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1.
Am J Physiol Renal Physiol ; 319(4): F712-F728, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32893663

RESUMO

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus/tratamento farmacológico , Glucosídeos/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Natriuréticos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Equilíbrio Ácido-Base/efeitos dos fármacos , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Glicosúria/metabolismo , Glicosúria/fisiopatologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Trocador 3 de Sódio-Hidrogênio/deficiência , Trocador 3 de Sódio-Hidrogênio/genética
2.
Am J Physiol Renal Physiol ; 319(3): F366-F379, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32657159

RESUMO

Carbonic anhydrase (CAII) binds to the electrogenic basolateral Na+-[Formula: see text] cotransporter (NBCe1) and facilitates [Formula: see text] reabsorption across the proximal tubule. However, whether the inhibition of CAII with acetazolamide (ACTZ) alters NBCe1 activity and interferes with the ammoniagenesis pathway remains elusive. To address this issue, we compared the renal adaptation of rats treated with ACTZ to NH4Cl loading for up to 2 wk. The results indicated that ACTZ-treated rats exhibited a sustained metabolic acidosis for up to 2 wk, whereas in NH4Cl-loaded rats, metabolic acidosis was corrected within 2 wk of treatment. [Formula: see text] excretion increased by 10-fold in NH4Cl-loaded rats but only slightly (1.7-fold) in ACTZ-treated rats during the first week despite a similar degree of acidosis. Immunoblot experiments showed that the protein abundance of glutaminase (4-fold), glutamate dehydrogenase (6-fold), and SN1 (8-fold) increased significantly in NH4Cl-loaded rats but remained unchanged in ACTZ-treated rats. Na+/H+ exchanger 3 and NBCe1 proteins were upregulated in response to NH4Cl loading but not ACTZ treatment and were rather sharply downregulated after 2 wk of ACTZ treatment. ACTZ causes renal [Formula: see text] wasting and induces metabolic acidosis but inhibits the upregulation of glutamine transporter and ammoniagenic enzymes and thus suppresses ammonia synthesis and secretion in the proximal tubule, which prevented the correction of acidosis. This effect is likely mediated through the inhibition of the CA-NBCe1 metabolon complex, which results in cell alkalinization. During chronic ACTZ treatment, the downregulation of both NBCe1 and Na+/H+ exchanger 3, along with the inhibition of ammoniagenesis and [Formula: see text] generation, contributes to the maintenance of metabolic acidosis.


Assuntos
Acetazolamida/farmacologia , Acidose/metabolismo , Amônia/metabolismo , Bicarbonatos/metabolismo , Diuréticos/farmacologia , Rim/efeitos dos fármacos , Acetazolamida/farmacocinética , Equilíbrio Ácido-Base/efeitos dos fármacos , Adaptação Fisiológica , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Cloretos/sangue , Diuréticos/farmacocinética , Eletrólitos/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Urinálise
3.
Physiol Rev ; 100(3): 1119-1147, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32347156

RESUMO

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl- absorption and HCO3- secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl-/HCO3- exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3 administration. In some rodent models, pendrin-mediated HCO3- secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl- absorption, as well as their effect on the epithelial Na+ channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+ and Cl- balance, pendrin affects the balance of other ions, such as K+ and I-. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.


Assuntos
Rim/citologia , Rim/fisiologia , Transportadores de Sulfato/metabolismo , Equilíbrio Ácido-Base/efeitos dos fármacos , Equilíbrio Ácido-Base/fisiologia , Aldosterona/farmacologia , Angiotensina II/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos
4.
J Int Soc Sports Nutr ; 17(1): 22, 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307012

RESUMO

BACKGROUND: The present study investigated the effects of chronic sodium bicarbonate (NaHCO3) ingestion on a single bout of high-intensity exercise and on acid-base balance during 7-day high-altitude exposure. METHODS: Ten recreationally active subjects participated in a pre-test at sea level and a 7-day hiking tour in the Swiss Alps up to 4554 m above sea level. Subjects received either a daily dose of 0.3 g/kg NaHCO3 solution (n = 5) or water as a placebo (n = 5) for 7 days. Anaerobic high-intensity exercise performance was assessed using the portable tethered sprint running (PTSR) test under normoxic and hypoxic conditions (3585 m). PTSR tests assessed overall peak force, mean force, and fatigue index. Blood lactate levels and blood gas parameters were assessed pre- and post-PTSR. Urinary pH and blood gas parameters were further analyzed daily at rest in early morning samples under normoxic and hypoxic conditions. RESULTS: There were no significant differences between the bicarbonate and control group in any of the PTSR-related parameters. However, urinary pH (p = 0.003, ηp2 = 0.458), early morning blood bicarbonate concentration (p < 0.001, ηp2 = 0.457) and base excess (p = 0.002, ηp2 = 0.436) were significantly higher in the bicarbonate group compared with the control group under hypoxic conditions. CONCLUSIONS: These results indicate that oral NaHCO3 ingestion does not ameliorate the hypoxia-induced impairment in anaerobic, high-intensity exercise performance, represented by PTSR-related test parameters, under hypobaric, hypoxic conditions, but the maximal performance measurements may have been negatively affected by other factors, such as poor implementation of PTSR test instructions, pre-acclimatization, the time course of hypoxia-induced renal [HCO3-] compensation, changes in the concentrations of intra- and extracellular ions others than [H+] and [HCO3-], or gastrointestinal disturbances caused by NaHCO3 ingestion. However, chronic NaHCO3 ingestion improves blood bicarbonate concentration and base excess at altitude, which partially represent the blood buffering capacity.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Altitude , Limiar Anaeróbio/efeitos dos fármacos , Montanhismo , Bicarbonato de Sódio/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Fenômenos Fisiológicos da Nutrição Esportiva
5.
Biochem Biophys Res Commun ; 525(3): 576-580, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32115151

RESUMO

Coral calcification is intricately linked to the chemical composition of the fluid in the extracellular calcifying medium (ECM), which is situated between the calcifying cells and the skeleton. Here we demonstrate that the acid-base sensing enzyme soluble adenylyl cyclase (sAC) is expressed in calcifying cells of the coral Stylophora pistillata. Furthermore, pharmacological inhibition of sAC in coral microcolonies resulted in acidification of the ECM as estimated by the pH-sensitive ratiometric indicator SNARF, and decreased calcification rates, as estimated by calcein labeling of crystal growth. These results indicate that sAC activity modulates some of the molecular machinery involved in producing the coral skeleton, which could include ion-transporting proteins and vesicular transport. To our knowledge this is the first study to directly demonstrate biological regulation of the alkaline pH of the coral ECM and its correlation with calcification.


Assuntos
Equilíbrio Ácido-Base , Adenilil Ciclases/metabolismo , Antozoários/enzimologia , Antozoários/fisiologia , Calcificação Fisiológica , Equilíbrio Ácido-Base/efeitos dos fármacos , Inibidores de Adenilil Ciclases/farmacologia , Álcalis/metabolismo , Animais , Antozoários/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Concentração de Íons de Hidrogênio , Solubilidade
6.
J Am Soc Nephrol ; 31(3): 469-482, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988269

RESUMO

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.


Assuntos
Acidose/complicações , Aldosterona/metabolismo , Angiotensina II/metabolismo , Progressão da Doença , Endotelina-1/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Equilíbrio Ácido-Base/efeitos dos fármacos , Equilíbrio Ácido-Base/fisiologia , Acidose/diagnóstico , Acidose/tratamento farmacológico , Adaptação Fisiológica/fisiologia , Biomarcadores/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Masculino , Estudos Prospectivos , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
8.
J Anim Sci ; 97(11): 4557-4566, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31504564

RESUMO

The present study was conducted to evaluate the effects of dietary garcinol supplementation during late gestation (from the 90th day of pregnancy; day 90) and lactation on the acid-base balance of the umbilical cord blood and performance of sows and piglets. Sixty sows (Duroc × Yorkshire × Landrace; second- or third-parity; n = 20) were randomly divided into 3 gestation (day 90 of pregnancy) or lactation treatments, control diet (CON; basal diet), basal diet with 200 mg garcinol, and basal diet with 600 mg garcinol per kg of feed. The body weight (BW); backfat thickness and litter size of the sows; and birth weight, weaning weight, and mortality of piglets were recorded. Sows' blood and piglets' umbilical cord blood were collected for the measurements of hematological parameters and antioxidative and immune indexes, and acid-base balance parameters, respectively. The colostrum and milk and fecal samples of the sows were also collected for analysis of milk composition and apparent total tract nutrient digestibility. Garcinol had no effect on the BW and backfat thickness of the sows but significantly increased the birth weight and weaning weight of piglets (P < 0.05) and decreased the mortality (P < 0.05). Moreover, the white blood cell counts and neutrophil count, mean cell hemoglobin, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in the plasma of the sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group, whereas the malondialdehyde (MDA) content was decreased (P < 0.05). The garcinol treatment significantly increased the pH, HCO3- and base excess values (P < 0.05), whereas it decreased the pCO2 and lactate content (P < 0.05) in the umbilical blood. Dry matter (DM), ash, and ether extract in the colostrum were similar between groups (P > 0.05), whereas the garcinol significantly increased the crude protein (CP) in the milk. In addition, the content of immunoglobulin A (IgA) and immunoglobulin G (IgG) in the plasma of piglets and in colostrum and milk of sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group. The apparent total tract nutrient digestibility was similar between treatments. Collectively, this study indicates that sows fed with garcinol in late gestation and lactation showed improved maternal health and antioxidative status, milk protein content, acid-base balance in the umbilical cord blood, and growth performance in piglets, showing promise in natural plant extract nutrition for sows.


Assuntos
Suplementos Nutricionais/análise , Leite/química , Suínos/fisiologia , Terpenos/administração & dosagem , Equilíbrio Ácido-Base/efeitos dos fármacos , Ração Animal/análise , Animais , Colostro/química , Dieta/veterinária , Feminino , Sangue Fetal/efeitos dos fármacos , Imunoglobulina A/sangue , Lactação/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Paridade , Gravidez , Distribuição Aleatória , Suínos/sangue , Suínos/imunologia , Desmame
9.
Artigo em Inglês | MEDLINE | ID: mdl-31301422

RESUMO

Aquatic CO2 tensions may exceed 30-60 Torr (ca. 30,000-79,000 µatm, respectively; hypercarbia) in some environments inducing severe acid-base challenges in fish. Typically, during exposure to hypercarbia blood pH (pHe) is initially reduced and then compensated in association with an increase in plasma HCO3- in exchange for Cl-. Typically, intracellular pH (pHi) is reduced and recovery is to some degree coupled to pHe recovery (coupled pH regulation). However, during acute hypercarbia, pHe recovery has been proposed to be limited by an "apparent upper bicarbonate threshold", restricting complete pHe recovery to below 15 Torr PCO2. At PCO2 values beyond that which fish can compensate pHe, some fish are able to fully protect pHi despite large sustained reductions in pHe (preferential pHi regulation) and can tolerate PCO2 > 45 Torr. This review discusses pHe and pHi regulation during exposure to hypercarbia starting with modeling the capacity and theoretical limit to pHe compensation in 19 studies. Next, we discuss how fish compensate severe acute hypercarbia exposures beyond the putative limit of pHe compensation using preferential pHi regulation which has recently been observed to be common among fish subjected to severe hypercarbia. Finally, we consider the evolution of pH regulatory strategies in vertebrates, including how the presence of preferential pHi regulation in embryonic reptiles may indicate that it is an embryonic trait that is either lost or retained in adult vertebrates and may have served as an exaptation for key evolutionary transitions during vertebrate evolution.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Meio Ambiente , Peixes/fisiologia , Animais , Evolução Biológica , Concentração de Íons de Hidrogênio
10.
J Environ Sci Health B ; 54(8): 676-680, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230517

RESUMO

Members of TRP receptor family are involved in response to acidification. Here, we determined the effect of capsaicin, one of the TRP receptor activators, on hemolymph acid-base status in the American cockroach. Periplaneta americana adult individuals were injected with lactic acid (5% or 10%) and exposed to 100 µM capsaicin solution. Hemolymph pH was measured 15 min, 1, 4, 8 and 24 h after lactic acid and capsaicin application with a glass microelectrode. The results demonstrated that cockroaches recover from acidosis within 4 h from acid injection. Capsaicin impaired the buffering capacity of insects' hemolymph, resulting in significant drop of hemolymph pH observed even 24 h after application. Joint action of capsaicin and acidosis reveals new insight into possible mechanism of capsaicin action on TRP receptors in insects.


Assuntos
Capsaicina/farmacologia , Hemolinfa/efeitos dos fármacos , Periplaneta/efeitos dos fármacos , Equilíbrio Ácido-Base/efeitos dos fármacos , Animais , Feminino , Hemolinfa/química , Hemolinfa/metabolismo , Concentração de Íons de Hidrogênio , Inseticidas/farmacologia , Ácido Láctico/farmacologia , Masculino , Mortalidade , Periplaneta/metabolismo , Canais de Receptores Transientes de Potencial/metabolismo
11.
J Am Soc Nephrol ; 30(6): 946-961, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097611

RESUMO

BACKGROUND: Antagonists of the V1a vasopressin receptor (V1aR) are emerging as a strategy for slowing progression of CKD. Physiologically, V1aR signaling has been linked with acid-base homeostasis, but more detailed information is needed about renal V1aR distribution and function. METHODS: We used a new anti-V1aR antibody and high-resolution microscopy to investigate Va1R distribution in rodent and human kidneys. To investigate whether V1aR activation promotes urinary H+ secretion, we used a V1aR agonist or antagonist to evaluate V1aR function in vasopressin-deficient Brattleboro rats, bladder-catheterized mice, isolated collecting ducts, and cultured inner medullary collecting duct (IMCD) cells. RESULTS: Localization of V1aR in rodent and human kidneys produced a basolateral signal in type A intercalated cells (A-ICs) and a perinuclear to subapical signal in type B intercalated cells of connecting tubules and collecting ducts. Treating vasopressin-deficient Brattleboro rats with a V1aR agonist decreased urinary pH and tripled net acid excretion; we observed a similar response in C57BL/6J mice. In contrast, V1aR antagonist did not affect urinary pH in normal or acid-loaded mice. In ex vivo settings, basolateral treatment of isolated perfused medullary collecting ducts with the V1aR agonist or vasopressin increased intracellular calcium levels in ICs and decreased luminal pH, suggesting V1aR-dependent calcium release and stimulation of proton-secreting proteins. Basolateral treatment of IMCD cells with the V1aR agonist increased apical abundance of vacuolar H+-ATPase in A-ICs. CONCLUSIONS: Our results show that activation of V1aR contributes to urinary acidification via H+ secretion by A-ICs, which may have clinical implications for pharmacologic targeting of V1aR.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Receptores de Vasopressinas/efeitos dos fármacos , Vasopressinas/farmacologia , Equilíbrio Ácido-Base/genética , Animais , Células Cultivadas/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Imunofluorescência , Células HEK293/efeitos dos fármacos , Células HEK293/metabolismo , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Imuno-Histoquímica , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ratos Brattleboro , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptores de Vasopressinas/genética , Sensibilidade e Especificidade , Urinálise/métodos
12.
Aquat Toxicol ; 212: 54-69, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075620

RESUMO

In this era of global climate change, ocean acidification is becoming a serious threat to the marine ecosystem. Despite this, it remains almost unknown how fish will respond to the co-occurrence of ocean acidification with other conventional environmental perturbations typically salinity fluctuation and high ammonia threat. Therefore, the present work evaluated the interactive effects of elevated pCO2, salinity reduction and high environmental ammonia (HEA) on the ecophysiological performance of European sea bass (Dicentrarchus labrax). Fish were progressively acclimated to seawater (32 ppt), to brackish water (10 ppt) and to hyposaline water (2.5 ppt). Following acclimation to different salinities for at least two weeks, fish were exposed to CO2-induced water acidification representing present-day (control pCO2, 400 µatm, LoCO2) and future (high pCO2, 1000 µatm, HiCO2) sea-surface CO2 level for 3, 7 and 21 days. At the end of each exposure period, fish were challenged with HEA for 6 h (1.18 mM representing 50% of 96 h LC50). Results show that, in response to the individual HiCO2 exposure, fish within each salinity compensated for blood acidosis. Fish subjected to HiCO2 were able to maintain ammonia excretion rate (Jamm) within control levels, suggesting that HiCO2 exposure alone had no impact on Jamm at any of the salinities. For 32 and 10 ppt fish, up-regulated expression of Na+/K+-ATPase was evident in all exposure groups (HEA, HiCO2 and HEA/HiCO2 co-exposed), whereas Na+/K+/2Cl- co-transporter was up-regulated mainly in HiCO2 group. Plasma glucose and lactate content were augmented in all exposure conditions for all salinity regimes. During HEA and HEA/HiCO2, Jamm was inhibited at different time points for all salinities, which resulted in a significant build-up of ammonia in plasma and muscle. Branchial expressions of Rhesus glycoproteins (Rhcg isoforms and Rhbg) were upregulated in response to HiCO2 as well as HEA at 10 ppt, with a more moderate response in 32 ppt groups. Overall, our findings denote that the adverse effect of single exposures of ocean acidification or HEA is exacerbated when present together, and suggests that fish are more vulnerable to these environmental threats at low salinities.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Ácidos/química , Amônia/toxicidade , Bass/fisiologia , Oceanos e Mares , Osmorregulação/efeitos dos fármacos , Salinidade , Amônia/sangue , Animais , Bass/sangue , Glicemia/metabolismo , Dióxido de Carbono/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Glicoproteínas/metabolismo , Concentração de Íons de Hidrogênio , Íons/sangue , Ácido Láctico/sangue , Músculos/efeitos dos fármacos , Músculos/metabolismo , Análise de Componente Principal , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Poluentes Químicos da Água/toxicidade
13.
Semin Dial ; 32(3): 248-254, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30943580

RESUMO

In response to rapid alkali delivery during hemodialysis, hydrogen ions (H+ ) are mobilized from body buffers and from stimulation of organic acid production in amounts sufficient to convert most of the delivered bicarbonate to CO2 and water. Release of H+ from nonbicarbonate buffers serves to back-titrate them to a more alkaline state, readying them to buffer acids that accumulate in the interval between treatments. By contrast, stimulation of organic acid production only serves to remove added bicarbonate (HCO3 - ) from the body; the organic anions produced by this process are lost into the dialysate, irreversibly acidifying the patient as well as diverting metabolic activity from normal homeostasis. We have developed an analytic tool to quantify these acid-base events, which has shown that almost two-thirds of the H+ mobilized during hemodialysis comes from organic acid production when bath bicarbonate concentration ([HCO3 - ]) is 32 mEq/L or higher. Using data from the hemodialysis patients we studied with our analytical model, we have simulated the effect of changing bath solute on estimated organic acid production. Our simulations demonstrate that reducing bath [HCO3 - ] should decrease organic acid production, a change we propose as beneficial to the patient. They also highlight the differential effects of variations in bath acetate concentration, as compared to [HCO3 - ], on the amount and rate of alkali delivery. Our results suggest that transferring HCO3 - delivery from direct influx to acetate influx and metabolism provides a more stable and predictable rate of HCO3 - addition to the patient receiving bicarbonate-based hemodialysis. Our simulations provide the groundwork for the clinical studies needed to verify these conclusions.


Assuntos
Acetatos/farmacologia , Bicarbonatos/farmacologia , Falência Renal Crônica/terapia , Diálise Renal/métodos , Equilíbrio Ácido-Base/efeitos dos fármacos , Soluções para Diálise/farmacologia , Humanos , Falência Renal Crônica/sangue
14.
J Emerg Med ; 57(1): e1-e3, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31027990

RESUMO

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been reported to cause euglycemic diabetic ketoacidosis (eDKA), a diagnosis that may be challenging to establish in the emergency department (ED). CASE REPORT: This is a case report of missed eDKA in a 47-year-old male taking empagliflozin (a SGLT2 inhibitor) that presented to the ED with generalized weakness. His past medical history included multiple sclerosis (MS) diagnosed 4 years ago and type 2 diabetes mellitus. The patient attributed his weakness to MS. His neurologist was consulted and agreed with the plan to discharge the patient with diagnoses of asthenia and dehydration and a prescription of prednisone. The patient returned to the ED the next day with similar symptoms and was admitted to the hospital for treatment of eDKA. He was eventually treated per the hospital diabetic ketoacidosis (DKA) protocol and discharged home with instructions to discontinue empagliflozin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The increasing utilization of SGLT2 inhibitor in patients with type 2 diabetes mellitus will inevitably lead to more cases of eDKA seen in the ED. Emergency physicians need to consider this diagnosis in patients taking these medications that present with symptoms including weakness, nausea, vomiting, abdominal pain, and dehydration. Patients taking these medications should be warned about these symptoms, especially because they may be falsely reassured by relatively low plasma glucose levels on home glucometer readings.


Assuntos
Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/etiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Equilíbrio Ácido-Base/efeitos dos fármacos , Glicemia/análise , Diagnóstico Tardio/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Debilidade Muscular/etiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
15.
Exp Clin Transplant ; 17(Suppl 1): 257-259, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777570

RESUMO

OBJECTIVES: Optimal care of potential donors can lead to successful transplantation. Hemodynamic instability is a common complication in deceased potential donors. The most common underlying causes are hormonal and electrolyte disturbances as well as a hyperinflammatory state, which is rooted in activation of the cytokine cascade. In this study, our aim was to evaluate the efficacy of methylprednisolone injection, an agent introduced for inflammation suppression to achieve more stability in cases of hemodynamic disturbances. MATERIALS AND METHODS: This study covered the period from April 2016 to June 2017 and included 45 randomly selected hemodynamically unstable brain-dead cases (mean arterial pressure < 60 mm Hg). For these cases, primary management included trying to achieve stability; however, after many hours, we experienced hemodynamic instability again. Because of no other correctable methods, we decided to use methylprednisolone injection. The potential deceased donors received a total of 1 g methylprednisolone in two 500-mg divided doses after transfer to the organ procurement unit. RESULTS: Of 45 patients, 26 were male (58%), and the mean age of patients was 33 years. The most common causes of brain death were trauma (33%) and cerebrovascular accident (22%). Systolic and diastolic blood pressures increased significantly after methylprednisolone use. We observed no significant dif ferences in pulse rate. In addition, methylprednisolone could correct pH from 7.33 ± 0.11 to 7.38 ± 0.12 (P = .007). CONCLUSIONS: Use of methylprednisolone in hemodynamically unstable deceased donors could allow better management of these cases. Because there are various factors such as infusion of vasopressor drugs or fluid therapy that could affect the hemodynamic status of these cases, future studies with larger sample sizes are recommended to control these confounding factors.


Assuntos
Morte Encefálica/fisiopatologia , Seleção do Doador , Glucocorticoides/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Metilprednisolona/administração & dosagem , Doadores de Tecidos , Equilíbrio Ácido-Base/efeitos dos fármacos , Adulto , Feminino , Humanos , Concentração de Íons de Hidrogênio , Injeções , Masculino , Fatores de Tempo
16.
Crit Care ; 23(1): 22, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678706

RESUMO

BACKGROUND: Regional citrate anticoagulation (RCA) is a widely used strategy for continuous renal replacement therapy (CRRT). Most of the current guidelines recommend liver failure as one of the contraindications for citrate anticoagulation. However, some studies suggested that the use of citrate for CRRT in liver failure patients did not increase the risk of citrate-related complications. The purpose of this systematic review is to summarize the current evidences on the safety and efficacy of RCA for CRRT in liver failure patients. METHODS: We performed a comprehensive search on PubMed, Embase, and the Cochrane Library databases from the inception to March 1, 2018. Studies enrolled adult (age > 18 years) patients with various levels of liver dysfunction underwent RCA-CRRT were included in this systematic review. RESULTS: After the study screening, 10 observational studies with 1241 liver dysfunction patients were included in this systematic review. The pooled rate of citrate accumulation and bleeding was 12% [3%, 22%] and 5% [2%, 8%], respectively. Compared with the baseline data, the serum pH, bicarbonate, and base excess (BE), the rate of metabolic alkalosis, the serum ionized calcium (ionCa) and total calcium (totCa) level, and the ratio of total calcium/ionized calcium (totCa/ionCa) significantly increased at the end of observation. However, no significant increase was observed in serum citrate (MD - 65.82 [- 194.19, 62.55]), lactate (MD 0.49 [- 0.27, 1.26]) and total bilirubin concentration (MD 0.79 [- 0.70, 2.29]) at the end of CRRT. Compared with non-liver failure patients, the live failure patients showed no significant difference in the pH (MD - 0.04 [- 0.13, 0.05]), serum lactate level (MD 0.69 [- 0.26, 1.64]), and totCa/ionCa ratio (MD 0.03 [- 0.12, 0.18]) during CRRT. The median of mean filter lifespan was 55.9 h, with a range from 22.7 to 72 h. CONCLUSIONS: Regional citrate anticoagulation seems to be a safe anticoagulation method in liver failure patients underwent CRRT and could yield a favorable filter lifespan. Closely monitoring the acid base status and electrolyte balance may be more necessary during RCA-CRRT in patients with liver failure.


Assuntos
Anticoagulantes/administração & dosagem , Ácido Cítrico/administração & dosagem , Falência Hepática/fisiopatologia , Terapia de Substituição Renal/normas , Equilíbrio Ácido-Base/efeitos dos fármacos , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Ácido Cítrico/análise , Ácido Cítrico/uso terapêutico , Hemorragia/prevenção & controle , Humanos , Falência Hepática/tratamento farmacológico , Terapia de Substituição Renal/efeitos adversos , Terapia de Substituição Renal/métodos
17.
J Sports Sci ; 37(13): 1464-1471, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30668281

RESUMO

This study investigated the effects of two separate doses of sodium bicarbonate (NaHCO3) on 4 km time trial (TT) cycling performance and post-exercise acid base balance recovery in hypoxia. Fourteen club-level cyclists completed four cycling TT's, followed by a 40 min passive recovery in normobaric hypoxic conditions (FiO2 = 14.5%) following one of either: two doses of NaHCO3 (0.2 g.kg-1 BM; SBC2, or 0.3 g.kg-1 BM; SBC3), a taste-matched placebo (0.07 g.kg-1 BM sodium chloride; PLA), or a control trial in a double-blind, randomized, repeated-measures and crossover design study. Compared to PLA, TT performance was improved following SBC2 (p = 0.04, g = 0.16, very likely beneficial), but was improved to a greater extent following SBC3 (p = 0.01, g = 0.24, very likely beneficial). Furthermore, a likely benefit of ingesting SBC3 over SBC2 was observed (p = 0.13, g = 0.10), although there was a large inter-individual variation. Both SBC treatments achieved full recovery within 40 min, which was not observed in either PLA or CON following the TT. In conclusion, NaHCO3 improves 4 km TT performance and acid base balance recovery in acute moderate hypoxic conditions, however the optimal dose warrants an individual approach.


Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Desempenho Atlético/fisiologia , Ciclismo/fisiologia , Substâncias para Melhoria do Desempenho/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Gastroenteropatias/induzido quimicamente , Frequência Cardíaca , Humanos , Concentração de Íons de Hidrogênio , Hipóxia , Masculino , Oxigênio/sangue , Percepção , Substâncias para Melhoria do Desempenho/efeitos adversos , Substâncias para Melhoria do Desempenho/sangue , Esforço Físico , Bicarbonato de Sódio/efeitos adversos , Bicarbonato de Sódio/sangue , Adulto Jovem
18.
Acta Bioeng Biomech ; 21(4): 101-110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32022801

RESUMO

PURPOSE: The objective of this study was to fabricate PLA-based porous scaffold by 3D printing technology and to evaluate their cytotoxicity and biocompatibility under in vitro conditions in respect to bone tissue engineering. MATERIAL AND METHODS: Pure PLA in filamentous form was processed via 3D printing technology of fused filament fabrication into porous scaffolds. The structure and porosity of scaffolds were measured by metrotomography. PLA scaffolds were pre-treated by human serum, foetal bovine serum and complete cell culture medium to enhance bio-attractivity of the scaffold's surface for the adherence of the cells. Cells were enzymatically isolated from the periosteum of the proximal tibia and then expanded in monolayer. Periosteum-derived osteoprogenitors (PDOs) were seeded on the pre-treated PLA scaffolds and subsequent cell proliferation was measured by commercially available cell proliferation assay. Adherence of PDOs on the PLA scaffold was confirmed by scanning electron microscopy (SEM). RESULTS: Prepared scaffolds had well-defined structure and were characterized by uniform distribution of pores. They were non-toxic and biocompatible with PDOs, however, PLA scaffold with the periosteum-derived progenitor cells was significantly better in the group of scaffolds pre-treated with normal human serum. CONCLUSIONS: The obtained PLA porous scaffolds favored attachment of periosteum derived progenitors and proliferation, furthermore, cells penetrated into the scaffold through the interstitial pores which was meaningful for cytocompatibility evaluation.


Assuntos
Osso e Ossos/fisiologia , Poliésteres/farmacologia , Impressão Tridimensional , Engenharia Tecidual/métodos , Tecidos Suporte/química , Equilíbrio Ácido-Base/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Pessoa de Meia-Idade , Periósteo/citologia , Porosidade , Células-Tronco/citologia , Células-Tronco/ultraestrutura , Tomografia Computadorizada por Raios X
19.
J Nephrol ; 32(1): 93-100, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30465137

RESUMO

AIMS: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates. METHODS: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment. RESULTS: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non-significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D. CONCLUSIONS: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates.


Assuntos
Acidose/prevenção & controle , Citrato de Cálcio/farmacologia , Doenças Cardiovasculares/prevenção & controle , Ácido Cítrico/uso terapêutico , Hiperfosfatemia/prevenção & controle , Compostos de Magnésio/farmacologia , Deficiência de Magnésio/prevenção & controle , Compostos Organometálicos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Equilíbrio Ácido-Base/efeitos dos fármacos , Acidose/sangue , Acidose/diagnóstico , Acidose/etiologia , Idoso , Bicarbonatos/sangue , Biomarcadores/sangue , Citrato de Cálcio/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Ácido Cítrico/efeitos adversos , Ácido Cítrico/sangue , Estudos Cross-Over , Combinação de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hiperfosfatemia/sangue , Hiperfosfatemia/diagnóstico , Hiperfosfatemia/etiologia , Magnésio/sangue , Compostos de Magnésio/uso terapêutico , Deficiência de Magnésio/sangue , Deficiência de Magnésio/diagnóstico , Deficiência de Magnésio/etiologia , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/sangue , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Fósforo/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Texas , Fatores de Tempo , Resultado do Tratamento
20.
J Pharm Biomed Anal ; 164: 268-275, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30399533

RESUMO

Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre-eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC-MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 µL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex® 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC0-∞ (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R-bupivacaine (AUC(R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%).


Assuntos
Anestésicos Locais/sangue , Proteínas Sanguíneas/metabolismo , Bupivacaína/sangue , Troca Materno-Fetal , Equilíbrio Ácido-Base/efeitos dos fármacos , Anestesia Epidural/efeitos adversos , Anestesia Epidural/métodos , Anestesia Obstétrica/efeitos adversos , Anestesia Obstétrica/métodos , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Bupivacaína/química , Bupivacaína/farmacocinética , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Voluntários Saudáveis , Humanos , Gravidez , Ligação Proteica , Estereoisomerismo , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
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