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1.
Euro Surveill ; 28(16)2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37078882

RESUMO

BackgroundDuring the COVID-19 pandemic, international shipping activity was disrupted as movement of people and goods was restricted. The Port of Rotterdam, the largest port in Europe, remained operational throughout.AimWe describe the burden of COVID-19 among crew on sea-going vessels at the port and recommend improvements in future infectious disease event notification and response at commercial ports.MethodsSuspected COVID-19 cases on sea-going vessels were notified to port authorities and public health (PH) authorities pre-arrival via the Maritime Declaration of Health. We linked data from port and PH information systems between 1 January 2020 and 31 July 2021, derived a notification rate (NR) of COVID-19 events per arrival, and an attack rate (AR) per vessel (confirmed cases). We compared AR by vessel type (workship/tanker/cargo/passenger), during wildtype-, alpha- and delta-dominant calendar periods.ResultsEighty-four COVID-19 events were notified on ships, involving 622 cases. The NR among 45,030 new arrivals was 173 per 100,000 impacting 1% of vessels. Events per week peaked in April 2021 and again in July 2021, when the AR was also highest. Half of all cases were notified on workships, events occurring earlier and more frequently than on other vessels.ConclusionNotification of COVID-19 events on ships occurred infrequently, although case under-ascertainment was likely. Pre-agreed protocols for data-sharing between stakeholders locally and across Europe would facilitate more efficient pandemic response. Public health access to specimens for sequencing and environmental sampling would give greater insight into viral spread on ships.


Assuntos
COVID-19 , Navios , Humanos , Países Baixos/epidemiologia , Pandemias , COVID-19/epidemiologia , Surtos de Doenças , Notificação de Doenças
2.
Clin Sci (Lond) ; 136(9): 675-694, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35441670

RESUMO

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.


Assuntos
Hipertensão , Pré-Eclâmpsia , Inibidores da Angiogênese/uso terapêutico , Animais , Aspirina/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Endotelina-1/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Rim/metabolismo , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Gravidez , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Pharmacol Exp Ther ; 378(2): 173-183, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34099502

RESUMO

Diminished nitric oxide-cGMP-mediated relaxation plays a crucial role in cardiovascular aging, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately, cardiovascular dysfunction. Aging is the time-related worsening of physiologic function due to complex cellular and molecular interactions, and it is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in Ercc1Δ/- mice provides us an efficient tool to accelerate vascular aging, explore mechanisms, and test potential treatments. Previously, we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular aging. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular aging features in Ercc1Δ/- mice. Compared with wild-type mice, Ercc1Δ/- mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in Ercc1Δ/- mice. An 8-week treatment with 100 mg/kg per day ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in Ercc1Δ/- mice. These findings suggest phosphodiesterase 1 inhibition would provide a powerful tool for nitric oxide-cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to aging. SIGNIFICANCE STATEMENT: The findings implicate the key role of phosphodiesterase 1 in vascular function and might be of clinical importance for the prevention of mortalities and morbidities related to vascular complications during aging, as well as for patients with progeria that show a high risk of cardiovascular disease.


Assuntos
Diester Fosfórico Hidrolases , Animais , Endotélio Vascular , Camundongos
4.
Clin Sci (Lond) ; 134(7): 727-746, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32202295

RESUMO

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/deficiência , Endonucleases/deficiência , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Permeabilidade Capilar , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Células Endoteliais/patologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Superóxidos/metabolismo , Rigidez Vascular , Vasodilatação
5.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32630010

RESUMO

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.


Assuntos
Envelhecimento/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Sistema Vasomotor/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Feminino , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais , Vasoconstrição/efeitos dos fármacos
6.
J Headache Pain ; 20(1): 47, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053059

RESUMO

BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action. METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model. RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 µM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses. CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.


Assuntos
Vasos Coronários/efeitos dos fármacos , Artérias Meníngeas/efeitos dos fármacos , Metilaminas/farmacologia , Transtornos de Enxaqueca , Veia Safena/efeitos dos fármacos , Adulto , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Artérias Meníngeas/fisiologia , Metilaminas/química , Metilaminas/uso terapêutico , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Veia Safena/fisiologia , Estereoisomerismo , Vasoconstritores/química , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/química , Vasodilatadores/farmacologia
7.
J Headache Pain ; 19(1): 41, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802484

RESUMO

BACKGROUND: Migraine is considered a neurovascular disorder, but its pathophysiological mechanisms are not yet fully understood. Adenosine has been shown to increase in plasma during migraine attacks and to induce vasodilation in several blood vessels; however, it remains unknown whether adenosine can interact with the trigeminovascular system. Moreover, caffeine, a non-selective adenosine receptor antagonist, is included in many over the counter anti-headache/migraine treatments. METHODS: This study used the rat closed cranial window method to investigate in vivo the effects of the adenosine A2A receptor antagonists with varying selectivity over A1 receptors; JNJ-39928122, JNJ-40529749, JNJ-41942914, JNJ-40064440 or JNJ-41501798 (0.3-10 mg/kg) on the vasodilation of the middle meningeal artery produced by either CGS21680 (an adenosine A2A receptor agonist) or endogenous CGRP (released by periarterial electrical stimulation). RESULTS: Regarding the dural meningeal vasodilation produced neurogenically or pharmacologically, all JNJ antagonists: (i) did not affect neurogenic vasodilation but (ii) blocked the vasodilation produced by CGS21680, with a blocking potency directly related to their additional affinity for the adenosine A1 receptor. CONCLUSIONS: These results suggest that vascular adenosine A2A (and, to a certain extent, also A1) receptors mediate the CGS21680-induced meningeal vasodilation. These receptors do not appear to modulate prejunctionally the sensory release of CGRP. Prevention of meningeal arterial dilation might be predictive for anti-migraine drugs, and since none of these JNJ antagonists modified per se blood pressure, selective A2A receptor antagonism may offer a novel approach to antimigraine therapy which remains to be investigated in clinical trials.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/análogos & derivados , Artérias Meníngeas/efeitos dos fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Fenetilaminas/farmacologia , Vasodilatação/efeitos dos fármacos , Adenosina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Transtornos de Enxaqueca/fisiopatologia , Ratos , Ratos Sprague-Dawley
8.
Clin Sci (Lond) ; 130(14): 1209-20, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27129187

RESUMO

ARNI [dual AT1 (angiotensin II type 1) receptor-neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Pressão Sanguínea/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Neprilisina/antagonistas & inibidores , Aminobutiratos/uso terapêutico , Animais , Fator Natriurético Atrial/sangue , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Ratos , Ratos Sprague-Dawley , Estreptozocina , Tetrazóis/uso terapêutico , Valsartana
9.
Kidney Int ; 88(1): 109-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25830765

RESUMO

Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Compostos de Bifenilo/farmacologia , Rim/metabolismo , Miocárdio/patologia , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia , Tiorfano/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Fator Natriurético Atrial/metabolismo , Peso Corporal , Antagonistas do Receptor de Endotelina B/farmacologia , Endotelina-1/sangue , Irbesartana , Rim/patologia , Miócitos Cardíacos/patologia , Oligopeptídeos/farmacologia , Tamanho do Órgão , Piperidinas/farmacologia , Inibidores de Proteases/administração & dosagem , Ratos , Receptor de Endotelina B/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Tiorfano/administração & dosagem , Regulação para Cima , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
10.
Clin Sci (Lond) ; 129(12): 1061-75, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26464516

RESUMO

Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; ß=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; ß=-0.0061, P=2.89×10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.


Assuntos
Envelhecimento/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Vasodilatação , Envelhecimento/genética , Animais , Pressão Sanguínea , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Células Cultivadas , Senescência Celular , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Endonucleases/deficiência , Endonucleases/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hidrólise , Hiperplasia , Hipertensão/enzimologia , Hipertensão/genética , Hipertensão/fisiopatologia , Técnicas In Vitro , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Fenótipo , Inibidores da Fosfodiesterase 5/farmacologia , Polimorfismo de Nucleotídeo Único , Sistemas do Segundo Mensageiro , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
11.
Cephalalgia ; 35(2): 182-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25078720

RESUMO

BACKGROUND: Dihydroergotamine (DHE) and sumatriptan are contraindicated in patients with cardiovascular disease because of their vasoconstricting properties, which have originally been explored in proximal coronary arteries. Our aim was to investigate DHE and sumatriptan in the proximal and distal coronary artery, middle meningeal artery and saphenous vein. METHODS: Blood vessel segments were mounted in organ baths and concentration response curves for DHE and sumatriptan were constructed. RESULTS: In the proximal coronary artery, meningeal artery and saphenous vein, maximal contractions to DHE (proximal: 8 ± 4%; meningeal: 32 ± 7%; saphenous: 52 ± 11%) and sumatriptan (proximal: 17 ± 7%; meningeal: 61 ± 18%, saphenous: 37 ± 8%) were not significantly different. In the distal coronary artery, contractions to DHE (5 ± 2%) were significantly smaller than those to sumatriptan (17 ± 9%). At clinically relevant concentrations, mean contractions to DHE and sumatriptan were below 3% in proximal coronary arteries and below 6% in distal coronary arteries. Contractions in the meningeal artery and saphenous vein were higher (7%-38%). CONCLUSIONS: Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.


Assuntos
Vasos Coronários/efeitos dos fármacos , Di-Hidroergotamina/farmacologia , Artérias Meníngeas/efeitos dos fármacos , Veia Safena/efeitos dos fármacos , Sumatriptana/farmacologia , Vasoconstritores/farmacologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Vasoconstrição/efeitos dos fármacos , Adulto Jovem
12.
Eur J Pharmacol ; 962: 176199, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38029870

RESUMO

BACKGROUND: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. METHODS: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 µg/kg/day) for 8 days (n = 8-9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. RESULTS: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. CONCLUSION: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.


Assuntos
Albuminúria , Hipertensão , Animais , Masculino , Ratos , Albuminúria/induzido quimicamente , Albuminúria/prevenção & controle , Albuminúria/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Aspirina/uso terapêutico , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Iloprosta/farmacologia , Ratos Endogâmicos WKY , Sunitinibe/farmacologia
13.
Br J Pharmacol ; 181(15): 2478-2491, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38583945

RESUMO

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) is a potent vasodilator. While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP-induced relaxation of human isolated coronary arteries (HCA). EXPERIMENTAL APPROACH: HCA were obtained from heart valve donors (27 M, 25 F, age 54 ± 2 years). Concentration-response curves to human α-CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation. RESULTS: Adenylyl cyclase (AC) inhibitors SQ22536 + DDA and MDL-12330A, and PKA inhibitors Rp-8-Br-cAMPs and H89, did not inhibit CGRP-induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1/2 inhibitor ESI09, potassium channel blockers TRAM-34 + apamin, iberiotoxin or glibenclamide, or the Gαq inhibitor YM-254890. Phosphodiesterase inhibitors induced a concentration-dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of Gßγ subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries. CONCLUSION: While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gßγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Vasos Coronários , AMP Cíclico , Subunidades beta da Proteína de Ligação ao GTP , Subunidades gama da Proteína de Ligação ao GTP , Vasodilatação , Humanos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Masculino , Pessoa de Meia-Idade , AMP Cíclico/metabolismo , Vasodilatação/efeitos dos fármacos , Feminino , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Transdução de Sinais/efeitos dos fármacos , Técnicas In Vitro , Vasodilatadores/farmacologia
14.
Circulation ; 126(4): 468-78, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22705887

RESUMO

BACKGROUND: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. METHODS AND RESULTS: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. CONCLUSIONS: Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.


Assuntos
Envelhecimento/fisiologia , Senescência Celular/fisiologia , Reparo do DNA/fisiologia , Endotélio Vascular/fisiopatologia , Instabilidade Genômica/fisiologia , Rigidez Vascular/fisiologia , Animais , Pressão Sanguínea/fisiologia , Artérias Carótidas/fisiopatologia , Células Cultivadas , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Endotélio Vascular/patologia , Artéria Femoral/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Modelos Animais , Polimorfismo de Nucleotídeo Único/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética
15.
Biochim Biophys Acta ; 1813(2): 346-57, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21145921

RESUMO

Decreasing the temperature to 30°C is accompanied by significant enhancement of α(2C)-AR plasma membrane levels in several cell lines with fibroblast phenotype, as demonstrated by radioligand binding in intact cells. No changes were observed on the effects of low-temperature after blocking receptor internalization in α(2C)-AR transfected HEK293T cells. In contrast, two pharmacological chaperones, dimethyl sulfoxide and glycerol, increased the cell surface receptor levels at 37°C, but not at 30°C. Further, at 37°C α(2C)-AR is co-localized with endoplasmic reticulum markers, but not with the lysosomal markers. Treatment with three distinct HSP90 inhibitors, radicicol, macbecin and 17-DMAG significantly enhanced α(2C)-AR cell surface levels at 37°C, but these inhibitors had no effect at 30°C. Similar results were obtained after decreasing the HSP90 cellular levels using specific siRNA. Co-immunoprecipitation experiments demonstrated that α(2C)-AR interacts with HSP90 and this interaction is decreased at 30°C. The contractile response to endogenous α(2C)-AR stimulation in rat tail artery was also enhanced at reduced temperature. Similar to HEK293T cells, HSP90 inhibition increased the α(2C)-AR contractile effects only at 37°C. Moreover, exposure to low-temperature of vascular smooth muscle cells from rat tail artery decreased the cellular levels of HSP90, but did not change HSP70 levels. These data demonstrate that exposure to low-temperature augments the α(2C)-AR transport to the plasma membrane by releasing the inhibitory activity of HSP90 on the receptor traffic, findings which may have clinical relevance for the diagnostic and treatment of Raynaud Phenomenon.


Assuntos
Proteínas de Choque Térmico HSP90/fisiologia , Receptores Adrenérgicos alfa 2/metabolismo , Animais , Artérias , Benzoquinonas/farmacologia , Membrana Celular/metabolismo , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Rim/citologia , Rim/metabolismo , Lactamas Macrocíclicas/farmacologia , Macrolídeos/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Transporte Proteico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/genética , Frações Subcelulares , Temperatura
16.
Am J Physiol Heart Circ Physiol ; 302(1): H85-94, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21984550

RESUMO

Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.


Assuntos
Doença da Artéria Coronariana/etiologia , Vasos Coronários/fisiopatologia , Diabetes Mellitus Experimental/complicações , Angiopatias Diabéticas/etiologia , Endotélio Vascular/fisiopatologia , Vasoconstrição , Vasodilatação , Animais , Glicemia/metabolismo , Bradicinina/farmacologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Progressão da Doença , Relação Dose-Resposta a Droga , Endotelina-1/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Receptores de Endotelina/efeitos dos fármacos , Receptores de Endotelina/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologia , Suínos , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
17.
Transfusion ; 52(4): 742-51, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21981629

RESUMO

BACKGROUND: Our blood bank prepares, on indication or request, a volume-reduced (VR) platelet (PLT) product with greater than 95% reduced plasma content and a 15-fold higher PLT concentration, potentially minimizing adverse reactions due to plasma, in particular for human leukocyte antigen (HLA)/human PLT antigen (HPA)-matched PLTs when minor ABO incompatibility cannot be avoided. Here we compared the clinical effectiveness of VR apheresis PLTs (APs) with standard APs. STUDY DESIGN AND METHODS: We performed a single-center cohort study among consecutive alloimmunized patients who received either HLA/HPA-matched standard APs and/or VR-APs between 1994 and 2008. The endpoints were corrected count increments (CCIs), time to next transfusion, and frequency of adverse reactions. The CCI of VR PLTs was calculated using the PLT dose before volume reduction. Using a random effects model, 851 transfusions to 68 patients were evaluated for CCI and 731 transfusions to 64 patients for time to next transfusion. The frequency of reported adverse reactions was compared between the groups. RESULTS: The 1-hour CCI was 23% (95% confidence interval [CI], 9%-42%; p < 0.001) lower and the 24-hour CCI was 17% (95% CI, -11% to 59%; p = 0.278) lower after VR-APs. The mean time to next transfusion was similar: standard APs, 3.1 days (95% CI, 2.7-3.5); and VR-APs, 2.8 days (95% CI, 2.5-3.2). Eight adverse reactions were reported: 4 of 619 in the standard AP group and 4 of 1202 in the VR-AP group. CONCLUSION: VR-APs showed lower 1- and 24-hour CCIs than standard-APs, which can be largely explained by the lower PLT dose of VR-APs. The benefits of plasma reduction should seriously be outweighed given these lower increments.


Assuntos
Antígenos de Plaquetas Humanas/imunologia , Teste de Histocompatibilidade , Isoanticorpos/imunologia , Transfusão de Plaquetas/efeitos adversos , Plaquetoferese , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
18.
Pharmacol Res ; 66(5): 409-18, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22902525

RESUMO

To investigate the vasorelaxant efficacy of nitrite and nitroxyl (HNO) in porcine coronary (micro)arteries (PC(M)As), evaluating their role as endothelium-derived hyperpolarizing factors (EDHFs), preconstricted PCAs and PCMAs were exposed to UV light (a well-known inductor of nitrite; wave-length: 350-370nm), nitrite, the HNO donor Angeli's salt, or bradykinin. UV light-induced relaxation of PCAs increased identically after endothelium removal and endothelial nitric oxide (NO) synthase (eNOS) blockade. UV light-induced relaxation diminished during Na(+)-K(+)-ATPase inhibition and S-nitrosothiol-depletion, and disappeared during NO scavenging with hydroxocobalamin or soluble guanylyl cyclase (sGC) inhibition with ODQ. Nitrite-induced relaxation of PCAs required millimolar levels, i.e., >1000 times endogenous vascular nitrite. Angeli's salt relaxed PCMAs more potently than PCAs, and this was due to the fact that HNO directly activated sGC in PCMAs, whereas in PCAs this occurred following its conversion to NO only. sGC activation by NO/HNO resulted in Na(+)-K(+)-ATPase stimulation and K(v) channel activation. The HNO scavenger l-cysteine blocked bradykinin-induced relaxation in PCAs, and potentiated it in PCMAs. The latter did not occur in the presence of hydroxocobalamin, suggesting that it depended on l-cysteine-induced generation of vasorelaxant S-nitrosothiols. In all experimental setups, incubation with red wine extract mimicked the effects of ODQ. In conclusion, nitrite, via its conversion to NO and S-nitrosothiols, and HNO, either directly, or via its conversion to NO, mediate relaxant effects involving the sGC-cGMP pathway, Na(+)-K(+)-ATPase and/or K(v) channels. Red wine extract counteracts these beneficial effects. NO blocks nitrite activation, and HNO, but not nitrite, may act as EDHF in the coronary vascular bed.


Assuntos
Vasos Coronários/fisiologia , Nitritos/farmacologia , Óxidos de Nitrogênio/farmacologia , Vasodilatação/fisiologia , Animais , Fatores Biológicos/fisiologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/efeitos da radiação , GMP Cíclico/fisiologia , Guanilato Ciclase/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , ATPase Trocadora de Sódio-Potássio/fisiologia , Guanilil Ciclase Solúvel , Suínos , Raios Ultravioleta , Vasodilatação/efeitos dos fármacos , Vasodilatação/efeitos da radiação , Vinho
19.
Arthritis Rheum ; 63(7): 1823-32, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21506097

RESUMO

OBJECTIVE: Recent data suggest that a gene-environment interaction between smoking and the HLA shared epitope alleles plays a role in shaping the autoimmune reaction to specific citrullinated antigens. This study was undertaken to determine the effects of HLA shared epitope alleles and tobacco exposure on the immune response against various citrullinated antigens. These associations were analyzed in the anti-citrullinated protein antibody (ACPA)-positive stratum to control for the possibility that the associations found are explained by the known interaction between HLA shared epitope alleles and tobacco exposure on ACPA status. METHODS: In 661 patients with rheumatoid arthritis, reactivity against several citrullinated antigens from vimentin, fibrinogen, enolase, and myelin basic protein was determined by enzyme-linked immunosorbent assay. The effects of the HLA shared epitope alleles and tobacco exposure were assessed by logistic regression analysis. Biologic interaction was analyzed by investigating whether the effects of the risk factors combined exhibited departure from additivity. RESULTS: A significant interaction between tobacco exposure and HLA shared epitope alleles was found for the presence of ACPA as reported previously. When these interaction effects were studied for several ACPA "fine specificities," significant interactions were noted for several citrullinated peptides. However, these interactions were not present after stratification for ACPA status, indicating that the interaction between tobacco exposure and HLA shared epitope alleles influences autoimmunity not to specific citrullinated antigens, but rather to ACPA development. CONCLUSION: Our data indicate that the gene-environment interaction between HLA shared epitope alleles and smoking does not appear to shape the reactivity of the ACPA response. These data suggest that smoking promotes nonspecific citrullination rather than citrullination of specific antigens.


Assuntos
Artrite Reumatoide/genética , Autoanticorpos/genética , Epitopos/genética , Antígenos HLA/genética , Fumar/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Feminino , Predisposição Genética para Doença , Antígenos HLA/imunologia , Humanos , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Fumar/imunologia
20.
Br J Pharmacol ; 179(22): 5074-5088, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35861684

RESUMO

BACKGROUND AND PURPOSE: Recently pentoxifylline, a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre-eclampsia. We therefore investigated the placental transfer, vascular effects and anti-inflammatory actions of pentoxifylline in healthy and pre-eclamptic human placentas. EXPERIMENTAL APPROACH: The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants. KEY RESULTS: Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP- and cGMP-induced vasodilation, as well as causing vasodilation by adenosine A1 antagonism and via NO synthase and PKG. Pentoxifylline also reduced inflammatory factors secretion. In pre-eclamptic placentas, we observed that its vasodilator capacity was preserved, however not via NO-PKG but likely through adenosine signalling. Pentoxifylline neither potentiated vasodilation through cAMP and cGMP, nor suppressed the release of inflammatory factors from these placentas. CONCLUSION AND IMPLICATIONS: Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre-eclampsia, limiting its application in this disease, although it could be useful for other placenta-related disorders. Future studies might focus on selective A1 receptor antagonists as a new treatment for pre-eclampsia.


Assuntos
Pentoxifilina , Pré-Eclâmpsia , Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , GMP Cíclico/metabolismo , Feminino , Humanos , Óxido Nítrico Sintase/metabolismo , Pentoxifilina/metabolismo , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Antagonistas de Receptores Purinérgicos P1/metabolismo , Antagonistas de Receptores Purinérgicos P1/farmacologia , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Vasodilatadores/farmacologia
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