Effects of Cardiotoxins from Naja oxiana Cobra Venom on Rat Heart Muscle and Aorta: A Comparative Study of Toxin-Induced Contraction Mechanisms.

Alexey S Averin,Victor I Tsetlin,Vladislav G Starkov,Miroslav N Nenov,Yuri N Utkin

doi:10.3390/toxins14020088

Alexey S Averin, Victor I Tsetlin + Show 3 more

Open Access

https://doi.org/10.3390/toxins14020088

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Abstract

Cardiotoxins (CaTxs) are a group of snake toxins that affect the cardiovascular system (CVS). Two types (S and P) of CaTxs are known, but the exact differences in the effects of these types on CVS have not been thoroughly studied. We investigated cellular mechanisms of action on CVS for Naja oxiana cobra CaTxs CTX-1 (S-type) and CTX-2 (P-type) focusing on the papillary muscle (PM) contractility and contraction of aortic rings (AR) supplemented by pharmacological analysis. It was found that CTX-1 and CTX-2 exerted dose-dependent effects manifested in PM contracture and AR contraction. CTX-2 impaired functions of PM and AR more strongly than CTX-1. Effects of CaTxs on PM were significantly reduced by nifedipine, an L-type Ca2+ channel blocker, and by KB-R7943, an inhibitor of reverse-mode Na+/Ca2+ exchange. Furthermore, 2-aminoethoxydiphenyl borate, an inhibitor of store-operated calcium entry, partially restored PM contractility damaged by CaTxs. The CaTx influence on AR contracture was significantly reduced by nifedipine and KB-R7943. The involvement of reverse-mode Na+/Ca2+ exchange in the effect of CaTxs on the rat aorta was shown for the first time. The results obtained indicate that CaTx effects on CVS are mainly associated with disturbance of transporting systems responsible for the Ca2+ influx.

Highlights

The cardiovascular system (CVS) is one of the main targets of snake venom toxins. a significant number of venoms affect the activity of the CVS, not all of them act directly on the heart
A comparative analysis of the activity of CaTxs and the mechanisms of the development of their effects in time remains an unsolved problem. To make such a comparison, in this work we study the effects of cytotoxins I and II (CTX-1 and CTX-2), belonging to the S- and P-types, respectively, from the venom of the Central Asian cobra Naja oxiana [13] on the contractility of rat myocardial and thoracic aorta preparations, the latter preparation being used as a sample of smooth muscle tissue
We previously investigated the effect of CaTxs on the rat papillary muscles (PMs) and found that two cobra Naja oxiana CaTxs changed the force of contraction and the character of rhythmoinotropic phenomena in the rat myocardium [18]

Summary

Introduction

The cardiovascular system (CVS) is one of the main targets of snake venom toxins. a significant number of venoms affect the activity of the CVS, not all of them act directly on the heart. It should be noted that researchers did not provide exact data on the amino acid sequence of the CaTx used in all cases In those studies that provided precise indications of the structure of the CaTx, the toxin CTX A3 of the P-type from the venom of the cobra Naja atra was typically used (e.g., [12]). A comparative analysis of the activity of CaTxs and the mechanisms of the development of their effects in time remains an unsolved problem To make such a comparison, in this work we study the effects of cytotoxins I and II (CTX-1 and CTX-2), belonging to the S- and P-types, respectively, from the venom of the Central Asian cobra Naja oxiana [13] on the contractility of rat myocardial and thoracic aorta preparations, the latter preparation being used as a sample of smooth muscle tissue. We carried out an extensive pharmacological analysis in order to shed light on the possible role of various Ca2+ transport systems in the effects of CaTxs on the contractile activity of the PM and aorta ring (AR)

Results and Discussion

Materials

Animal Handling

Contractility of Papillary Muscles

Contractility of Aortic Rings

Data Analysis and Statistics