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hypertension in pregnan

Husna Yetti, Hisao Naito, Yuan Yuan, Xiaofang Jia, Yumi Hayashi, Hazuki Tamada, Kazuya Kitamori, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics...
2018: PloS One
Giulia Barda, Ohad Gluck, Yossi Mizrachi, Jacob Bar
OBJECTIVE: To compare the maternal and neonatal outcome of dichorionic diamniotic in vitro fertilization (IVF) twin and spontaneous twin pregnancies. MATERIAL AND METHODS: Maternal and fetal data of all consecutive dichorionic-diamniotic twin pregnancies delivered in our institution between January 2009 and May 2015 were abstracted from medical records and pregnancy outcome of IVF twin was compared to spontaneous twin. RESULTS: Overall 708 twin pregnancies (449 IVF and 259 spontaneous) were included...
December 2017: Journal of Maternal-fetal & Neonatal Medicine
Martina Štěpánková, Kristýna Krasulová, Aneta Dořičáková, Ondřej Kurka, Pavel Anzenbacher, Zdeněk Dvořák
Dihydropyridine calcium channel blockers (CCBs) are used as anti-hypertensives and in the treatment of angina pectoris. Structurally, CCBs have at least one chiral center in the molecule, thereby existing in two or more different enantiomers. In the current paper we examined effects of benidipine, felodipine and isradipine enantiomers on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450. All CCBs dose-dependently activated aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), as revealed by gene reporter assays...
November 16, 2016: Toxicology Letters
Hisao Naito, Xiaofang Jia, Husna Yetti, Yukie Yanagiba, Hazuki Tamada, Kazuya Kitamori, Yumi Hayashi, Dong Wang, Masashi Kato, Akira Ishii, Tamie Nakajima
OBJECTIVES: High-fat and -cholesterol diet (HFC) induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive rat (SHRSP) 5/Dmcr, the fifth substrain from SHRSP, by dysregulating bile acid (BA) kinetics. This study aimed to clarify the histopathological and BA kinetic differences in HFC-induced fibrosis between SHRSP5/Dmcr and SHRSP. METHODS: Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8 weeks...
September 2016: Environmental Health and Preventive Medicine
Nicolas Hohmann, Raphael Reinhard, Sven Schnaidt, Lukas Witt, Alexandra Carls, Jürgen Burhenne, Gerd Mikus, Walter E Haefeli
OBJECTIVES: Antiretroviral combination therapy of patients infected with HIV has greatly increased their life expectancy. Hence, the treatment of HIV-related long-term complications and age-related comorbidities has become more important. Reported incidence rates of erectile dysfunction (ED) and pulmonary arterial hypertension (PAH) are increasing in HIV-positive patients, potentially requiring treatment with phosphodiesterase 5 inhibitors such as sildenafil or tadalafil. In vitro, the NNRTI rilpivirine is both a pregnane X receptor agonist and cytochrome P450 (CYP) 3A inhibitor...
August 2016: Journal of Antimicrobial Chemotherapy
Zofia Mazerska, Anna Mróz, Monika Pawłowska, Ewa Augustin
The final therapeutic effect of a drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of at least one element of ADME may result in serious drug resistance. In this work we described the role of one element of this resistance: phase II metabolism with UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the ABC transporters, MDR1, MRP and BCRP, than the native drug...
March 2016: Pharmacology & Therapeutics
Johanna Weiss, Sybille Baumann, Dirk Theile, Walter Emil Haefeli
The endothelin-1 receptor antagonists bosentan and ambrisentan used for the treatment of pulmonary arterial hypertension remarkably differ in their potential to act as perpetrators in pharmacokinetic drug-drug interactions. So far, it is not clear whether the metabolites of bosentan and ambrisentan contribute to the extent of drug interactions. We therefore investigated the effects of 4-hydroxymethyl ambrisentan, hydroxy bosentan, desmethyl bosentan, and hydroxy desmethyl bosentan on targets which are inhibited or induced by the parent compounds...
February 2015: Pulmonary Pharmacology & Therapeutics
Kuen-Bao Chen, Hsin-Yi Chen, Kuan-Chung Chen, Calvin Yu-Chian Chen
Recently, cardiovascular disease, also known as loop circulatory system diseases or disorders, is one of the serious diseases including heart disease, stroke, atherosclerosis, myocardial infarction, hypertension, hypotension, and thrombosis. Human pregnane X receptor, PXR, plays a crucial role in exogenous and endobiotic metabolism for rabbit, rat, mouse, and human. The PXR activation can protect the blood vessels from damage of hazardous substances. In this study we aim to investigate the potent lead compounds as PXR receptor agonist against cardiovascular disease...
2014: BioMed Research International
Lei Xiao, Zihui Zhang, Xiaoqin Luo
The pregnane X receptor (PXR) and constitutive androstane receptor (CAR), 2 closely related and liver-enriched members of the nuclear receptor superfamily, and aryl hydrocarbon receptor (AhR), a nonnuclear receptor transcription factor (TF), are major receptors/TFs regulating the expression of genes for the clearance and detoxification of xenobiotics. They are hence defined as "xenobiotic receptors". Recent studies have demonstrated that PXR, CAR and AhR also regulate the expression of key proteins involved in endobiotic responses such as the metabolic homeostasis of lipids, glucose, and bile acid, and inflammatory processes...
2014: Circulation Journal: Official Journal of the Japanese Circulation Society
Verena Rickert, Walter Emil Haefeli, Johanna Weiss
Riociguat is a new soluble guanylate cyclase stimulator under development for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. So far, the interaction potential of riociguat with other drugs is nearly unknown. Therefore, we assessed in vitro the potency of riociguat to inhibit important drug metabolising enzymes (cytochrome P450 (CYP) 3A4, CYP2C19, and CYP2D6) and drug transporters (P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and organic anion transporting polypeptides (OATP) 1B1 and 1B3)...
August 2014: Pulmonary Pharmacology & Therapeutics
Xiaofang Jia, Hisao Naito, Husna Yetti, Hazuki Tamada, Kazuya Kitamori, Yumi Hayashi, Dong Wang, Yukie Yanagiba, Juncai Wang, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima
BACKGROUND AND AIMS: Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified. METHODS: Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet...
August 2013: Digestive Diseases and Sciences
Johanna Weiss, Dirk Theile, Maximilian Alexander Rüppell, Tobias Speck, Adriana Spalwisz, Walter Emil Haefeli
Macitentan is a new non-selective endothelin-1 receptor antagonist under development for the treatment of pulmonary arterial hypertension. Information on the potential for macitentan to influence the pharmacokinetics of concomitantly administered drugs by inhibition or induction of drug metabolising enzymes or drug transporters is sparse. We therefore studied the potential of macitentan to inhibit and induce critical targets of drug metabolism and drug distribution (transporters) in vitro. Induction was quantified at the mRNA level by real-time RT-PCR in LS180 cells and revealed that macitentan significantly induced mRNA expression of cytochrome P450 3A4 (CYP3A4), P-glycoprotein (P-gp, ABCB1), solute carrier of organic anions 1B1 (SLCO1B1), and uridinediphosphate-glucuronosyltransferase 1A3 (UGT1A9)...
February 15, 2013: European Journal of Pharmacology
Johanna Weiss, Dirk Theile, Adriana Spalwisz, Jürgen Burhenne, Klaus-Dieter Riedel, Walter Emil Haefeli
The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access...
January 15, 2013: Biochemical Pharmacology
Claudia Tovar-Palacio, Nimbe Torres, Andrea Diaz-Villaseñor, Armando R Tovar
Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of renal physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes, including kidney lipid metabolism, drug clearance, inflammation, fibrosis, cell differentiation, and oxidative stress. Derangement of nuclear receptor regulation, that is, mainly due to obesity may induce metabolic syndrome, may contribute to the pathogenesis and progression of chronic renal disease and may result in end-stage renal disease...
October 2012: Genes & Nutrition
Irene Lambrinoudaki, Marc Brincat, C Tamer Erel, Marco Gambacciani, Mette H Moen, Karin Schenck-Gustafsson, Florence Tremollieres, Svetlana Vujovic, Margaret Rees, Serge Rozenberg
INTRODUCTION: Obesity is a public health problem, with overweight individuals representing approximately 20% of the adult world population. Postmenopausal status is associated with higher prevalence of obesity, as 44% of postmenopausal women are overweight, among whom 23% are obese. Obesity often co-exists with other diseases, the most important being diabetes mellitus, dyslipidemia and hypertension. Furthermore, obesity increases the risk of gynecologic cancer, cardiovascular disease, venous thromboembolism, osteoarthritis and chronic back pain...
July 2010: Maturitas
Christine E Staatz, Lucy K Goodman, Susan E Tett
The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582)...
April 2010: Clinical Pharmacokinetics
Grégory Maurice Pinon, Jérôme Fagart, Anny Souque, Gilles Auzou, Alain Vandewalle, Marie-Edith Rafestin-Oblin
The ability of steroid ligands to inactivate the human mineralocorticoid receptor (MR(WT)) has been shown to be due to their inability to contact Asn770, a residue of the H3 helix involved in stabilizing contacts with the H11-H12 loop region. However, all steroid ligands that display antagonist properties when bound to MR(WT), have been shown to activate a mutant receptor (MR(L810)) associated with a severe form of hypertension. Biochemical studies revealed that S810L mutation induces a change in the receptor conformation and increases the steroid-receptor complexes stability...
March 31, 2004: Molecular and Cellular Endocrinology
Yuping Chen, Stephen S Ferguson, Masahiko Negishi, Joyce A Goldstein
Human CYP2C9 is important in the metabolism of numerous clinically used drugs such as the anticoagulant warfarin, the anticonvulsant phenytoin, antidiabetic drugs such as tolbutamide and glipizide, the hypertensive agent losartan, and numerous nonsteroidal anti-inflammatory drugs. Several studies have reported that certain drugs such as rifampicin and phenobarbital induce CYP2C9, but the molecular basis for this induction remains unknown. In the present study, we demonstrate that the human pregnane X receptor (hPXR) mediates induction of CYP2C9 by the prototype drugs rifampicin, hyperforin (found in St...
February 2004: Journal of Pharmacology and Experimental Therapeutics
R E Purdy
Endogenous Na, K pump inhibitors may contribute to the pathogenesis of hypertension, and could do so by causing direct vasoconstriction and/or enhancing sensitivity to other vasoconstrictor agents. These effects of the Na, K pump inhibitors are likely due to inhibition of Na-K-ATPase. In turn, cells become depolarized, internal sodium concentration increases and internal calcium is increased by exchange for sodium via the sodium/calcium exchange carrier. This extra calcium is sequestered, increasing the size of the releasable intracellular calcium pool...
July 1998: Clinical and Experimental Hypertension: CHE
S Abdelhamid, S Lewicka, K Bige, D Haack, H Lorenz, U Nensel, A Röckel, P Fiegel, D Walb, P Vecsei
21-Deoxyaldosterone has been postulated to be a precursor of aldosterone in an alternative biosynthesis pathway and Kelly's-M1 is considered to be its metabolite. In healthy volunteers, the excretion rate of 21-deoxyaldosterone and of Kelly's-M1 are significantly lower than the aldosterone metabolites, aldosterone-18-glucuronide and tetrahydro-aldosterone and than the aldosterone precursor 18-OH-corticosterone. Essential hypertension patients (with low and normal renin) excrete comparable values of 21-deoxyaldosterone and Kelly's-M1 as normotensives...
September 1994: Journal of Steroid Biochemistry and Molecular Biology
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