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1.
Heart Rhythm ; 2010 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-21193060

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

2.
Circ Res ; 105(8): 737-45, 2009 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-19745168

RESUMO

RATIONALE: Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (I(Na)) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism. OBJECTIVE: Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5). METHODS AND RESULTS: HEK293 cells stably expressing Na(v)1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD+ on arrhythmic risk was evaluated in wild-type or SCN5A(+/-) mouse heart. A280V GPD1-L caused a 2.48+/-0.17-fold increase in intracellular NADH level (P<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased I(Na) (0.48+/-0.09 or 0.19+/-0.04 of control group, respectively; P<0.01), which was reversed by NAD+, chelerythrine, or superoxide dismutase. NAD+ antagonism of the Na+ channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI(6-22). The effects of NADH and NAD+ were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD+ to SCN5A(+/-) mouse hearts ameliorated the risk of ventricular tachycardia. CONCLUSIONS: Our results show that Na(v)1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I(Na). This effect required protein kinase C activation and was mediated by oxidative stress. NAD+ could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na(v)1.5 by altering the oxidized to reduced NAD(H) balance.


Assuntos
Síndrome de Brugada/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Proteínas Musculares/metabolismo , Mutação , NAD/metabolismo , Canais de Sódio/metabolismo , Sódio/metabolismo , Animais , Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Síndrome de Brugada/genética , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Inibidores Enzimáticos/farmacologia , Glicerolfosfato Desidrogenase/genética , Humanos , Camundongos , Proteínas Musculares/genética , Miocárdio/metabolismo , NAD/genética , Canal de Sódio Disparado por Voltagem NAV1.5 , Oxirredução , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Ratos , Canais de Sódio/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo
3.
Endocrinology ; 148(1): 189-97, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17053025

RESUMO

UNLABELLED: During pregnancy and chronic relaxin administration to nonpregnant rats (for days), vascular MMP (matrix metalloproteinase)-2 is increased and mediates renal vasodilation, hyperfiltration, and inhibition of myogenic reactivity of small renal arteries. However, the renal vasodilatory actions of relaxin also occur after only several hours of hormone administration to nonpregnant rats, and we hypothesized a pivotal role for vascular MMP-2. Accordingly, we used gelatin zymography, which reveals not only vascular MMP-2, but also MMP-9 activity in small renal arteries isolated from rats administered recombinant human relaxin (rhRLX) or vehicle for 4-6 h. Furthermore, we tested whether myogenic reactivity is inhibited, and if so, whether the inhibition is mediated by increased vascular MMP-2. Surprisingly, we detected no significant difference in either pro or active MMP-2 in small renal arteries isolated from rhRLX and vehicle control treatment groups. In contrast, vascular MMP-9 was up-regulated by 70% (P < 0.0005 vs. vehicle). These results were completely unexpected and novel. MMP-9 protein expression was confined to the vascular smooth muscle. MMP-9, but not MMP-2 activity, was also increased in mesenteric arteries after short-term rhRLX administration (P < 0.005 and >0.05 vs. vehicle, respectively). Myogenic reactivity was inhibited in small renal arteries isolated from nonpregnant rats treated with rhRLX for 4-6 h (P < 0.01 vs. vehicle) and was completely restored by incubation with MMP-9, but not MMP-2 neutralizing antibodies in vitro. CONCLUSION: In contrast to chronic rhRLX administration, MMP-9 rather than MMP-2 plays a central role in the vasodilatory effect of short-term relaxin administration.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Artérias Mesentéricas/enzimologia , Relaxina/farmacologia , Artéria Renal/enzimologia , Vasodilatação/efeitos dos fármacos , Animais , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Artérias Mesentéricas/citologia , Artérias Mesentéricas/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Gravidez , Ratos , Ratos Long-Evans , Proteínas Recombinantes/farmacologia , Artéria Renal/citologia , Artéria Renal/efeitos dos fármacos , Vasodilatação/fisiologia
4.
FASEB J ; 20(13): 2352-62, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17077312

RESUMO

Relaxin is a 6 kDa protein hormone produced by the corpus luteum and secreted into the blood during pregnancy in rodents and humans. Growing evidence indicates that circulating relaxin causes vasodilatation and increases in arterial compliance, which may be among its most important actions during pregnancy. Here we investigated whether there is local expression and function of relaxin and relaxin receptor in arteries of nonpregnant females and males. Relaxin-1 and its major receptor, Lgr7, mRNA are expressed in thoracic aortas, small renal and mesenteric arteries from mice and rats of both sexes, as well as in small renal arteries from female tammar wallabies (an Australian marsupial). Using available antibodies for rat and mouse Lgr7 receptor and rat relaxin, we also identified protein expression in arteries. Small renal arteries isolated from relaxin-1 gene-deficient mice demonstrate enhanced myogenic reactivity and decreased passive compliance relative to wild-type (WT) and heterozygous mice. Taken together, these findings reveal an arterial-derived, relaxin ligand-receptor system that acts locally to regulate arterial function.


Assuntos
Artérias/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores de Peptídeos/fisiologia , Relaxina/fisiologia , Animais , Western Blotting , Feminino , Humanos , Ligantes , Macropodidae , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-Evans , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Relaxina/genética , Artéria Renal/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
J Appl Physiol (1985) ; 100(6): 1955-63, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16484357

RESUMO

Vascular gelatinase activity is essential for pregnancy- and relaxin (Rlx)-induced renal vasodilation and hyperfiltration in rats. The objective of this study was to further elucidate the mechanisms for the increase in vascular matrix metalloproteinase (MMP)-2 activity caused by pregnancy and Rlx. We first corroborated our earlier work by showing that pro- and active forms of MMP-2 were increased in small renal arteries from pregnant compared with virgin rats and Rlx-treated compared with vehicle-treated nonpregnant rats. We next investigated other artery types and showed that MMP-2 activity was upregulated in mesenteric arteries from pregnant rats (pro-MMP-2 by 50% and active MMP-2 by 40%, both P<0.05) and from Rlx-treated nonpregnant rats (pro-MMP-2 by 50% and active MMP-2 by 90%, both P<0.005) compared with their respective controls. To corroborate these results obtained by gelatin zymography, pro-MMP-2 protein was determined by Western analysis in the same small arteries. Pro-MMP-2 protein was increased in small renal arteries from pregnant compared with virgin rats and from Rlx- compared with vehicle-treated nonpregnant rats: pro-MMP-2-to-beta-actin ratio=0.29 vs. 0.21 (P<0.01) and 0.43 vs. 0.32 (P<0.005). Findings were similar for mesenteric arteries. MMP-2 mRNA as measured by real-time PCR was increased in small renal arteries from pregnant and Rlx-treated nonpregnant rats compared with their respective controls. There were no significant differences in tissue inhibitor of metalloproteinase (TIMP-1 or TIMP-2) activity by reverse zymography in small renal arteries. Thus increases in MMP-2 mRNA and protein expression are major factors contributing to increased MMP-2 activity in small arteries from pregnant and Rlx-treated nonpregnant rats.


Assuntos
Artérias/química , Metaloproteinase 2 da Matriz/metabolismo , Prenhez/fisiologia , RNA Mensageiro/análise , Relaxina/farmacologia , Inibidores Teciduais de Metaloproteinases/análise , Animais , Artérias/citologia , Artérias/fisiologia , Endotélio Vascular/química , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Feminino , Artérias Mesentéricas/química , Artérias Mesentéricas/citologia , Artérias Mesentéricas/fisiologia , Gravidez , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/análise , Inibidor Tecidual de Metaloproteinase-2/análise , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
6.
Ann N Y Acad Sci ; 1041: 147-54, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15956700

RESUMO

The remarkable hemodynamic changes of normal pregnancy are briefly reviewed. In addition, new findings and current concepts related to the underlying hormonal and molecular mechanisms are presented. Finally, work that is in progress as well as future directions is briefly discussed.


Assuntos
Rim/irrigação sanguínea , Rim/metabolismo , Gravidez/fisiologia , Relaxina/metabolismo , Vasodilatação/fisiologia , Animais , Feminino , Hemodinâmica , Humanos , Rim/fisiologia
7.
Endocrinology ; 146(6): 2791-7, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15761039

RESUMO

The endothelial endothelin B (ET(B)) receptor subtype is critical for renal vasodilation induced by relaxin in nonpregnant rats and during pregnancy (the latter via endogenous circulating relaxin). Here we tested whether expression of vascular ET(B) receptor protein is regulated by relaxin. Small renal arteries were harvested from virgin and midterm pregnant rats as well as nonpregnant rats that were administered recombinant human relaxin (rhRLX) at 4 mug/h or vehicle for 5 d or 4-6 h. Small renal arteries dissected from additional virgin rats were incubated in vitro with rhRLX or vehicle for 3 h at 37 C. ET(B) expression was also evaluated in cultured human endothelial cells: aortic, coronary, umbilical vein, and dermal microvascular endothelial cells. Cells were incubated for 4, 8, or 24 h with rhRLX (5, 1, or 0.1 ng/ml) or vehicle. ET(B) protein expression in arteries and cells was evaluated by Western analysis. No regulation of ET(B) expression was observed in small renal arteries in any of the experimental protocols, nor was there an increase in the vasorelaxation response to ET-3 in small renal arteries incubated in vitro with rhRLX. rhRLX only sporadically altered ET(B) expression in human coronary artery endothelial cells and human umbilical vein endothelial cells at certain time points or doses, and no regulation was observed in human aortic endothelial cells or human dermal microvascular endothelial cells. These results suggest that regulation of ET(B) receptor protein has little or no role in relaxin stimulation of the endothelial ET(B)/nitric oxide vasodilatory pathway.


Assuntos
Prenhez/metabolismo , Receptor de Endotelina B/metabolismo , Relaxina/metabolismo , Vasodilatação/fisiologia , Animais , Anticorpos Monoclonais , Feminino , Masculino , Gravidez , Ratos , Ratos Long-Evans , Receptor de Endotelina B/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Relaxina/farmacologia , Artéria Renal/efeitos dos fármacos , Artéria Renal/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Vasodilatação/efeitos dos fármacos
8.
J Soc Gynecol Investig ; 11(1): 45-50, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14706683

RESUMO

OBJECTIVE: Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in preeclampsia. The goal of this study was to investigate the role of the maternal kidney in the changes of plasma homocysteine during normal pregnancy and preeclampsia. METHODS: Plasma and 24-hour urine samples were collected in the same women before, during (first, second, and third trimesters), and after normal pregnancy; and in a separate cross-sectional study of normal pregnant, preeclamptic and nonpregnant women and homocysteine concentrations were measured. RESULTS: Longitudinally, maternal plasma homocysteine decreased significantly by the first trimester compared with prepregnancy and postpartum levels (5.6 +/- 1.8 versus 6.8 +/- 0.5 and 7.4 +/- 0.4 microM, respectively, P<.05 by analysis of variance) and paralleled a significant increase in the renal clearance of homocysteine (2.9 +/- 0.4 versus 1.8 +/- 0.2 and 1.6 +/- 0.2 L/24 hours, respectively, P<.001). In addition, plasma homocysteine was significantly elevated in preeclampsia compared with normal pregnancy (4.4 +/- 0.6 versus 3.2 +/- 0.2 microM, P<.04); however, renal clearance was not different (1.2 +/- 0.1 versus 1.0 +/- 0.1 L/24 hours, P=.55). CONCLUSION: Increases in renal clearance contribute to the decrease in plasma homocysteine during normal pregnancy. However, changes in renal handling do not appear to contribute to the increase in plasma homocysteine in preeclampsia.


Assuntos
Homocisteína/sangue , Rim/metabolismo , Pré-Eclâmpsia/sangue , Estudos Transversais , Feminino , Idade Gestacional , Taxa de Filtração Glomerular , Homocisteína/urina , Humanos , Estudos Longitudinais , Taxa de Depuração Metabólica , Pré-Eclâmpsia/urina , Gravidez
9.
Circ Res ; 93(12): 1249-57, 2003 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-14593002

RESUMO

During pregnancy, relaxin stimulates nitric oxide (NO)-dependent renal vasodilation, hyperfiltration and reduced myogenic reactivity of small renal arteries via the endothelial ETB receptor subtype. Our objective in this study was to elucidate the mechanisms by which relaxin stimulates the endothelial ETB receptor/NO vasodilatory pathway. Using chronically instrumented conscious rats, we demonstrated that a specific peptide inhibitor of the gelatinases MMP-2 and -9, cyclic CTTHWGFTLC (cyclic CTT), but not the control peptide, STTHWGFTLS (STT), completely reversed renal vasodilation and hyperfiltration in relaxin-treated rats. Comparable findings were observed with a structurally different and well-established, general antagonist of MMPs, GM6001. In contrast, phosphoramidon, an inhibitor of endothelin-converting enzyme, did not significantly change the renal vasodilatory response to relaxin administration. When small renal arteries were incubated with either of the general MMP inhibitors, GM6001 or TIMP-2 (tissue inhibitor of MMP), or with the specific gelatinase inhibitor, cyclic CTT, the reduced myogenic reactivity of these blood vessels from relaxin-treated nonpregnant and midterm pregnant rats was totally abolished. Moreover, a neutralizing antibody specific for MMP-2 completely abrogated the reduced myogenic reactivity of small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats. In contrast, phosphoramidon did not significantly affect the reduction in myogenic reactivity. Using gelatin zymography, we showed increased pro and active MMP-2 activity in small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats relative to the control animals. Thus, inhibitors of MMPs in general and of gelatinases in particular reverse the renal vascular changes induced by pregnancy or relaxin administration to nonpregnant rats. Finally, the typical reduction in myogenic reactivity of small renal arteries from relaxin-treated nonpregnant rats was absent in ETB receptor-deficient rats, despite an increase in vascular MMP-2 activity. These results indicate an essential role for vascular gelatinase, which is in series with, and upstream of, the endothelial ETB receptor/NO signaling pathway in the renal vasodilatory response to relaxin and pregnancy.


Assuntos
Gelatinases/metabolismo , Rim/efeitos dos fármacos , Relaxina/farmacologia , Artéria Renal/efeitos dos fármacos , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Dipeptídeos/farmacologia , Enzimas Conversoras de Endotelina , Feminino , Gelatinases/antagonistas & inibidores , Gelatinases/fisiologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Técnicas In Vitro , Rim/fisiologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/fisiologia , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Gravidez , Inibidores de Proteases/farmacologia , Ratos , Ratos Long-Evans , Proteínas Recombinantes/farmacologia , Artéria Renal/fisiologia , Vasodilatação/efeitos dos fármacos
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