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1.
Cardiovasc Toxicol ; 22(2): 99-107, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34800264

RESUMO

Cardiomyocyte senescence is involved in the pathological mechanism of cardiac diseases. Metoprolol is a ß1 receptor blocker used for the treatment of hypertension. Recent studies show that Metoprolol can protect cardiomyocytes against ischemia injury. The present study aims to investigate the protective effects of Metoprolol against arginine vasopressin (AVP)-induced cellular senescence in cultured cardiomyocytes. The cell proliferation assay and cytotoxicity lactate dehydrogenase assay showed that the highest tolerated dosage of Metoprolol in H9C2 cardiomyocytes was optimized as 10 µM. The enzyme-linked immunosorbent assay showed that Metoprolol significantly ameliorated the elevated level of the DNA oxidation product 8-hydroxy-2 deoxyguanosine. Metoprolol also decreased the percentage of senescence-associated ß-galactosidase positive cells and improved the telomerase activity under AVP exposure. Moreover, treatment with Metoprolol ameliorated the decreased intracellular nicotinamide phosphoribosyltransferase activity, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD+/NADPH) ratio, and Sirtuin1 activity in cardiomyocytes by AVP. Finally, Metoprolol was able to downregulate the AVP-induced expression of acetylated p53 and p21. Taken together, our data reveal that Metoprolol protected the cardiomyocytes from AVP-induced senescence.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Arginina Vasopressina/toxicidade , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Metoprolol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Acetilação , Animais , Linhagem Celular , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , NAD/metabolismo , NADP/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Ratos , Transdução de Sinais , Telomerase/metabolismo
2.
Mol Brain ; 8: 86, 2015 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-26651338

RESUMO

BACKGROUND: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS. RESULTS: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene. CONCLUSIONS: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation.


Assuntos
Arginina Vasopressina/fisiologia , Enjoo devido ao Movimento/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Receptores de Vasopressinas/fisiologia , Núcleos Vestibulares/fisiopatologia , Vias Aferentes/fisiopatologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Arginina Vasopressina/biossíntese , Arginina Vasopressina/genética , Arginina Vasopressina/toxicidade , Transporte Axonal , Canais de Cálcio Tipo L/fisiologia , Sinalização do Cálcio , Células Cultivadas , Condicionamento Clássico , Modelos Animais de Doenças , Disgeusia/induzido quimicamente , Disgeusia/fisiopatologia , Feminino , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Microinjeções , Enjoo devido ao Movimento/genética , Enjoo devido ao Movimento/prevenção & controle , Terminações Nervosas/química , Núcleo Hipotalâmico Paraventricular/metabolismo , Polimorfismo de Nucleotídeo Único , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores de Vasopressinas/biossíntese , Receptores de Vasopressinas/genética , Rotação , Sacarina , Sinaptofisina/análise , Núcleos Vestibulares/citologia , Núcleos Vestibulares/metabolismo
3.
Crit Care ; 10(5): R144, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17032443

RESUMO

INTRODUCTION: Arginine vasopressin (AVP) is increasingly used to treat sepsis-related vasodilation and to decrease catecholamine requirements. However, AVP infusion may be associated with a marked decrease in systemic blood flow and oxygen transport. The purpose of the present study was to evaluate whether dobutamine may be titrated to reverse the AVP-related decrease in cardiac index (CI) and systemic oxygen delivery index (DO2I) in an established model of ovine endotoxemia. METHODS: Twenty-four adult ewes were chronically instrumented to determine cardiopulmonary hemodynamics and global oxygen transport. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation and death of five sheep. After 16 hours of endotoxemia, the surviving ewes (n = 19; weight 35.6 +/- 1.5 kg (mean +/- SEM)) were randomized to receive either AVP (0.04 Umin-1) and dobutamine (n = 8) or the vehicle (normal saline; n = 6) and compared with a third group treated with AVP infusion alone (n = 5). Dobutamine infusion was started at an initial rate of 2 microg kg-1min-1 and was increased to 5 and 10 microg kg-1 min-1 after 30 and 60 minutes, respectively. RESULTS: AVP infusion increased mean arterial pressure (MAP) and systemic vascular resistance index at the expense of a markedly decreased CI (4.1 +/- 0.5 versus 8.2 +/- 0.3 l min-1 m-2), DO2I (577 +/- 68 versus 1,150 +/- 50 ml min-1 m-2) and mixed-venous oxygen saturation (SvO2; 54.5 +/- 1.8% versus 69.4 +/- 1.0%; all p < 0.001 versus control). Dobutamine dose-dependently reversed the decrease in CI (8.8 +/- 0.7 l min-1 m-2 versus 4.4 +/- 0.5 l min-1 m-2), DO2I (1323 +/- 102 versus 633 +/- 61 ml min-1 m-2) and SvO2 (72.2 +/- 1.7% versus 56.5 +/- 2.0%, all p < 0.001 at dobutamine 10 microg kg-1 min-1 versus AVP group) and further increased MAP. CONCLUSION: This study provides evidence that dobutamine is a useful agent for reversing the AVP-associated impairment in systemic blood flow and global oxygen transport.


Assuntos
Arginina Vasopressina/farmacologia , Débito Cardíaco/efeitos dos fármacos , Dobutamina/uso terapêutico , Endotoxemia/tratamento farmacológico , Consumo de Oxigênio/efeitos dos fármacos , Animais , Arginina Vasopressina/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Dobutamina/farmacologia , Relação Dose-Resposta a Droga , Endotoxemia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Consumo de Oxigênio/fisiologia , Ovinos
4.
Blood Press ; 15(6): 375-83, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17472029

RESUMO

The heart adapts to increased pressure overload by hypertrophic growth of terminally differentiated cardiomyocytes. At the genetic level, the hypertrophic response is characterized by the reprogramming of gene expression, i.e. upregulation of immediate early genes, natriuretic peptide genes and genes encoding structural proteins. In the present study, we characterized the early changes in gene expression with cDNA expression arrays in response to increase in blood pressure produced by arginine8-vasopressin infusion (0.05 microg/kg/min, i.v.) for 30 min and 4 h in conscious normotensive rats. Expression profiling revealed differential expression of 14 genes in the left ventricle, and several novel factors of immediate early genetic response to pressure overload were identified, such as growth arrest and DNA damage inducible protein 45 (GADD45alpha), epidermal fatty acid-binding protein (E-FABP) and Bcl-X. Administration of angiotensin II (Ang II) for 6 h by osmotic minipumps also increased left ventricular GADD45alpha, E-FABP and Bcl-X gene expression. Furthermore, the induction of GADD45alpha and Bcl-X gene expression by Ang II was blocked by angiotensin II type 1 receptor antagonist losartan. In summary, our analysis provided new insights into the pathogenesis of pressure overload-induced hypertrophy by suggesting the existence of novel regulators of the immediate early gene expression program.


Assuntos
Arginina Vasopressina/toxicidade , Pressão Sanguínea , Regulação da Expressão Gênica/fisiologia , Ventrículos do Coração/metabolismo , Hipertensão/genética , Proteína bcl-X/biossíntese , Doença Aguda , Angiotensina II/toxicidade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Arginina Vasopressina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Doença Crônica , Estado de Consciência , DNA Complementar/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteínas do Olho/biossíntese , Proteínas do Olho/genética , Proteínas de Ligação a Ácido Graxo/biossíntese , Proteínas de Ligação a Ácido Graxo/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/genética , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Fator de Crescimento Neural/biossíntese , Fator de Crescimento Neural/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Proteína bcl-X/genética
5.
J Cardiovasc Pharmacol ; 42(1): 132-5, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12827038

RESUMO

The abnormal proliferation of cardiac fibroblasts is involved in the pathophysiologic process of left ventricular hypertrophy (LHV) associated with essential hypertension. Arginine vasopressin (AVP) has been reported to contribute significantly to the pathogenesis of hypertension. In this study, the authors investigated the effects of AVP and its V1 receptor antagonist [d(CH2)5Tyr2(Me)]AVP on the growth of rat cardiac fibroblasts. Cardiac fibroblasts of neonatal Sprague-Dawley rats were isolated, and growth-arrested cardiac fibroblasts were stimulated with 2.5% fetal calf serum in the presence and absence of AVP (0.001, 0.01, 0.1, and 1 microM) and [d(CH2)5Tyr2(Me)]AVP (0.1 microM). DNA synthesis was measured by [3H]thymidine incorporation. Thiazolyl blue assay and flow cytometry techniques were adopted to measure cell numbers and analyze cell cycle, respectively. Arginine vasopressin (0.1 and 1 microM) significantly increased DNA synthesis in cardiac fibroblasts. Moreover, AVP (0.1 and 1 microM) significantly increased the number of cardiac fibroblasts. Analysis of cell cycle showed that AVP (0.1 microM) increased S-stage percentage and proliferation index (PI). The V1 receptor antagonist [d(CH2)5Tyr2(Me)]AVP (0.1 microM) significantly inhibited DNA synthesis in cardiac fibroblasts. The cell number, S-stage percentage, and PI induced by AVP (0.1 microM) were significantly decreased by [d(CH2)5Tyr2(Me)]AVP (0.1 microM). These findings suggest that AVP might promote the proliferation of rat cardiac fibroblasts, which seems to be mediated via the V1 receptor. Arginine vasopressin may be involved in the pathophysiologic process of LVH by promoting cardiac fibroblast proliferation.


Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/toxicidade , Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/metabolismo , Receptores de Vasopressinas/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , DNA/biossíntese , Fibroblastos/citologia , Fibroblastos/metabolismo , Coração/crescimento & desenvolvimento , Miocárdio/citologia , Ratos , Ratos Sprague-Dawley
6.
J Pharm Pharmacol ; 54(3): 413-8, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11902808

RESUMO

The anti-anginal effect of CP-060S, a new cardioprotective agent that prevents myocardial Na+-, Ca2+-overload and has Ca2+-channel blocking activity, was evaluated in a rat model of arginine8-vasopressin (AVP)-induced cardiac ischaemia. Infusion of AVP (0.2 IU kg(-1)) depressed the electrocardiogram (ECG) ST segment, an index of myocardial ischaemia. Vehicle, CP-060S and diltiazem were given orally 1, 2, 4, 8, 12 and 24 h before the administration of AVP. CP-060S, at 3 mg kg(-1) and 10 mg kg(-1), suppressed AVP-induced ST-segment depression for 2 h and 12 h, respectively. In contrast, diltiazem, at 10 and 30 mg kg(-1), suppressed AVP-induced ST-segment depression for only 1 h. The persistent suppression of the AVP-induced ST-segment depression by CP-060S correlated with the time course of changes in its plasma concentration. The minimum effective concentration of CP-060S was estimated to be 30 ng mL(-1) (approximately 50 nM), consistent with its vasorelaxant potency in rat isolated aortic strips (concentration producing 50% relaxation of KCl contraction, IC50 = 32.6+/-8.3 nM). Intravenously administered CP-060S, at 300 microg kg(-1) and diltiazem at 500 microg kg(-1) showed similar haemodynamic changes, whereas CP-060S, at 300 microg kg(-1), significantly suppressed AVP-induced ST-segment depression and diltiazem, at 500 microg kg(-1), had no effect on AVP-induced ST-segment depression. In summary, orally administered CP-060S exerted a long-lasting anti-anginal effect proportionate to the time course of changes in its plasma concentration in a rat model of AVP-induced ischaemia.


Assuntos
Arginina Vasopressina/toxicidade , Isquemia Miocárdica/tratamento farmacológico , Tiazóis/uso terapêutico , Animais , Arginina Vasopressina/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diltiazem/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Masculino , Isquemia Miocárdica/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Tiazolidinas , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/toxicidade
7.
J Neuropathol Exp Neurol ; 55(5): 594-601, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8627349

RESUMO

Brain myelinolysis occurs after excessive correction (delta SNa > 20 mEq/1/24 hours) of chronic hyponatremia. However, we showed recently that the mechanisms leading to brain myelinolysis remain reversible. Indeed, reinduction of the hyponatremia by water administration despite 12 hours of sustained excessive correction could prevent the development of demyelination in rats still asymptomatic at that time. Whether this therapeutic maneuver could be also beneficial to rats with preexisting myelinolysis-related neurologic symptoms is unknown. Therefore we evaluated here the effect of reinduction of the hyponatremia on the survival and on brain damage in rats presenting obvious neurologic symptoms after excessive correction of hyponatremia. After 3 days of severe hyponatremia induced by 2.5 D-glucose in water and continuous infusion of AVP, rats were submitted to a large correction (delta SNa approximately 30 mEq/l) by 2 i.p. injections of hypertonic saline given over 24 hours. In group I (n = 15) the rats developing neurologic symptoms during the first 24 hours of correction received one i.p. injection of distilled water which rapidly decreased the natremia to a final correction gradient <20 mEq/l/24 hour. In group II (n = 13, controls) the symptomatic rats were left permanently overcorrected. In group I, after water administration, the neurological manifestations were generally attenuated or disappeared. Seven of the 15 rats (47%) in this group survived up to day 10 with a mean survival time of 7.5 +/- 2 days, an outcome clearly improved as compared to group II (controls): only 1 of the 13 rats (7%, p < 0.03) was still alive on day 10 and the mean survival time was 3.3 +/- 2 days (p < 0.001) in this group II. The duration of the symptoms also influences the prognosis. In group I, in 9 rats the water administration was performed 4 hours after symptoms onset. These rats had a better outcome than the 6 rats with more sustained (8-10 hours) neurologic symptoms before water loading. Brain analysis in the 7 surviving rats of group I demonstrated demyelinating lesions in only 2 of them, suggesting the reversibility of the process even when neurologic manifestation developed. In conclusion, after exposure to an excessive correction of chronic hyponatremia, even when rats have developed myelinolysis-related neurologic symptoms, hypotonic fluids administration could improve survival and could prevent the subsequent development of brain myelinolysis.


Assuntos
Encefalopatias Metabólicas/prevenção & controle , Doenças Desmielinizantes/prevenção & controle , Hiponatremia/fisiopatologia , Solução Salina Hipertônica/uso terapêutico , Animais , Arginina Vasopressina/toxicidade , Dano Encefálico Crônico/induzido quimicamente , Dano Encefálico Crônico/prevenção & controle , Encefalopatias Metabólicas/etiologia , Doenças Desmielinizantes/induzido quimicamente , Hiponatremia/complicações , Hiponatremia/tratamento farmacológico , Soluções Hipotônicas/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Pressão Osmótica , Ratos , Ratos Wistar , Sódio/sangue , Água/administração & dosagem
8.
Fundam Appl Toxicol ; 18(2): 307-13, 1992 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-1601232

RESUMO

SK&F 101926 is a synthetic octapeptide which was designed to promote free water excretion by antagonizing the action of antidiuretic hormone. The clinical and pathologic changes in rats resulting from lethal doses of SK&F 101926 have suggested that death is associated with respiratory failure and/or cardiovascular collapse. To define the relationships between respiratory failure, cardiovascular collapse, and death, respiratory and cardiovascular parameters were monitored in anesthetized rats following the intravenous administration of SK&F 101926 at a dosage (3 mg/kg) which resulted in 70% mortality. Within 5 min after receiving this dosage, mean arterial blood pressure was reduced to values between 30 and 40 mm Hg in all rats. This degree of hypotension was well tolerated by some rats and, consequently, was not considered to be the cause of death. Deaths occurred between 9 and 58 min after dosing and were preceded by respiratory depression involving marked reductions in respiratory rate and the lack of compensatory increases in tidal volume. At the time of respiratory arrest, heart rates remained above 200 beats/min, mean arterial blood pressure remained between 30 and 40 mm Hg, and there were no consistent changes in dynamic lung compliance or total pulmonary resistance. Pretreatment of rats with a mast cell stabilizing agent (disodium cromoglycate), a mast cell degranulating agent (compound 48/80), or a histamine/5-hydroxytryptamine blocking agent (cyproheptadine) prevented the reductions in respiratory rate and death caused by SK&F 101926. These pretreatments also reduced the effect of SK&F 101926 on blood pressure, but were not able to completely prevent the hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Arginina Vasopressina/análogos & derivados , Sistema Cardiovascular/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Vasopressinas/antagonistas & inibidores , Animais , Arginina Vasopressina/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Masculino , Mastócitos/efeitos dos fármacos , Peptídeos/toxicidade , Ratos , Ratos Endogâmicos
10.
Adv Neurol ; 52: 149-54, 1990.
Artigo em Inglês | MEDLINE | ID: mdl-2144395

RESUMO

Arginine vasopressin-containing nerve fibers release AVP at extrahypothalamic sites where the hormone appears to regulate brain water. To determine its role in brain edema, we intracerebrally infused AVP, thus bypassing the blood-brain barrier. Thirteen adult cats had 2 mU (5 ng) of AVP infused into the caudate nucleus in 4 microliters CSF: 2 microliters at the start of the experiment and 2 microliters at 2 hr of a 4-hr experiment. Thirteen controls had similar microinfusions into the caudate nucleus of 4 microliters artificial CSF alone. A third group of nine animals had 2 mU AVP infused along with 50 ng of the V1 receptor antagonist (Manning compound). A fourth group of 10 animals had AVP infused along with 50 ng of a V1/V2 receptor antagonist (SK&F 101926). After 4 hr the brains were removed, and water content was measured in anterior, middle, and posterior areas in gray and white matter. We found that animals given AVP had a statistically significant increase in water content in both the gray (F = 7.1, p = 0.0002) and white matter (F = 9.4, p = 0.0001) compared with controls. Both the V1 and the V1/V2 antagonists blocked the increase in water content. We conclude that the V1 AVP receptor is important in water regulation.


Assuntos
Arginina Vasopressina/toxicidade , Edema Encefálico/induzido quimicamente , Receptores de Angiotensina/fisiologia , Animais , Edema Encefálico/fisiopatologia , Gatos , Núcleo Caudado/efeitos dos fármacos , Receptores de Angiotensina/classificação , Receptores de Vasopressinas , Sistemas do Segundo Mensageiro
11.
Toxicol Appl Pharmacol ; 102(1): 117-27, 1990 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1688665

RESUMO

SK&F 101926, a synthetic peptide, is a potent antagonist of vasopressin at both the V2 and the V1 receptors. Following intravenous administration of SK&F 101926 (5 mg/kg), mean arterial pressure (MAP) immediately fell 75 mm Hg. Heart rate increased approximately 50 beats/min. Cutaneous flushing and cyanosis appeared approximately 2 to 5 min after the SK&F 101926 administration. Three of the five rats died within 40 min with no improvement in either color or MAP. The two surviving animals slowly recovered from these symptoms. The hypotension and flushing recorded in these studies resembled the effects during hypotensive shock. SK&F 101926 degranulated rat peritoneal mast cells in vitro as measured by the liberation of histamine. Analogs of SK&F 101926 were identified having reduced activity to release histamine from mast cells in vitro. The activity of these analogs to release histamine in vivo was also tested, as reflected by rat paw edema. A positive correlation was found between the potency to produce edema in vivo and the potency to release mast cell histamine in vitro (r = 0.94, p less than 0.05). In addition, compounds that released mast cell histamine and induced rat paw edema also produced hypotension and death when administered intravenously, while analogs which produced minimal histamine release in vitro produced minimal or no cardiovascular changes or lethality in vivo at the same dosages (5 mg/kg). Finally, cyproheptadine (10 mg/kg), an antagonist at both the serotonin and the histamine receptors, blunted the effects of SK&F 101926 on MAP and blocked the lethality. Pretreatment with a combination of histamine (H1 and H2) antagonists provided little protection against the SK&F 101926-induced toxicity. These data indicate that the cardiovascular toxicity of SK&F 101926 (and related peptides) is mediated via the release of autocoids from mast cells. Serotonin appears to play a major role in mediating the cardiovascular toxicity of SK&F 101926.


Assuntos
Degranulação Celular/efeitos dos fármacos , Hipotensão/induzido quimicamente , Mastócitos/efeitos dos fármacos , Vasopressinas/antagonistas & inibidores , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Arginina Vasopressina/toxicidade , Degranulação Celular/fisiologia , Edema/induzido quimicamente , Edema/fisiopatologia , Membro Posterior , Liberação de Histamina/efeitos dos fármacos , Liberação de Histamina/fisiologia , Hipotensão/fisiopatologia , Masculino , Mastócitos/fisiologia , Ratos , Ratos Endogâmicos , Fatores de Tempo
12.
Peptides ; 9(6): 1335-44, 1988.
Artigo em Inglês | MEDLINE | ID: mdl-3247252

RESUMO

Intrathecal (IT) injection of arginine vasopressin (AVP) in rats caused a transient (less than 30 min), dose-related paralysis of the hindlimbs, loss of hindlimb and tail nociceptive responsiveness, and increased mean arterial pressure. Motor dysfunction was produced with comparable potency by lysine vasopressin (LVP) and arginine vasotocin (AVT); oxytocin (OXY) was approximately 1000 times less potent. Paralysis induced by these peptides was selectively blocked following IT pretreatment with 0.5 nmoles of the vasopressin V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] Arg8-vasopressin (d(CH2)5[Tyr(Me2)]AVP). Pressor and antinociceptive responses to AVP were also blocked by this compound. However, at higher doses (2-5 nmoles, IT), d(CH2)5[Tyr(Me2)]AVP produced hindlimb paralysis, antinociception, and pressor responses by itself. In contrast to the fiber degeneration, cell loss, and necrosis found in lumbosacral cords of rats persistently paralyzed by other peptides (dynorphin A, somatostatin, and ICI 174864), neuropathological changes were not evident in spinal cords of rats transiently paralyzed by IT AVP. These results indicate that AVP-related peptides affected diverse spinal cord functions through interactions with a V1-like receptor. The similar pattern of cardiovascular and antinociceptive responses to other peptides (dynorphin A, somatostatin, and ICI 174864), which also caused hindlimb paralysis, suggests that the former responses may actually reflect the nonselective consequences of a peptide-induced disruption of spinal cord function, rather than specific shared pharmacological effects.


Assuntos
Arginina Vasopressina/toxicidade , Atividade Motora/efeitos dos fármacos , Paralisia/induzido quimicamente , Medula Espinal/fisiologia , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/farmacologia , Membro Posterior , Injeções Espinhais , Lipressina/farmacologia , Masculino , Ocitocina/farmacologia , Dor/fisiopatologia , Ratos , Ratos Endogâmicos , Valores de Referência , Medula Espinal/efeitos dos fármacos , Relação Estrutura-Atividade , Espaço Subaracnóideo , Vasotocina/farmacologia
13.
Brain Res ; 445(1): 117-29, 1988 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-2896527

RESUMO

Barrel rotation (BR) is an abnormal, long-axis rotation induced by intracerebroventricular (i.c.v.) injections of peptides, including somatostatin (SRIF) and arginine-vasopressin (AVP). This study examined the effects of two i.c.v. doses of SRIF and combined injections of SRIF and AVP in conscious, adult Wistar and Sprague-Dawley rats. Mortality after i.c.v. SRIF was dose-dependent; 0/16 rats died after a 20 microgram dose, while 21/43 died after 40 micrograms SRIF. On the other hand, BR incidence was similar after the two doses, but the hazard function of the BR latency data was shifted to the left by the higher dose. Although the incidence data imply that BR and mortality are independent, the hazard function of BR latency data is predictive of mortality. An interaction study employing a combined i.c.v. dose of 20 micrograms SRIF and 0.5 micrograms AVP established that the effects add non-linearly. This is illustrated by a marked increment in mortality (0/16 for 20 micrograms SRIF, 1/25 for 0.5 micrograms AVP and 12/18 for SRIF + AVP). The hazard plot shows a similar, non-linear interaction. In addition, SRIF, but not AVP, produced a characteristic pattern of Purkinje cell death in cerebellar regions projecting to the fastigial and lateral vestibular nuclei. These results imply that SRIF and AVP act at independent sites to produce BR and mortality, and that the effects summate non-linearly at a common central site. This raises the issue of whether these neuropeptides, endogenous in human CSF, interact to produce similar biological effects.


Assuntos
Arginina Vasopressina/farmacologia , Ventrículos Cerebrais/fisiologia , Atividade Motora/efeitos dos fármacos , Neurotoxinas , Somatostatina/farmacologia , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/toxicidade , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/patologia , Interações Medicamentosas , Injeções Intraventriculares , Células de Purkinje/citologia , Células de Purkinje/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Somatostatina/administração & dosagem , Somatostatina/toxicidade
14.
Brain Res ; 342(2): 316-22, 1985 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-4041833

RESUMO

Motor disturbances observed in Brattleboro rats (homozygous for the diabetes insipidus (DI) trait) following a first intracerebroventricular injection of 1.0 microgram of arginine vasopressin (AVP) were not significantly different from those of the parent Long-Evans (LE) strain. These disturbances consisted of periods of staring and immobility, locomotor difficulties and discrete myoclonic jerks, often followed by scratching behavior. Following a second central injection of 10.0 ng AVP, however, the DI strain exhibited more pronounced motor disturbances than the LE strain. This increased sensitivity of the DI strain to the behavioral actions of AVP does not appear to be due to a generalized decrease of seizure threshold, since no significant differences were observed between the two strains in their susceptibility to convulse following pentylenetetrazol. As the behavioral and motor effects of AVP appear to be receptor-mediated, these findings suggest that homozygous DI rats possess central AVP receptors, which, in the absence of endogenous vasopressin, may have increased sensitivity to a second central injection of AVP.


Assuntos
Arginina Vasopressina/toxicidade , Atividade Motora/efeitos dos fármacos , Transtornos dos Movimentos/induzido quimicamente , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/farmacologia , Eletroencefalografia , Injeções Intraventriculares , Masculino , Pentilenotetrazol/toxicidade , Ratos , Ratos Brattleboro
16.
J Hypertens Suppl ; 2(3): S333-5, 1984 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-6599676

RESUMO

The role of arginine-vasopressin (AVP) in the pathogenesis of deoxycorticosterone acetate (DOCA) salt hypertension in rats was studied with AVP receptor antagonists for its tubular (V2) and/or vascular (V1) actions. When chronic (six weeks) infusion of the antagonists was started concomitantly with DOCA-salt treatment the development of hypertension was attenuated by the V1-antagonist and prevented by the V1V2-antagonist. However, the V1V2-antagonist induced severe and persistent hypernatraemia in all rats. When chronic (two weeks) infusion of the antagonists was started in rats with established hypertension after five weeks of DOCA-salt treatment blood pressure was not influenced by the V1-antagonist. The rats which received the V1V2-antagonist died from hypernatraemia within four days. These results suggest that in DOCA-salt treated rats AVP is essential for the prevention of severe and life-threatening hypernatraemia. AVP appears to contribute significantly to the development of this form of hypertension through both its vascular and tubular effects.


Assuntos
Arginina Vasopressina/fisiologia , Desoxicorticosterona/toxicidade , Hipertensão/induzido quimicamente , Receptores de Vasopressinas , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/antagonistas & inibidores , Arginina Vasopressina/farmacologia , Arginina Vasopressina/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Hipernatremia/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos , Receptores de Angiotensina/efeitos dos fármacos , Fatores de Tempo
17.
Proc Natl Acad Sci U S A ; 80(17): 5330-4, 1983 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-6351057

RESUMO

Previous work has shown that the presence of a phorbol ester tumor promoter, phorbol 12-myristate 13-acetate (PMA), during a single-step selection for methotrexate (MTX)-resistant mouse 3T6 cells results in an up to 100-fold increase in the incidence of MTX-resistant, colony-forming cells. MTX resistance of most of these cells is due to amplification of the gene for dihydrofolate reductase (DHFR), the target enzyme for MTX. We show here that other active, noncytotoxic phorbol ester tumor promoters, such as phorbol 12, 13-didecanoate and 20-phorbol 12,13-butyrate, at their optimal concentrations (approximately equal to 0.1 microM) are approximately equal to PMA in increasing the incidence of MTX-resistant 3T6 colonies. Mezerein, a potent second-stage tumor promoter, but a weak complete promoter, increases the incidence of MTX resistance up to 350-fold, the strongest effect for any of the agents so far tested. PMA analogs that are inactive as tumor promoters, such as phorbol or phorbol 12,13,20-triacetate, have no effect on the incidence of MTX-resistant 3T6 colonies. Anthralin, a nonphorbol tumor promoter, is approximately equal to 40% as active as PMA in the MTX selection assay. Remarkably, the hormones insulin, arginine vasopressin, and epidermal growth factor, all of which are mitogenic for 3T6 cells, also exert a strong PMA-like effect on the incidence of MTX-resistant 3T6 colonies under conditions of MTX selection. The effect of insulin at its optimal concentration (approximately equal to 1 microgram/ml) is approximately equal to 70% that of PMA. Although the effect of PMA on the incidence of MTX-resistant 3T6 colonies does not significantly depend on the initial density of seeded cells or volume of the medium added, the analogous effect of insulin is strongly influenced by these parameters. Mevalonic acid, arachidonic acid, thymidine, caffeine, and nicotine, all of which are known to influence patterns of DNA synthesis in mammalian cells, were tested at their highest noncytotoxic concentrations and failed to produce any significant effect on the incidence of MTX-resistant 3T6 colonies. We discuss possible mechanisms of hormone- and tumor promoter-facilitated gene amplification in mammalian cells, relationship of mitogenic hormones to tumor promoters, and also implications of our findings for the problem of drug resistance in cancer chemotherapy.


Assuntos
Carcinógenos/toxicidade , Amplificação de Genes/efeitos dos fármacos , Genes/efeitos dos fármacos , Hormônios/toxicidade , Metotrexato/toxicidade , Ésteres de Forbol/toxicidade , Forbóis/toxicidade , Tetra-Hidrofolato Desidrogenase/genética , Animais , Arginina Vasopressina/toxicidade , Células Cultivadas , Células Clonais , Resistência a Medicamentos , Fator de Crescimento Epidérmico/toxicidade , Insulina/toxicidade , Camundongos , Acetato de Tetradecanoilforbol/toxicidade
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