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- Expression of the Transmembrane Lysosomal Protein SCARB2/Limp-2 in Renin Secretory Granules Controls Renin Release. [JOURNAL ARTICLE]
- Nephron Exp Nephrol 2013 Apr 26; 122(3-4):103-113.
Background/Aims:Renin processing and storage is believed to occur in lysosome-like structures in the afferent arteriole. SCARB2/Limp-2 is a transmembrane lysosomal protein responsible for the intracellular trafficking of β-glucocerebrosidase. This study aimed to confirm the expression of SCARB2/Limp-2 in renin secretory granules, and explore its role in renin processing and secretion.
Methods:Co-localisation studies of (pro)renin with lysosomal membrane proteins, SCARB2/Limp-2, LAMP-1 and LAMP-2, were performed in mouse and human kidney sections. Intrarenal expression and secretion of (pro)renin in wild-type (WT) and Limp-2(-/-) mice were compared with and without stimulation.
Results:SCARB2/Limp-2, LAMP-1 and LAMP-2 co-localised with (pro)- renin in mouse and human kidney. Plasma renin concentration was increased in Limp-2(-/-) mice when compared to WT littermates. No change in (pro)renin expression, however, was observed in Limp-2(-/-) mouse kidney cortex by immunofluorescence microscopy, Western blotting, quantitative RT-PCR or the ultrastructural appearance of renin secretory granules. Acute stimulation of renin release by isoprenaline or hydralazine was similar in WT and Limp-2(-/-) mice. Following chronic salt restriction, however, immunofluorescence microscopy showed less (pro)renin expressed in Limp-2(-/-) compared with WT mouse kidneys, and there was significantly less prorenin but not renin by Western blotting in Limp-2(-/-) mouse kidney cortex, despite no difference in circulating renin levels.
Conclusion:Renin secretory granules possess integral lysosomal proteins, confirming that they are indeed modified lysosomes. Limp-2 deficiency leads to a minor increase in circulating renin. Limp-2, however, is not required for acute or chronic stimulation of renin release.
- Prevention and treatment of postpartum hypertension. [Journal Article]
- Cochrane Database Syst Rev 2013.:CD004351.
Postpartum blood pressure (BP) is highest three to six days after birth when most women have been discharged home. A significant rise in BP may be dangerous (e.g., can lead to stroke), but there is little information about how to prevent or treat postpartum hypertension.To assess the relative benefits and risks of interventions to: (1) prevent postpartum hypertension, by assessing whether 'routine' postpartum medical therapy is better than placebo/no treatment; and (2) treat postpartum hypertension, by assessing whether (i) one antihypertensive therapy is better than placebo/no therapy for mild-moderate postpartum hypertension; and (ii) one antihypertensive agent offers advantages over another for mild-moderate or severe postpartum hypertension.We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013), bibliographies of retrieved papers, and personal files.For women with antenatal hypertension, trials comparing a medical intervention with placebo/no therapy. For women with postpartum hypertension, trials comparing one antihypertensive with either another or placebo/no therapy.We extracted the data independently and were not blinded to trial characteristics or outcomes. We contacted authors for missing data when possible.Nine trials are included.Prevention: Four trials (358 women) compared furosemide, nifedipine capsules, or L-arginine with placebo/no therapy. For women with antenatal pre-eclampsia, postnatal furosemide is associated with a strong trend towards reduced use of antihypertensive therapy in hospital.Treatment: For treatment of mild-moderate postpartum hypertension, three trials (189 women) compared timolol, oral hydralazine, or oral nifedipine with methyldopa. Use of additional antihypertensive therapy did not differ between groups (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.20 to 4.20; three trials), but the trials were not consistent in their effects. The drugs were well tolerated.For treatment of severe postpartum hypertension, two trials (120 women) compared intravenous hydralazine with either sublingual nifedipine or intravenous labetalol. There were no maternal deaths or hypotension. Use of additional antihypertensive therapy did not differ between groups (RR 0.58, 95% CI 0.04 to 9.07; two trials), but the trials were not consistent in their effects.For women with pre-eclampsia, postnatal furosemide may decrease the need for postnatal antihypertensive therapy in hospital, but more data are needed on substantive outcomes before this practice can be recommended. There are no reliable data to guide management of women who are hypertensive postpartum. Any antihypertensive agent used should be based on a clinician's familiarity with the drug. Future studies should include data on postpartum analgesics, severe maternal hypertension, breastfeeding, hospital length of stay, and maternal satisfaction with care.
- [Ethnicity in pharmacogenetics]. [English Abstract, Journal Article]
- Ned Tijdschr Geneeskd 2013; 157(17):A6118.
- Individuals originating from different ethnic groups can respond differently to certain medicines. In this article, we differentiated persons with a European, African and Asian origin into three main groups.- The combination of a fixed dose of isosorbide dinitrate and hydralazine (known as BiDil) was marketed specifically in the US for Afro-Americans with heart failure, as patients from this group respond less well to ACE inhibitors.- Ethnic differences in the effects of medications are partly linked to genetic variations.- These ethnicity-related differences in the effects of medicines could be caused by variations in the enzymes that metabolise medications, e.g. cytochrome P450 (CYP) or, genetic variations in the receptors to which these substances bind. These differences could have consequences for dosing.- Besides the pharmacokinetic and pharmacodynamic differences, there are also ethnic differences related to undesirable effects: HLA-mediated hypersensitivity reactions, for example.- Ethnicity is not a suitable basis for adjusting the dosages of medicines. Genotyping can prove helpful at times.
- Impact of High Salt Independent of Blood Pressure on PRMT/ADMA/DDAH Pathway in the Aorta of Dahl Salt-Sensitive Rats. [Journal Article]
- Int J Mol Sci 2013; 14(4):8062-72.
Endothelial dysfunction participates in the development and progression of salt-sensitive hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). The objectives of this study were to investigate the impact of a high salt diet on the PRMT/ADMA/DDAH (protein arginine methyltransferases; dimethylarginine dimethylaminohydrolase) pathway in Dahl salt-sensitive (DS) rats and SS-13BN consomic (DR) rats, and to explore the mechanisms that regulate ADMA metabolism independent of blood pressure reduction. Plasma levels of nitric oxide (NO) in DS rats given a high salt diet and subjected to intragastric administration of hydralazine (SH + HYD group) were lower than those given a normal salt diet (SN group). There were significant decreases in expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) and endothelial NO synthase (eNOS) in DS rats given a high diet (SH group) in comparison to the SN group. The activity of DDAH and expression of eNOS in the SH + HYD group decreased more significantly than SN group. The mRNA expression of DDAH-1 and DDAH-2 were lowest in the SH group. The results suggest that salt, independent of blood pressure, can affect the PRMT-1/ADMA/DDAH system to a certain degree and lead to endothelial dysfunction in Dahl salt-sensitive rats.
- Left Ventricular Responses to Acute Changes in Late Systolic Pressure Augmentation in Older Adults. [JOURNAL ARTICLE]
- Am J Hypertens 2013 Mar 28.
BACKGROUND:Changes in the cardiovascular system with age may predispose older persons to development of heart failure with preserved ejection fraction. Vascular stiffening, aortic pressure augmentation, and ventricular-vascular coupling have been implicated. We explored the potential for acute reductions in late systolic pressure augmentation to impact left ventricular relaxation in older persons without heart failure.
METHODS:Sixteen older persons free of known cardiovascular disease with the exception of hypertension had noninvasive tonometry and cardiac ultrasound to evaluate central augmentation index (AI) and diastolic function at baseline and after randomized, blinded administration of intravenous B-type natriuretic peptide (BNP) and hydralazine in a crossover design.
RESULTS:AI was significantly reduced after BNP (11.4±8.9 to -0.2±14.7%; P = 0.02) and nonsignificantly reduced after hydralazine (14.7±8.4% to 11.5±8.8%; P = 0.39). With decreased AI during BNP, a trend toward worsened myocardial relaxation by tissue Doppler imaging occurred (E' velocity pre- and post-BNP: 10.0±2.5 and 8.8±2.0cm/s, respectively; P = 0.06). There was a significant fall in stroke volume with BNP (68.5±18.3 to 60.9±18.1ml; P = 0.02), suggesting that changes in preload overwhelmed effects of afterload reduction on ventricular performance. With hydralazine, neither relaxation nor stroke volume changed.
CONCLUSIONS:Acute changes in late systolic aortic pressure augmentation do not necessarily lead to improved systolic or diastolic function in older people. Preload may be a more important determinant of cardiac performance than afterload in older people with compensated ventricular function. The potential for changes in preload to impair rather than enhance left ventricular systolic and diastolic function in older people warrants further study. CLINICAL TRIALS REGISTRATION: This study is registered at clinicaltrials.gov as NCT00204984.
- DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer. [Journal Article]
- Curr Cancer Drug Targets 2013 May 1; 13(4):379-99.
DNA methylation is an epigenetic modification involved in gene expression regulation. In cancer, the DNA methylation pattern becomes aberrant, causing an array of tumor suppressor genes to undergo promoter hypermethylation and become transcriptionally silent. Reexpression of methylation silenced tumor suppressor genes by inhibiting the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) has emerged as an effective strategy against cancer. The expression of DNA methyltransferase 1 (DNMT1) being high in S-phase of cell cycle makes it a specific target for methylation inhibition in rapidly dividing cells as in cancer. This review discusses nucleoside analogues (azacytidine, decitabine, zebularine, SGI-110, CP-4200), non-nucleoside ihibitors both synthetic (hydralazine, RG108, procaine, procainamide, IM25, disulfiram) and natural compounds (curcumin, genistein, EGCG, resveratrol, equol, parthenolide) which act through different mechanisms to inhibit DNMTs. The issues of bioavailability, toxicity, side effects, hypomethylation resistance and combinatorial therapies have also been highlighted.
- Pharmacotherapy for preeclampsia in low and middle income countries: an analysis of essential medicines lists. [Journal Article]
- J Obstet Gynaecol Can 2013 Mar; 35(3):215-23.
Objective:To determine the prevalence of drugs for comprehensive management of preeclampsia in national essential medicine lists (EMLs) in low and middle income countries (LMICs)
Methods:We collected EMLs from the 144 LMICs identified by the World Bank through broad-based Internet searches and in collaboration with the World Health Organization. We identified therapies for hypertension, eclampsia, preeclampsia complications (e.g., pulmonary edema, thrombosis), preterm birth, and labour induction contained in the EMLs.
Results:In 91 EMLs obtained from 144 LMICs, the most commonly listed parenteral antihypertensive therapies were verapamil (63.7%), hydralazine (61.5%), sodium nitroprusside (48.3%), and propranolol (39.6%). The most prevalent oral antihypertensive therapies were nifedipine (95.6%), methyldopa (93.4%), propranolol (90.1%), and atenolol (87.9%). For eclampsia/preeclampsia, magnesium sulphate was present in 84.6% of EMLs and calcium gluconate in 85.7%. For pulmonary edema, most EMLs (94.5%) listed oral furosemide, for thrombosis 92.3% listed heparin, for acceleration of fetal pulmonary maturity 90.1% listed parenteral dexamethasone, and for labour induction 97.8% listed oxytocin or a prostanoid (usually misoprostol, 40.7%).
Conclusion:EMLs of LMICs provide comprehensive coverage of preeclampsia pharmacotherapy. These EMLs may be used as advocacy tools to ensure the availability of these therapies within each country.
- Irreversible renal damage after transient renin-angiotensin system stimulation: involvement of an AT1-receptor mediated immune response. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2013; 8(2):e57815.
Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.
- Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. [Journal Article]
- Toxicol Sci 2013 May; 133(1):22-8.
Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general.
- Hydralazine in infants with persistent hypoxemic respiratory failure. [Journal Article, Research Support, N.I.H., Extramural, Review]
- Cochrane Database Syst Rev 2013.:CD009449.
Most deaths of infants with chronic lung disease (CLD) are caused by respiratory failure, unremitting pulmonary artery hypertension (PAH) with cor pulmonale, or infection. Although the exact prevalence of PAH in infants with CLD is unknown, infants with CLD and severe PAH have a high mortality rate. Except for oxygen supplementation, no specific interventions have been established as effective in the treatment for PAH in premature infants with CLD. Little has been proven regarding the clinical efficacy of vasodilators and concerns remain regarding adverse effects.To review current evidence for the benefits and harms of hydralazine therapy to infants with persistent hypoxemic respiratory failure.We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE via PubMed and EMBASE, and other clinical trials registries through November 2011 using the standard search strategy of the Cochrane Neonatal Review Group. We searched these databases using a strategy combining a variation of the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE; sensitivity-maximising version with selected MeSH and free-text terms: hydralazine, vasodilator agent, antihypertensive agent, heart diseases, lung diseases, respiratory tract diseases, infant, and randomised controlled trial.We considered only randomised controlled trials and quasi-randomised trials for inclusion. We included low birth weight (LBW) infants with persistent hypoxemic respiratory failure who were treated with any type of hydralazine therapy.Two review authors independently assessed trial quality according to pre-specified criteria.We found no studies meeting the criteria for inclusion in this review.There was insufficient evidence to determine the safety and efficacy of hydralazine in LBW infants with persistent hypoxemic respiratory failure. Since hydralazine is inexpensive and potentially beneficial, randomised controlled trials are recommended. Such trials are particularly needed in settings where other medications such as sildenafil, inhaled nitric oxide (iNO), or extracorporeal membrane oxygenation (ECMO) are not available.