Abstract 16216: Increases in Renal Nkcc2 and Ncc Preceded the Elevation of Blood Pressure in Mice Treated With Clozapine

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zhiyun Ren ◽  
Laureano D Asico ◽  
Xiaoyan Wang
Keyword(s):  
Protein Expression ◽  
Sodium Transport ◽  
Transport Proteins ◽  
No Synthase ◽  
Ros Generation ◽  
Serum Concentrations ◽  
Drug Induced ◽  
Induced Hypertension ◽  
Different Doses ◽  
Mini Pump

One of major side effects of clozapine, a common antipsychotic drug, is hypertension. In order to explore the pathogenesis of the drug-induced hypertension, we examined the renal sodium transport proteins and BP in the C57Bl6/J male mice treated with clozapine at different doses for 1 week. Clozapine at 20mg/kg/day via osmotic mini-pump increased SBP ( 110±0.6,mmHg, femoral artery, under anesthesia) and DBP (76.7±1) relative to vehicle (97.6±1.2/71.2±2.7) while the renal protein expression of NKCC2 (180±21, % of vehicle) and NCC (171±22), and ENaC-α (140±7), β(166±21) and γ(130±7) was increased without changes in NHE3 and α1-NKA (n=5/group). Clozapine at lower doses (5&10mg/kg/day,IP) did not change the conscious SBP and DBP monitored daily by tail-cuff, even on day 7 in 5 mg/kg group (115.61±1.6/90.1±1.3) and in 10mg/kg group (116.8±2/89.0±1.6) relative to vehicle (111.9±1.5/86.9±1.4) (n=4/group). Urinary excretion of Na + & K + and serum concentrations of Na + , K + , Cl - , creatinine were similar in all groups. However, renal protein expression of NKCC2 was increased in 5mg/kg (360±80, % of vehicle) and 10mg/kg (247±50) groups; NCC was increased at 5 mg/kg (175±9); α1-NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. No increases were found in the protein expression of NHE3 and ENaCs. Those increases in renal NKCC2 &NCC at 5 & 10 mg/kg were consistent with those at 20 mg/kg. AT1R was increased at 5 (221±20) &10mg/kg (255±21) while renin (186±15) and ACE1 (186±5), not ACE2, were increased at 5 mg/kg suggesting an activation of RAAS in kidney. NOX4, not NOX2, was increased at 5 mg/kg (453±69) while NOS3, not NOS1&2, was decreased at 5 (60±21) and 10mg/kg (64±5) groups. TNFα, not IL-6 was increased at 5 (222±18) &10 mg/kg (321±26). In cultured mouse distal convoluted tubule cells, clozapine also increased NCC and α1-NKA at 1nM (169±4;156±7) and 10nm(175±23;183±15) respectively ( 24h,n=4/group). Those changes in kidney, including increases in sodium transport proteins, RAAS components, ROS generation enzymes, inflammation factors and decrease in NO synthase, preceded the elevation of BP suggesting that direct or indirect regulations of clozapine on those proteins may play an important role in the pathogenesis of the drug-induced hypertension.

scholarly journals Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

2021 ◽  
pp. 026988112110034
Author(s):  
Leif Hommers ◽  
Maike Scherf-Clavel ◽  
Roberta Stempel ◽  
Julian Roth ◽  
Matthias Falter ◽  
...  
Keyword(s):  
Qt Interval ◽  
Multivariate Regression Analysis ◽  
Cardiac Repolarization ◽  
Qtc Interval ◽  
Serum Concentrations ◽  
Drug Induced ◽  
Individual Level ◽  
Main Determinants ◽  
The Individual ◽  
Polygenic Variation

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia’s formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = −0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

Transport proteins PotD and Crr of Escherichia coli, novel fusion partners for heterologous protein expression

2007 ◽  
Vol 1774 (12) ◽  
pp. 1536-1543 ◽  
Author(s):  
Kyung-Yeon Han ◽  
Hyuk-Seong Seo ◽  
Jong-Am Song ◽  
Keum-Young Ahn ◽  
Jin-Seung Park ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Expression ◽  
Heterologous Protein ◽  
Transport Proteins ◽  
Heterologous Protein Expression

Iatrogenic and Drug-Induced Hypertension

2004 ◽  
pp. 21-35 ◽  
Author(s):  
Ehud Grossman ◽  
Franz H. Messerli
Keyword(s):  
Drug Induced ◽  
Induced Hypertension

Low protein diet exacerbates NO synthase inhibitor-induced hypertension in rats

1999 ◽  
Vol 3 (1) ◽  
pp. 34-40 ◽  
Author(s):  
H. Kumagai ◽  
Yoshiko Kikuchi ◽  
Noriko Kumeta ◽  
Masato Kimura ◽  
Toshio Sakai
Keyword(s):  
No Synthase ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Low Protein ◽  
No Synthase Inhibitor ◽  
Induced Hypertension ◽  
Synthase Inhibitor

Effects of ZnCl2 on ROS generation, plasma membrane properties, and changes in protein expression in grapevine root explants

Biologia ◽  
2016 ◽  
Vol 71 (5) ◽  
Author(s):  
Vladimír Repka ◽  
Roderik Fiala ◽  
Milada Čiamporová ◽  
Ján Pavlovkin
Keyword(s):  
Plasma Membrane ◽  
Protein Expression ◽  
Adventitious Root ◽  
Membrane Properties ◽  
Ros Generation ◽  
Root Explants

AbstractThis study is aimed at the responses of grapevine adventitious root explants to zinc (Zn

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

Abstract 93: Hypertension and Renal Injury Induced by Nitric Oxide Depletion are Ameliorated by Concomitant Depletion of Hydrogen Sulfide

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Sebastiaan Wesseling ◽  
Joost O Fledderus ◽  
Johanna A Dijk ◽  
Chantal Tilburgs ◽  
Marianne C Verhaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Renal Injury ◽  
Renal Damage ◽  
No Synthase ◽  
Tubular Epithelium ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Synthase Inhibitor

Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease is associated with decreased NO availability and less renal H 2 S production. We hypothesized that combined depletion of NO and H 2 S aggravates hypertension and renal injury. Male 8-wk old Sprague Dawley rats were treated with vehicle, NO synthase inhibitor L-NG-nitroarginine (LNNA; 125 mg/L in drinking water), cystathionine-γ-lyase (CSE) inhibitor propargylglycine (PAG; 37.5 mg/kg BW ip daily) or LNNA + PAG for 1 and 4 weeks (6 rats/group). LNNA after 4w increased systolic blood pressure (SBP; 223±10 vs . 137±3 mmHg in controls; P<0.01), proteinuria (144±35 vs. 17±2 mg/d; P<0.01), uremia (16.6±4.2 vs . 7.0±0.4 mmol/L; P<0.05) and tubulo-interstitial injury (P<0.01). LNNA reduced urinary NO metabolite (NOx) excretion by ∼85% after 1w and 4w. PAG alone had no effect on SBP, renal function or injury, but did reduce urinary NOx excretion. Co-treatment with PAG ameliorated LNNA-induced hypertension (182±10 mmHg; P<0.01) and prevented proteinuria (27±3 mg/d), uremia (8.3±0.4 mmol/L) and tubulo-interstitial injury, but did not further reduce urinary NOx excretion. Renal H 2 S production was almost absent in all PAG groups after 1w and 4w (P<0.01) and was reduced in LNNA-treated rats after 4w (4.6±1.4 vs . 9.2±0.5 μmol/hr/mg; P<0.01). Renal HO-1 gene expression was strongly induced in all PAG-treated groups after 1w and 4w (4 to 19-fold; P<0.01) whereas LNNA only increased HO-1 gene expression at 4w (P<0.01). Immunohistochemistry showed that renal HO-1 protein was primarily interstitial in all PAG-treated groups at 1w and 4w. In contrast, LNNA only showed HO-1 in tubular epithelium in conjunction with protein casts. Depleting NO caused hypertension and renal damage followed by reduced renal H 2 S production and increased renal HO-1 expression. Surprisingly, concomitant inhibition of CSE ameliorated hypertension and prevented renal injury. PAG almost completely blocked renal H 2 S production and caused strong induction of renal HO-1, independently of injury, suggesting that H 2 S suppresses renal HO-1 expression. In conclusion, concomitant upregulation of HO-1 expression by inhibition of H 2 S production, prevents LNNA-induced hypertension and renal injury.

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

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