Elsevier

Toxicon

Volume 43, Issue 7, June 2004, Pages 743-750
Toxicon

Cardiovascular effects of the toxin(s) of the Australian paralysis tick, Ixodes holocyclus, in the rat

https://doi.org/10.1016/j.toxicon.2004.02.025Get rights and content

Abstract

An extract of toxin(s) from the Australian paralysis tick, Ixodes holocyclus, produced positive inotropic responses in rat left ventricular papillary muscles and positive contractile responses in rat thoracic aortic rings. There was no measurable chronotropic response in rat right atria, but positive inotropic concentrations in papillary muscles produced arrhythmias in right atria. Positive inotropic responses were attenuated by verapamil, but unaffected by metoprolol, cimetidine, pyrilamine, tetrodotoxin and pinacidil. Microelectrode studies on isolated left ventricular papillary muscles demonstrated that the extract prolonged action potential duration at 20, 50 and 90% of repolarisation and delayed ventricular papillary muscle relaxation. Cardiovascular tissues isolated from rats with experimentally induced tick paralysis showed no myocardial damage as identified by histological and ultrastructural examination. The basal rate and force of contraction of isolated cardiac tissues were lower from tick-paralysed than normal rats. Concentration–response curves to dobutamine and calcium chloride were similar between tissues from tick-paralysed and normal rats. Thus, the Australian paralysis tick, I. holocyclus, produces one or more toxins with direct cardiovascular effects which mimic the effects produced by direct blockade of cardiac and vascular K+ channels.

Introduction

Of the 869 known tick species, the Australian paralysis tick, Ixodes holocyclus, is one of the 69 species that produce toxins causing paralysis (Gothe and Neitz, 1991). The toxin produced by I. holocyclus inhibits the release of acetylcholine from the neuromuscular junction to produce an ascending flaccid paralysis in the host (Cooper and Spence, 1976). Tick toxins may also produce cardiovascular responses. In dogs with naturally occurring tick paralysis, cardiac mechanical and electrical dysfunction shown as reductions in echocardiographically-derived functional indices with accompanying QT prolongation have been described (Campbell and Atwell, 2002, Campbell and Atwell, 2003). Sinus arrhythmia was described in marmots parasitised by Dermacentor andersoni (Emmons and McLennan, 1960). Electrocardiographic alterations, including QT prolongation were reported in mice following injection of toxin extracts of the tick, Ornithodoros savignyi (Mans et al., 2002).

The cardiovascular responses to many naturally-occurring toxins are due to blockade of voltage-dependent ion channels, especially K+ channels on neurones and myocytes. Such toxins, usually peptides in nature, have been derived from scorpions (Harvey et al., 1995, Goudet et al., 2002), spiders (Sanguinetti et al., 1997), snakes (Harvey, 2001), sea anemones (Kalman et al., 1998) and bees (Bond et al., 1999). Some of these toxins are remarkably selective; for example, the scorpion toxin charybdotoxin alters large conductance Ca2+ activated K+ channels (Kaczorowski et al., 1996) and the heteropodatoxins modify transient outward K+ channels on rat myocytes (Sanguinetti et al., 1997). These toxins may produce marked cardiovascular responses, in particular direct inotropic, action potential duration (APD) prolonging and positive lusitropic effects on isolated left ventricular papillary muscles and contractile responses on isolated thoracic aortic rings similar to 4-aminopyridine, indicating an action involving K+ channel blockade.

This study was performed to determine the effects of the toxin(s) from a crude extract of I. holocyclus on isolated rat cardiovascular tissues. Mechanical and electrical responses were determined in isolated tissues to measure responses independent of the loading conditions and reflex mechanisms that occur in vivo. Various antagonists were utilised to determine the likely cellular mechanisms of the responses. In addition, responses were measured in tissues taken from normal or tick-paralysed male Wistar rats. The current study is the first to identify that a crude tick extract, like other naturally-occurring toxins, produces direct cardiovascular responses probably by membrane ion channel alteration.

Section snippets

Methods

Male Wistar rats (9–11 weeks old) and suckling mice (4–5 g) obtained from The University of Queensland Central Animal Breeding House were used in these experiments. All experimental protocols were approved by the Animal Experimentation Ethics Committee of The University of Queensland (Phys/Ph/469/99 and P&Ch/Para/409/98) under the guidelines of the National Medical and Health Research Council of Australia.

Biological assays

Suckling mice injected with crude tick toxin developed clinical signs identical to the clinical signs produced by injected salivary gland extracts of I. holocyclus. Furthermore, when combined in a 4:7 ratio with crude tick toxin, tick antitoxin serum was protective and no clinical signs developed when the combination was injected into suckling mice. This verified that the crude tick toxin contained the paralysis toxin(s) that are produced and secreted by the tick and this crude extract was

Discussion

This study has shown that a crude tick toxin from I. holocyclus produces marked cardiovascular responses, in particular direct inotropic, APD prolonging and positive lusitropic effects on isolated left ventricular papillary muscles and contractile responses on isolated thoracic aortic rings. Higher concentrations produced arrhythmic responses in isolated right atria. Positive inotropic responses were not due to activation of β-adrenoceptors, histamine receptors, KATP or Na+ channels. Further,

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