present in drinking waters in England and Wales do not pose an appreciable risk to human health