endothelin-1 and aminaftone

The foam sclerotherapy technique has become one of the most commonly used treatments for superficial venous insufficiency. Despite excellent results, few visual/neurologic disturbances have been recently reported; their pathogenesis is still debated but a correlation with endothelin-1 (ET-1) release from the treated vein has been proposed.. The purpose of this work was to evaluate the ET-1 release after sclerotherapy and to investigate the effects of the anti-endothelin drug aminaphtone.. As in vitro sclerotherapy model, an endothelial cell culture, mimicking vascular endothelium, was pretreated with aminaphtone and exposed to detergents. Cell survival and ET-1 release were measured. In in vivo experiments, 45 rats, fed with different aminaphtone-rich diets, were subjected to sclerotherapy, and the systemic ET-1 was measured.. Aminaphtone cell exposure caused a statistically significant reduction in ET-1 release, both before and after in vitro sclerotherapy. Rats fed with aminaphtone showed a trend toward reduced mortality and a significant decrease of ET-1 release after sclerotherapy.. This is the first study in which an anti-endothelin agent was able to cause a significant reduction of ET-1 release during sclerotherapy. Although clinical studies are required, these findings might advocate the use of anti-endothelin agents in prophylaxis of neurologic or visual disturbances after sclerotherapy.

Topics: Animals; Cell Survival; Cumulus Cells; Dietary Supplements; Endothelin-1; Hemostatics; Human Umbilical Vein Endothelial Cells; Humans; Male; para-Aminobenzoates; Rats; Rats, Wistar; Sclerosing Solutions; Sclerotherapy

Pulmonary hypertension is characterized by increased vascular resistances, that could lead to right heart failure and death. Endothelin-1 (ET-1) is a peptide with strong vasoconstrictive and pro-fibrotic properties and is one of the main mediators of pulmonary hypertension. Aminaftone, a synthetic molecule derivative of 4-amynobenzoic acid, down-regulates ET-1 production in vitro by interfering with the transcription of the pre-pro-ET-1 gene. The aim of this study was to test whether the inhibition of ET-1 production by aminaftone attenuates the effects of pulmonary hypertension. Pulmonary hypertension was induced through s.c. injection of 60 mg/kg monocrotaline. The rats were randomly assigned to the following experimental groups: Control; Monocrotaline; Aminaftone 30 mg/kg/day; Aminaftone 150 mg/kg/day. After 5 weeks, mortality was significantly lower in the animals treated with aminaftone at both doses compared to monocrotaline alone. Aminaftone reduced plasma concentration of ET-1 and seemed to reduce right heart hypertrophy and the wall thickness of the pulmonary arteries at the highest dose. Aminaftone may represent a novel treatment strategy of pulmonary hypertension.

Topics: 4-Aminobenzoic Acid; Animals; Body Weight; Cardiomegaly; Disease Models, Animal; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; para-Aminobenzoates; Pulmonary Artery; Rats; Rats, Wistar; Survival Analysis

Endothelin-1 (ET-1) plays a central role in the pathogenesis of several vascular diseases. Aminaftone is a drug used for the treatment of capillary disorders but which has a mechanism of action that is not fully understood. We investigated whether aminaftone may exert its effect by interfering with the production of ET-1.. Human ECV304 endothelial cells were incubated with interleukin-1beta (IL-1beta) 100 IU/mL with or without the addition of increasing concentrations of aminaftone (2, 4 or 6 microg/mL). ET-1 concentrations in surnatants were quantified by enzyme immunoassay kit at 3, 6 and 12 hours. Pre-pro-endothelin-1 (PPET-1) gene expressions were also analysed by real-time polymerase chain reaction (RT-PCR) at the same time points. Endothelin-converting enzyme (ECE) activity was also determined.. Incubation with IL-1beta increased concentrations of ET-1 and PPET-1 relative gene expression. Incubation with aminaftone significantly reduced production of ET-1 in a concentration-dependent manner. A strong direct correlation was found between ET-1 concentrations and PPET-1 relative gene expression, but aminaftone did not influence ECE activity.. Aminaftone inhibits ET-1 production in cell cultures by interfering with transcription of the PPET-1 gene. These findings may account for the clinical efficacy of aminaftone in the treatment of capillary disorders and may encourage conduct of further clinical trials.

Topics: 4-Aminobenzoic Acid; Aspartic Acid Endopeptidases; Cell Line; Down-Regulation; Endothelial Cells; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Hemostatics; Humans; Interleukin-1beta; Metalloendopeptidases; para-Aminobenzoates; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger