s6c-sarafotoxin and Inflammation

The heart failure syndrome is associated with a reduced vasodilatory capacity in cutaneous microvessels. The aim of this study was to investigate the hypothesis that an altered activity of the endothelin system contributes to this reduction. The skin blood flow was recorded by laser Doppler flowmetry in patients with congestive heart failure and in age- and gender-matched controls without clinical signs of heart failure. The vessels were stimulated by iontophoretic administration of endothelin-1. The involvement of the endothelin(A) receptor was studied by co-administration of a specific antagonist; the role of the endothelin(B) receptor was studied by the administration of the selective agonist sarafotoxin 6c. The plasma levels of endothelin-1, C-reactive peptide and N-terminal-pro-Brain Natriuretic Peptide were elevated in heart failure patients. Unexpected, endothelin-1 induced an endothelin(A) mediated vasodilation. In the heart failure group the dilation was reduced to less than half as compared to control. The response to local warming was reduced in parallel indicating that the attenuation of the response in the heart failure group can be explained by the general decline in vascular reactivity. The response to endothelin(B) receptor stimulation did not differ between the groups. The reduction in endothelin-1 responsiveness is paralleled by a general reduction in microvascular vasodilatory capacity, a phenomenon of increased vascular stiffness in the of heart failure subjects.

Topics: Aged; Aged, 80 and over; Area Under Curve; Biomarkers; Blood Pressure; Cholesterol, LDL; Endothelins; Female; Heart Failure; Humans; Inflammation; Iontophoresis; Male; Microcirculation; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Receptor, Endothelin B; Skin; Vasodilation; Vasodilator Agents; Viper Venoms

Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions.. Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c.. Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP.. ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Topics: Animals; Antimicrobial Cationic Peptides; Blood Proteins; Capillary Leak Syndrome; Carrier Proteins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Endotoxins; Extravascular Lung Water; Female; Hemodynamics; Inflammation; Infusions, Intravenous; Leukocyte Count; Male; Neutrophil Activation; Pulmonary Edema; Pyridines; Random Allocation; Receptor, Endothelin B; Sus scrofa; Swine; Tetrazoles; Viper Venoms

The hypothesis that up-regulation of bronchial constrictor endothelin receptors in airway smooth muscle cells may contribute to hyperreactivity during airway inflammation was tested in the present study by quantitative endothelin receptor mRNA analysis and functional responses in ring segments of rat trachea and bronchi. Real time reverse transcription polymerase chain reaction was used to quantify endothelin receptor expression in rat airway smooth muscle cells following Sephadex-induced inflammation. Compared with controls, Sephadex-induced airway inflammation caused a significant increase (3.9 times P<0.05) of endothelin receptor type B mRNA expression in bronchial smooth muscle cells, but not in tracheal smooth muscle cells. Functional myograph studies of bronchial and tracheal ring segments without epithelium (mechanically denuded) revealed an increase of the maximum contractile effects of endothelin-1 (a dual agonist for both endothelin type A and B receptors) and sarafotoxin 6c (a selective agonist for endothelin B receptors) in bronchial smooth muscle cells in Sephadex-induced inflammation, but not in tracheal smooth muscle cells. The enhanced maximal responses of bronchial smooth muscle cells to endothelin-1 and sarafotoxin 6c in Sephadex-induced inflammation support our molecular findings and hence imply a role for endothelin B receptors in airway hyperreactivity during airway inflammation.

Topics: Animals; Bronchi; Dextrans; Endothelin-1; In Vitro Techniques; Inflammation; Male; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trachea; Up-Regulation; Viper Venoms