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.

Snake Venom Peptides: Tools of Biodiscovery

“…C-terminal extension can result in different spatial conformation of the two peptides [ 163 ]. SRTXs can serve to better understand the endothelin system and related diseases, such as pulmonary hypertension, asthma, and/or heart failure [ 163 , 164 , 165 ]. SRTX was used to uncover the communication pathways between the peptide and ET receptor.…”

Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

“…Despite their evolutionary novelty and documented severe envenomation effects, their venom is underinvestigated relative to the intensive efforts on elapid and viperid snake venoms. Work to-date has largely focused on the endothelin-type peptides called sarafotoxins which are responsible for the dramatic rise in blood pressure observed clinically (Abd-Elsalam, 2011;Atkins et al, 1995;Borgheresi et al, 2001;Goyffon, 1994;Ismail et al, 2007;Kawanabe and Nauli, 2011;Kolb, 1991;Mahjoub et al, 2015;Malaquin et al, 2016;Nakajima et al, 1989;Nayler et al, 1989;Patocka et al, 2004;Takasaki et al, 1992;Tilbury and Verster, 2016;Warrell et al, 1976). The only other characterized toxin type from Atractaspis venom has been a hemorrhagic metalloprotease (Ovadia, 1987).…”

Respiratory Effects of Sarafotoxins from the Venom of Different Atractaspis Genus Snake Species

“…This hemodynamic phenomenon cannot be evaluated, as left ventricular pressure was not assessed in this protocol. However, in a previous experimental study focusing on the hemodynamic effects of SRTX-b, we demonstrated that SRTX-b exerted a negative lusitropic effect, i.e., impairment of left ventricular (LV) relaxation reflected by an increase of Tau, the relaxation time constant [ 8 ]. This finding was in accordance with previous animal and human studies [ 24 ].…”

“…Third, we did not study the dose-response relationship for SRTX. We used only one dose of 1 LD 50 as in previous studies in order to have a comparable effect [ 8 ]. Finally, SRTX-m was initially reported to have been isolated from the venom of Atractaspis microlepidota microlepidota , and that finding was confirmed by molecular cloning from the corresponding venom-gland cells [ 4 ].…”

“…Nevertheless, the toxicity as assessed by the LD 50 of these two sarafotoxins is in the same range (15 μg/g vs. 30 μg/g for SRTX-m). A previous in vivo animal study showed that SRTX-b and SRTX-m have very different cardiovascular effects: SRTX-b induces left ventricular dysfunction, resulting in decreased cardiac output, while SRTX-m induces right ventricular dysfunction and increased airway pressure [ 8 ]. However, the precise effects of SRTX-m on respiratory mechanics and gas exchange have not been investigated yet.…”