title: Short- versus Long-Sarafotoxins: Two Structurally Related Snake Toxins with Very Different in vivo Haemodynamic Effects.
abstract: Sarafotoxin-m (24 amino acids) from the venom of Atractaspis microlepidota microlepidota was the first long-sarafotoxin to be identified, while sarafotoxin-b (21 aa) is a short-sarafotoxin from Atractaspis engaddensis. Despite the presence of three additional C-terminus residues in sarafotoxin-m, these two peptides display a high sequence homology and share similar three-dimensional structures. However, unlike sarafotoxin-b, sarafotoxin-m shows a very low in vitro affinity for endothelin receptors, but still has a very high in vivo toxicity in mammals, similar to that of sarafotoxin-b. We have previously demonstrated, in vitro, the crucial role of the C-terminus extension in terms of pharmacological profiles and receptor affinities of long- versus short-sarafotoxins. One possible hypothesis to explain the high in vivo toxicity of sarafotoxin-m could be that its C-terminus extension is processed in vivo, resulting in short-like sarafotoxin. To address this possibility, we investigated, in the present study, the in vivo cardiovascular effects of sarafotoxin-b, sarafotoxin-m and sarafotoxin-m-Cter (sarafotoxin-m without the C -terminus extension). Male Wistar rats were anaesthetised and mechanically ventilated. Invasive haemodynamic measurements and echocardiographic measurements of left and right ventricular function were performed. The rats were divided into four groups that respectively received intravenous injections of: saline, sarafotoxin-b (one LD50), sarafotoxin-m (one LD50) or sarafotoxin-m-Cter (one LD50). All measurements were performed at baseline, at 1 minute (+1) and at 6 minutes (+6) after injection.
  
  
  RESULTS
  Sarafotoxin-b and sarafotoxin-m-Cter decreased cardiac output and impaired left ventricle systolic and diastolic function, whilst sarafotoxin-m decreased cardiac output, increased airway pressures and led to acute right ventricular dilatation associated with a decreased tricuspid annulus peak systolic velocity. Sarafotoxin-b and sarafotoxin-m-Cter appear to exert toxic effects via impairment of left ventricular function, whilst sarafotoxin-m increases airway pressures and impairs right ventricular function. These results do not support the hypothesis of an in vivo processing of long sarafotoxins.
authors.affiliation: Pôle d'anesthésie, réanimation et médecine d'urgence, CHU Amiens, Amiens, France; Unité INSERM U1088, Amiens, France.
authors.forename: Yazine
authors.initials: Y
authors.lastname: Mahjoub
authors.affiliation: Pôle d'anesthésie, réanimation et médecine d'urgence, CHU Amiens, Amiens, France; Unité INSERM U1088, Amiens, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Malaquin
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA Saclay, F-91191 Gif sur Yvette, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mourier
authors.affiliation: Pôle d'anesthésie, réanimation et médecine d'urgence, CHU Amiens, Amiens, France; Unité INSERM U1088, Amiens, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lorne
authors.affiliation: Pôle d'anesthésie, réanimation et médecine d'urgence, CHU Amiens, Amiens, France; Unité INSERM U1088, Amiens, France.
authors.forename: Osama
authors.initials: O
authors.lastname: Abou Arab
authors.affiliation: Unité INSERM U1088, Amiens, France.
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
authors.affiliation: Pôle d'anesthésie, réanimation et médecine d'urgence, CHU Amiens, Amiens, France; Unité INSERM U1088, Amiens, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dupont
authors.affiliation: CEA, iMETI, Service d'Immuno Virologie (SIV), CEA Fontenay-aux-Roses, F-92265 Fontenay-aux-Roses, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ducancel
mesh_terms: D000818:Animals; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008168:Lung / Q000187:drug effects; D008297:Male; D011312:Pressure; D017208:Rats, Wistar; D015203:Reproducibility of Results; D040681:Structural Homology, Protein; D016276:Ventricular Function / Q000187:drug effects; D014757:Viper Venoms / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D014757:Viper Venoms