Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

Hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage

PURPOSE: To evaluate hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage. METHODS: Thirty patients with acute intracerebral hemorrhage were enrolled. Transcranial doppler was used to detect variables of bilateral middle cerebral arteria (MCA) including mean velocity (Vm) and pulsitility index (PI) before and after125ml and 250ml mannitol infusion (0, 30, 60, 90, 120, 180, 240 min). RESULTS: When 125ml or 250ml mannitol was infused in patients with acute intracerebral hemorrhage, Vm of bilateral MCA elevated, and reached the top at 30min, and then decreased. PI decreased in the affected MCA (250ml) and in the unaffected MCA (125ml and 250ml). CONCLUSION: Mannitol infusion in patients with acute intracerebral hemorrhage can improve cerebral blood flow in bilateral hemispheres and decrease intracranial pressure in the hemorrhagic hemisphere (250ml) and in the nonhemorrhagic hemisphere (125ml and 250ml).

Partially folded intermediates during trypsinogen denaturation

The equilibrium unfolding of bovine trypsinogen was studied by circular dichroism, differential spectra and size exclusion HPLC. The change in free energy of denaturation was delta GH2O = 6.99 + ou - 1.40 kcal/mol for guanidine hydrochloride and delta GH2O = 6.37 + ou - 0.57 kcal/mol for urea. Satisfactory fits of equilibrium unfolding transitions required a three-state model involving an intermediate in addition to the native and unfolded forms. Size exclusion HPLC allowed the detection of an intermediate population of trypsinogen whose Stokes radii varied from 24.1 + ou - 0.4 angstron to 26.0 + ou - 0.3 angstron 1.5 M and 2.5 M guanidine hydrochloride, respectively. During urea denaturation, the range of Stokes radii varied from 23.9 + ou - 0.3 angstron to 25.7 + ou - 0.6 angstron for 4.0 M and 6.0 M urea, respectively. Maximal intrinsic fluorescence was observed at about 3.8 M urea with 8-aniline-1-naphthalene sulfonate (ANS) binding. These experimental data indicate that the unfolding of bovine trypsinogen is not a simple transition and suggest that the equilibrium intermediate population comprises one intermediate that may be characterized as a molten globule. To obtain further insight by studying intermediates representing different stages of unfolding, we hope to gain a better understanding of the complex interrelations between protein conformation and energetics.

Manitol- fundamentos para sua utilizaçäo / Mannitol- reasons for its utilization

O diurético osmótico manitol é uma droga amplamente utilizada em neurociruriga e neurologia a fim de diminuir a pressäo intracraniana e melhorar a microcirculaçäo cerebral. As teorias sobre seu mecanismo de açäo säo revisadas: gradiente osmótico pela barreira hematoencefálica, auto-regulaçäo vascular e neutralizaçäo dos radicais livres do oxigênio. Sua posologia é empírica, segunda a experiência própria de cada autor. O conhecimento dos critérios básicos para o uso do manitol e de sua reposiçäo hidreletrolítica é fundamental para a manutençäo da osmolaridade sérica em valores terapêuticos

Influencia de los diuréticos en el resultado de los análisis clínicos / Influence of diuretics on the result of clinical analysis

En este trabajo se realizó una revisión de los principales grupos de diuréticos, sus sitios y mecanismos de acción y sus efectos sobre las pruebas de laboratorio. Se analizó el efecto de los diuréticos sobre: el estado ácido base, los electrolitos séricos y urinarios, el ácido úrico sérico y urinario y sobre la glucemia. También se describió la influencia de los diuréticos sobre los análisis de orina. Finalmente, los efectos hematológicos de los mismos. El objetivo de este trabajo fue estudiar la influencia de los diuréticos en los análisis clínicos, buscando los mecanismos fisiopatológicos o metodológicos de los casos citados

Influencia de los diuréticos en el resultado de los análisis clínicos / Influence of diuretics on the result of clinical analysis

En este trabajo se realizó una revisión de los principales grupos de diuréticos, sus sitios y mecanismos de acción y sus efectos sobre las pruebas de laboratorio. Se analizó el efecto de los diuréticos sobre: el estado ácido base, los electrolitos séricos y urinarios, el ácido úrico sérico y urinario y sobre la glucemia. También se describió la influencia de los diuréticos sobre los análisis de orina. Finalmente, los efectos hematológicos de los mismos. El objetivo de este trabajo fue estudiar la influencia de los diuréticos en los análisis clínicos, buscando los mecanismos fisiopatológicos o metodológicos de los casos citados (AU)

Influência do acréscimo de manitol à solução nutriente no desempenho mecânico e no grau de edema miocárdico de coraçoes isolados de ratos / Influence of Mannitol Added to the Perfusion Solution on Mechanical Properties and Myocardial Edema of Isolated Rat Hearts

PURPOSE--To analyse the influence of mannitol added to Krebs-Henseleit (KH) solution on the myocardium edema and myocardial function. METHODS--Isolated rat heart under isovolumetric contractions studied according to Langendorff's technique were perfused with KH solution at constant flow during 90 min. The coronary perfusion pressure, diastolic and systolic pressures were recorded at every 15 min. At the end of the experiment, myocardium water content was measured in hearts perfused with KH solution (group I, n = 9) and in hearts perfused with KH solution plus 8mM mannitol (group II, n = 8). These results were compared to non-perfused control heart (n = 9). RESULTS--Myocardial water content was statistically higher in group I (80.8 +/- 1.3) compared to group II (78.1 +/- 0.7) and control group (75.5 +/- 0.5). Systolic arterial pressure was statistically higher in group I (86.2 +/- 11.5mmHg) compared to group II (72.7 +/- 21.1mmHg). There was no difference in the diastolic pressure between the two groups. Coronary perfusion pressure (Pp) increased progressively during the experiment in both groups. However, Pp was lower in group II than in group I. CONCLUSION--Mannitol added to KH solution significantly attenuates the myocardium edema in the isolated perfused rat heart.

Avanços terapêuticos em cardiologia; Parte 2. Diureticos: estado atual em cardiologia / Therapeutic advances in cardiology; Part 2. Diuretics: up-to-date cardiology

Os diuréticos constituem-se na principal arma no tratamento da insuficiência cardíaca e da hipertensäo arterial sistêmica. Os pacientes têm uma boa e prolongada resposta com alívio da dispnéia, reduzem a pressäo venosa e a congestäo hepática. Chamamos atençäo para os efeitos adversos e o uso indevido em pacientes com edema e obesidade