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1.
Clin Sci (Lond) ; 138(14): 901-920, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38949825

RESUMO

We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.


Assuntos
Pressão Sanguínea , Hipertensão , Inflamação , Rim , Camundongos Endogâmicos C57BL , Cloreto de Sódio na Dieta , Animais , Hipertensão/imunologia , Hipertensão/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Masculino , Feminino , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Rim/imunologia , Rim/efeitos dos fármacos , Inflamação/imunologia , Linfangiogênese/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Camundongos , Hidralazina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Modelos Animais de Doenças , Gônadas/efeitos dos fármacos
2.
Hypertens Res ; 47(8): 2133-2143, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38802501

RESUMO

Mineralocorticoid receptor (MR) is involved in the mechanisms of blood pressure elevation, organ fibrosis, and inflammation. MR antagonists have been used in patients with hypertension, heart failure, or chronic kidney disease. Esaxerenone, a recently approved MR blocker with a nonsteroidal structure, has demonstrated a strong blood pressure-lowering effect. However, blood pressure reduction may lead to sympathetic activation through the baroreflex. The effect of esaxerenone on the sympathetic nervous system remains unclear. We investigated the effect of esaxerenone on organ damage and the sympathetic nervous system in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP), a well-established model of essential hypertension with sympathoexcitation and organ damage. Three-week administration of esaxerenone or hydralazine successfully attenuated the blood pressure elevation. Both esaxerenone and hydralazine comparably suppressed left ventricular hypertrophy and urinary albumin excretion. However, renal fibrosis and glomerular sclerosis were suppressed by esaxerenone but not hydralazine. Furthermore, plasma norepinephrine level, a parameter of systemic sympathetic activity, was significantly increased by hydralazine but not by esaxerenone. Consistent with these findings, the activity of the control centers of sympathetic nervous system, the parvocellular region of the paraventricular nucleus in the hypothalamus and the rostral ventrolateral medulla, was enhanced by hydralazine but remained unaffected by esaxerenone. These results suggest that esaxerenone effectively lowers blood pressure without inducing reflex sympathetic nervous system activation. Moreover, the organ-protective effects of esaxerenone appear to be partially independent of its blood pressure-lowering effect. In conclusion, esaxerenone demonstrates a blood pressure-lowering effect without concurrent sympathetic activation and exerts organ-protective effects in salt-loaded SHRSP. Esaxerenone has antihypertensive and cardiorenal protective effects without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats.


Assuntos
Pressão Sanguínea , Hidralazina , Hipertensão , Rim , Ratos Endogâmicos SHR , Sistema Nervoso Simpático , Animais , Pressão Sanguínea/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Masculino , Ratos , Rim/efeitos dos fármacos , Rim/inervação , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hidralazina/farmacologia , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Cloreto de Sódio na Dieta , Barorreflexo/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis , Sulfonas
3.
Chem Res Toxicol ; 37(6): 1023-1034, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38743824

RESUMO

The clinically used antihypertensive agent hydralazine rapidly generates hydrazone-derived adducts by reaction with apurinic/apyrimidinic (also known as abasic or AP) sites in many different sequences of duplex DNA. The reaction rates are comparable to those of some AP-trapping reagents previously described as "ultrafast." Initially, reversible formation of a hydrazone adduct is followed by an oxidative cyclization reaction that generates a chemically stable triazolo[3,4-a]phthalazine adduct. The net result is that the reaction of hydralazine with AP sites in duplex DNA yields a rapid and irreversible adduct formation. Although the hydrazone and triazolo[3,4-a]phthalazine adducts differ by only two mass units, it was possible to use MALDI-TOF-MS and ESI-QTOF-nanospray-MS to quantitatively characterize mixtures of these adducts by deconvolution of overlapping isotope envelopes. Reactions of hydralazine with the endogenous ketone pyruvate do not prevent the formation of the hydralazine-AP adducts, providing further evidence that these adducts have the potential to form in cellular DNA. AP sites are ubiquitous in cellular DNA, and rapid, irreversible adduct formation by hydralazine could be relevant to the pathogenesis of systemic drug-induced lupus erythematosus experienced by some patients. Finally, hydralazine might be developed as a probe for the detection of AP sites, the study of cellular BER, and marking the location of AP sites in DNA-sequencing analyses.


Assuntos
Adutos de DNA , DNA , Hidralazina , Ftalazinas , Hidralazina/química , DNA/química , DNA/efeitos dos fármacos , Adutos de DNA/química , Ftalazinas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Anti-Hipertensivos/química , Triazóis/química , Espectrometria de Massas por Ionização por Electrospray
4.
Biochem Biophys Res Commun ; 722: 150147, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38788356

RESUMO

We used an animal model of salt-sensitive hypertension (SSH) in which ovariectomized (oVx) rats developed hypertension with high salt (HS) intake. Hypertension is accompanied by changes in the percentage of CD4+ T lymphocytes, immune CD45+ cell infiltration into renal tissue, and changes in Na+, K+- ATPase (NKA) expression in both renal tissue and peripheral blood mononuclear cells (PBMCs). To determine whether the observed changes resulted from HS intake, high blood pressure, or both, hydralazine (HDZ) was used to lower blood pressure. The oVx HS rats received two HDZ schedules either to prevent or to treat hypertension. NKA was overexpressed in the kidneys of all oVx groups and in PBMCs of oVx HS rats. This pattern was not altered with HDZ treatment. Changes in CD4+ T lymphocytes and renal infiltration of CD45+ cells were not reversed either. High salt, but not high blood pressure, induces immune cell activation and renal infiltration. Overexpressed NKA is the primary event, and HS is the perturbation to the system in this model of SSH, which resembles the postmenopausal state.


Assuntos
Hipertensão , Rim , Ovariectomia , Ratos Wistar , Animais , Feminino , Ratos , Rim/patologia , Rim/metabolismo , Rim/imunologia , Hipertensão/imunologia , Hipertensão/patologia , Hipertensão/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Hidralazina/farmacologia
5.
Ultrastruct Pathol ; 48(4): 317-322, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38685716

RESUMO

CONTEXT: IgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine. DESIGN: Seven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail. RESULTS: Patients' ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases. CONCLUSION: The hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.


Assuntos
Hidralazina , Imunoglobulina M , Humanos , Pessoa de Meia-Idade , Feminino , Hidralazina/efeitos adversos , Masculino , Idoso de 80 Anos ou mais , Idoso , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Glomerulonefrite Membranoproliferativa/induzido quimicamente , Anti-Hipertensivos/efeitos adversos , Glomerulonefrite/imunologia , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Complexo Antígeno-Anticorpo
6.
J Nanobiotechnology ; 22(1): 193, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643134

RESUMO

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.


Assuntos
Neoplasias , Piroptose , Humanos , Piroptose/fisiologia , Microbolhas , Neoplasias/tratamento farmacológico , Apoptose , Hidralazina/farmacologia , Hidralazina/uso terapêutico
7.
Biomed Pharmacother ; 174: 116504, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38552442

RESUMO

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.


Assuntos
Alendronato , Inibidores da Aromatase , Hidralazina , Síndrome do Ovário Policístico , Animais , Feminino , Ratos , Alendronato/farmacologia , Inibidores da Aromatase/farmacologia , Modelos Animais de Doenças , Estradiol/sangue , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Letrozol , Hormônio Luteinizante/sangue , Ovário/efeitos dos fármacos , Ovário/patologia , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos Wistar , Testosterona/sangue
8.
Int J Mol Sci ; 25(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38542088

RESUMO

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include ß-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.


Assuntos
Insuficiência Cardíaca , Ureia/análogos & derivados , Humanos , Volume Sistólico , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Dinitrato de Isossorbida/farmacologia , Dinitrato de Isossorbida/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Estudos Multicêntricos como Assunto
9.
Hypertens Res ; 47(4): 1017-1023, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38337004

RESUMO

Increased blood pressure variability (BPV) was shown to be associated with cardiovascular morbidities and/or mortalities. There are various types of BPV depending on time intervals of BP measurements, ranging from beat-to-beat to visit-to-visit or year-to-year. We previously found that continuous infusion of noradrenaline (NA) for 14 days increased short-term BPV every 15 min in rats. The aims of this study were to examine (1) whether NA infusion increases very short-term beat-to-beat BPV, (2) the effects of azelnidipine and hydralazine on NA-induced BPV, and (3) whether baroreceptor reflex sensitivity (BRS) is affected by NA or NA plus those vasodilators. Nine-week-old Wistar rats infused subcutaneously with 30 µg/h NA were orally treated with or without 9.7 mg/day azelnidipine or 5.9 mg/day hydralazine over 14 days. BP levels were continuously monitored via abdominal aortic catheter with a telemetry system in an unrestrained condition. Standard deviations (SDs) were used to evaluate beat-to-beat BPV and BPV every 15 min which was obtained by averaging BP levels for 10-s segment at each time point. BRS was determined by a sequence analysis. Continuous NA infusion over 14 days increased average BP, beat-to-beat BPV, and BPV every 15 min, lowering BRS. Comparing the two vasodilators, hydralazine reduced BP elevation by NA; meanwhile, azelnidipine alleviated BPV augmentation, preserving BRS, despite a smaller BP reduction. Thus, NA infusion increased both very short- and short-term BPV concomitantly with impaired BRS, while azelnidipine had an inhibitory effect, possibly independent of BP-lowering, on those types of BPV and impairment of BRS.


Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas , Norepinefrina , Vasodilatadores , Ratos , Animais , Pressão Sanguínea , Vasodilatadores/farmacologia , Norepinefrina/farmacologia , Ratos Wistar , Hidralazina/farmacologia
10.
ESC Heart Fail ; 11(1): 198-208, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37897153

RESUMO

AIMS: Patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) accompanied by significant mitral regurgitation (MR) had poor outcome. Several vasodilator trials showed neutral results. We aimed to investigate the effect of early up-titration of hydralazine combined with conventional treatment in acute HF with severe systolic dysfunction and significant MR. METHODS AND RESULTS: The study was open-labelled, one-to-one ratio randomized designed. Consecutively hospitalized patients with decompensated HF symptoms, LVEF < 35%, and MR more than moderate severity were enrolled after exclusion. All participants with inadequate preload should have intake promotion with/without fluid supply. Patients receiving evidence-based medications (EBMs) as conventional treatment served as the control. Hydralazine + conventional treatment group received up-titration of hydralazine at Days 1-5 of the index admission combined with EBMs and throughout the course of follow-up. The endpoints included cardiovascular (CV) death and HF rehospitalization. Totally, 408 patients were enrolled (203 in conventional treatment and 205 in hydralazine + conventional treatment). The mean follow-up period was 3.5 years. The mean dose of hydralazine was 191 mg at index admission and 264 mg at study end in hydralazine + conventional treatment group. Both groups did not significantly differ in prescription rates and dosages of EBMs (all P > 0.05) at study end. Side effects did not differ between the two groups. Finally, 51% (104 out of 203 cases) reached endpoints in conventional group and 34.6% (71 out of 205 cases) in hydralazine + conventional treatment group, which had a significant reduction in CV events (hazard ratio 0.613, 95% confidence interval 0.427-0.877, P < 0.001). In-hospital death during the index admission was significantly higher in conventional group (5.4% vs. 0.5%, respectively; P = 0.001). CONCLUSIONS: When administered without inadequate preload, combining early up-titration of hydralazine with EBMs improves outcome in patients with severe systolic dysfunction and significant MR, and it is safe and well tolerated.


Assuntos
Insuficiência Cardíaca , Insuficiência da Valva Mitral , Humanos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Mortalidade Hospitalar , Hidralazina/uso terapêutico , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/tratamento farmacológico , Volume Sistólico , Função Ventricular Esquerda
11.
Am J Respir Crit Care Med ; 209(2): 206-218, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37934691

RESUMO

Rationale: Unraveling immune-driven vascular pathology in pulmonary arterial hypertension (PAH) requires a comprehensive understanding of the immune cell landscape. Although patients with hereditary (H)PAH and bone morphogenetic protein receptor type 2 (BMPR2) mutations have more severe pulmonary vascular pathology, it is not known whether this is related to specific immune cell subsets. Objectives: This study aims to elucidate immune-driven vascular pathology by identifying immune cell subtypes linked to severity of pulmonary arterial lesions in PAH. Methods: We used cutting-edge multiplexed ion beam imaging by time of flight to compare pulmonary arteries (PAs) and adjacent tissue in PAH lungs (idiopathic [I]PAH and HPAH) with unused donor lungs, as controls. Measurements and Main Results: We quantified immune cells' proximity and abundance, focusing on those features linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells. Distinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In patients with HPAH, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving T cell immunoglobulin and mucin domain-3 (TIM-3)+ T cells. This correlated with an expanded DC subset expressing indoleamine 2,3-dioxygenase 1, TIM-3, and SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1, alongside increased neutrophils, SMCs, and alpha-smooth muscle actin (ACTA2)+ endothelial cells, reinforcing the heightened severity of pulmonary vascular lesions. Conclusions: This study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared with IPAH. Our findings emphasize the therapeutic potential of targeting monocyte-derived dendritic cells, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.


Assuntos
Hidralazina/análogos & derivados , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Células Endoteliais/metabolismo , Hipertensão Pulmonar Primária Familiar/genética , Artéria Pulmonar , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proliferação de Células , Hidrazonas
12.
J Biochem Mol Toxicol ; 38(1): e23583, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37986032

RESUMO

Hypoxia-induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti-inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa-B (NF-κB) signalling. Matrine, sildenafil and NF-κB inhibitor Bay 11-7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl-2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α-smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor-α and interleuki-1ß, thus improved hypoxia-induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH.


Assuntos
Hidralazina/análogos & derivados , Hipertensão Pulmonar , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Matrinas , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Remodelação Vascular , Proliferação de Células , Hipóxia/complicações , Hipóxia/metabolismo , Inflamação/metabolismo , Miócitos de Músculo Liso/metabolismo , Hidrazonas
13.
Can J Cardiol ; 40(4): 613-621, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37944814

RESUMO

BACKGROUND: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy. METHODS: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy. RESULTS: Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes. CONCLUSIONS: Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.


Assuntos
Epoprostenol/análogos & derivados , Hidralazina/análogos & derivados , Hipertensão Pulmonar , Humanos , Criança , Feminino , Pré-Escolar , Masculino , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar/genética , Epoprostenol/uso terapêutico , Epoprostenol/efeitos adversos , Estudos Retrospectivos , Receptores de Activinas Tipo II/uso terapêutico , Hidrazonas
14.
Obstet Gynecol ; 143(2): 277-280, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38033320

RESUMO

We aimed to evaluate physiologic treatment of severe hypertension. This was a retrospective cohort study of pregnant and postpartum patients with severe hypertension (systolic blood pressure [BP] 160 mm Hg or higher or diastolic BP 110 mm Hg or higher) treated with intravenous labetalol or hydralazine at a single tertiary care center between 2013 and 2018. Patients were classified as having physiologic treatment if they had hyperdynamic physiology (pulse pressure 65 mm Hg or higher) and received labetalol or had vasoconstrictive physiology (diastolic BP 100 mm Hg or higher) and received hydralazine. The primary outcome was number of antihypertensive doses to achieve nonsevere BP. Of 1,120 patients included in the analysis, 653 had physiologic treatment and 467 had nonphysiologic treatment, with 16 (1.4%) excluded for inability to classify physiology. Physiologic treatment was associated with fewer antihypertensive doses (1.4±0.9 doses vs 1.6±1.4 doses; adjusted ß -0.28, 95% CI, -0.42 to -0.14) and lower odds of medication conversion (2.5% vs 4.7%; adjusted odds ratio 0.48, 95% CI, 0.24-0.93) but no difference in time to nonsevere BP (31 minutes [interquartile range 16-66 minutes] vs 34 minutes [interquartile range 15-76 minutes]; adjusted hazard ratio 1.0, 95% CI, 0.9-1.2). Physiologic treatment of severe hypertension warrants further evaluation.


Assuntos
Hipertensão , Labetalol , Feminino , Humanos , Gravidez , Anti-Hipertensivos , Pressão Sanguínea , Hidralazina/efeitos adversos , Hipertensão/tratamento farmacológico , Nifedipino/uso terapêutico , Período Pós-Parto , Estudos Retrospectivos , Hipertensão Induzida pela Gravidez
15.
Calcif Tissue Int ; 114(3): 295-309, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38102510

RESUMO

Vascular dysfunction contributes to the development of osteopenia in hypertensive patients, as decreased blood supply to bones results in tissue damage and dysfunction. The effect of anti-hypertensive medicines on bone mass in hypertensive individuals is inconclusive because of the varied mechanism of their action, and suggests that reducing blood pressure (BP) alone is insufficient to enhance bone mass in hypertension. Pentoxifylline (PTX), a hemorheological drug, improves blood flow by reducing blood viscosity and angiogenesis, also has an osteogenic effect. We hypothesized that improving vascular function is critical to increasing bone mass in hypertension. To test this, we screened various anti-hypertensive drugs for their in vitro osteogenic effect, from which timolol and hydralazine were selected. In adult female spontaneously hypertensive rats (SHRs), timolol and hydralazine did not improve vascular function and bone mass, but PTX improved both. In female SHR animals, PTX restored bone mass, strength and mineralization, up to the level of normotensive control rats. In addition, we observed lower blood vasculature in the femur of adult SHR animals, and PTX restored them. PTX also restored the bone vascular and angiogenesis parameters that had been impaired in OVX SHR compared to sham SHR. This study demonstrates the importance of vascular function in addition to increased bone mass for improving bone health as achieved by PTX without affecting BP, and suggests a promising treatment option for osteoporosis in hypertensive patients, particularly at-risk postmenopausal women.


Assuntos
Hipertensão , Pentoxifilina , Humanos , Ratos , Feminino , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Densidade Óssea , Timolol/farmacologia , Timolol/uso terapêutico , Hipertensão/tratamento farmacológico , Ratos Endogâmicos SHR , Pentoxifilina/farmacologia , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Pressão Sanguínea
16.
PLoS One ; 18(12): e0293497, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38127996

RESUMO

BACKGROUND: To curb the growing impact of drug shortages, Health Canada developed the Tiered Notification and Communication Framework which assigns potential shortages a corresponding tiered status. Tier-3 is assigned to shortages with the greatest potential impact on the healthcare system. This study aims to describe drug purchasing trends in response to Tier-3 shortages using three case-examples. METHODS: We conducted a time-series analysis of monthly purchasing data for three out of 17 Tier-3 drug shortages (hydralazine, sarilumab, and medroxyprogesterone acetate) with publicly available reports in July 2021 and available IQVIA MIDAS data from January 2016 to December 2021. We assessed percent changes in purchasing at 1-, 3-, and 6-months after the onset of each Tier-3 drug shortage and interventional ARIMA modelling was used to assess the statistical significance. RESULTS: Medroxyprogesterone acetate experienced a significant shift (p = 0.0370) in purchasing following its shortage, and the 1-, 3-, and 6-month percent changes were +14.9%, +6.8% and -3.1%, respectively. Hydralazine and sarilumab did not show a significant shift. The 1-, 3-, and 6-month percent changes for hydralazine were +15.5%, +10.2%, and +9.6% respectively and +25.2%, +45.1% and +39.2 for sarilumab. CONCLUSIONS: These results indicate that drugs assigned a Tier-3 status may not show declines in purchasing in the months following status assignment, which may be due to policy responses following the assignment. However, more insight is needed into the mechanisms through which these policy measures impact shortages and whether they are functioning as intended.


Assuntos
Atenção à Saúde , Acetato de Medroxiprogesterona , Estudos Transversais , Canadá , Hidralazina
17.
Lupus Sci Med ; 10(2)2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37989321

RESUMO

OBJECTIVE: In this study, we investigated the in vivo ameliorative effects of vitamin E in a hydralazine-induced lupus model, which closely resembles SLE in humans. We aim to shed light on its potential as a therapeutic agent for managing SLE. METHODS: Forty BALB/c mice were used in this study. Hydralazine hydrochloride was orally administered in a concentration of 25 mg/kg to the five mice groups once weekly for a period of 5 weeks to induce a lupus-like condition. The untreated group was the normal control group. To confirm the development of lupus, an ANA test was conducted. After the mice tested positive for ANA, drug treatments commenced. The negative control group did not receive any drug treatment. The treatments included prednisolone, methotrexate and vitamin E, all administered at a concentration of 25 mg/kg, with a higher dose of vitamin E (50 mg/kg) also administered. RESULTS: Notably, on day 35, after drug treatment, we observed that mice that received vitamin E at a dosage of 50 mg/kg (3.01±0.100) had a slight decrease in lymphocyte hydrogen peroxide radicals when compared with the group receiving 25 mg/kg of vitamin E (3.30±0.100) (p<0.05). This finding suggests that the scavenging potential of vitamin E is dose dependent. CONCLUSION: This study suggests that vitamin E supplementation, especially at a higher dose (50 mg/kg), holds promise in ameliorating lupus-like conditions. These findings warrant further exploration and may offer a potential avenue for improving the disease status of patients experiencing SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Vitamina E , Humanos , Animais , Camundongos , Vitamina E/farmacologia , Vitamina E/uso terapêutico , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Hidralazina/farmacologia , Hidralazina/uso terapêutico
18.
Pregnancy Hypertens ; 34: 74-82, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37857042

RESUMO

BACKGROUND: Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. OBJECTIVE: To compare treatment success with antihypertensives and categorize by route of administration. SEARCH STRATEGY: MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction. DATA COLLECTION: Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO). ANALYSIS: Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions. RESULTS: Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49). CONCLUSION: Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.


Assuntos
Hipertensão , Pré-Eclâmpsia , Feminino , Humanos , Recém-Nascido , Gravidez , Anti-Hipertensivos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hidralazina/uso terapêutico , Hipertensão/tratamento farmacológico , Ketanserina/uso terapêutico , Metildopa , Metanálise em Rede , Nifedipino/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Afr Health Sci ; 23(1): 320-325, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37545898

RESUMO

Objectives: To compare the efficacy of intravenous Labetalol and intravenous Hydralazine in reduction of blood pressure in patients with severe pre-eclampsia. Methodology: This comparative study was conducted at the Department of Obstetrics and Gynecology at Ziauddin University Hospital, Karachi from1st June 2019 to 30th June 2020. Total 208 pregnant women having severe pre-eclampsia (systolic pressure ≥160 mmHg and diastolic pressure ≥110mmHg) were included in study. Group A received I/V Labetalol. Group B received I/V Hydralazine. Efficacy of drugs was observed by reduction in blood pressure and the number of doses administered. Data was analysed using SPSS version 26. Results: Systolic blood pressure reduction in Labetalol group was significantly lower than in hydralazine group (105.5 ±11.3 vs. 115.8 ±17.1, p≤ 0.001). Diastolic blood pressure reduction was also lower in labetalol group than in hydralazine group (p= 0.03). Number of dosage of drugs in Group A (Labetalol) was 3.2 ±1.2 vs. Group B (Hydralazine) was 4.4±1.4, p =0.006). Conclusion: The results of this study show that Labetalol is more effective as compared to Hydralazine in terms of reducing the systolic and diastolic blood pressure and number of doses (Drugs) for in patients with severe preeclampsia.


Assuntos
Hipertensão , Hipotensão , Labetalol , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Labetalol/efeitos adversos , Pré-Eclâmpsia/tratamento farmacológico , Anti-Hipertensivos , Gestantes , Hidralazina/uso terapêutico , Hidralazina/efeitos adversos , Pressão Sanguínea , Hipotensão/induzido quimicamente , Hipertensão/tratamento farmacológico
20.
Curr Med Sci ; 43(4): 749-758, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37558864

RESUMO

OBJECTIVE: This study aims to investigate the effects of hydralazine on inflammation induced by spinal cord injury (SCI) in the central nervous system (CNS) and its mechanism in promoting the structural and functional recovery of the injured CNS. METHODS: A compressive SCI mouse model was utilized for this investigation. Immunofluorescence and quantitative real-time polymerase chain reaction were employed to examine the levels of acrolein, acrolein-induced inflammation-related factors, and macrophages at the injury site and within the CNS. Western blotting was used to evaluate the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway to study macrophage regulation. The neuropathic pain and motor function recovery were evaluated by glutamic acid decarboxylase 65/67 (GAD65/67), vesicular glutamate transporter 1 (VGLUT1), paw withdrawal response, and Basso Mouse Scale score. Nissl staining and Luxol Fast Blue (LFB) staining were performed to investigate the structural recovery of the injured CNS. RESULTS: Hydralazine downregulated the levels of acrolein, IL-1ß, and TNF-α in the spinal cord. The downregulation of acrolein induced by hydralazine promoted the activation of the PI3K/AKT pathway, leading to M2 macrophage polarization, which protected neurons against SCI-induced inflammation. Additionally, hydralazine promoted the structural recovery of the injured spinal cord area. Mitigating inflammation and oxidative stress by hydralazine in the animal model alleviated neuropathic pain and altered neurotransmitter expression. Furthermore, hydralazine facilitated motor function recovery following SCI. Nissl staining and LFB staining indicated that hydralazine promoted the structural recovery of the injured CNS. CONCLUSION: Hydralazine, an acrolein scavenger, significantly mitigated SCI-induced inflammation and oxidative stress in vivo, modulated macrophage activation, and consequently promoted the structural and functional recovery of the injured CNS.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Ratos , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Acroleína/metabolismo , Acroleína/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Hidralazina/farmacologia , Neuralgia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse Oxidativo , Macrófagos/metabolismo
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