Buffalo, NY - A peptide found in tarantula venom could become the first of a new class of drugs for atrial fibrillation (AF), according to a brief communication in the January 4, 2001 issue of Nature. Dr Fredrick Sachs (Department of Physiology and Biophysics, SUNY, Buffalo, NY) and colleagues report that the venom peptide, known as GsMtx-4, inhibits AF following atrium dilatation in explanted perfused rabbit hearts. According to the researchers, the peptide differs from current AF drugs, as it works by directly blocking the excitatory currents responsible for arrhythmia.
Sachs et al suspected GsMtx-4 as a possible antiarrhythmic because the peptide can bind and obstruct stretch-activated ion channels (SACs) present in cardiocytes. These SACs, the researchers believe, conduct excitatory ion currents responsible for AF. As Sachs explained to heart wire , when the atrium is stretched, cardiocyte SACs open, allowing an influx of positive ions (mostly sodium) into the cells, sufficient to generate AF. Such stretching, he notes, occurs particularly during systole and in regions of damaged and weakened heart tissue.
The researchers tested their theory by inducing sustained AF in explanted rabbit hearts by subjecting the hearts to atrial pressures > 12.5 cm H2O. They then demonstrated that perfusion of the hearts with GsMtx-4 reduced both the inducibility and duration of the AF. At atrial pressures <17.5 cm H2O, GsMtx-4 completely inhibited sustained fibrillation.
The authors conclude, "Atrial fibrillation potentiated by dilatation in rabbit heart can be inhibited by blocking stretch-activated ion channels with a specific peptide from tarantula venom." They add, "Stretch sensitivity is not unique to the atrium, so GsMtx-4 should act similarly on all chambers."An antiarrhythmic that targets the causes rather than the symptoms of AF
One of the surprising results of this work was that GsMtx-4 did not lengthen the refractory period of the cardiocytes - which is generally how antiarrhythmics work. This suggests to the researchers that they have a whole new class of antiarrhythmics on their hands, one "directed against the causes rather than the symptoms of fibrillation." "Most of the antiarrhythmic agents are designed to change the shape of the action potential so that there is less time available for uncoordinated contraction. That's masking the symptoms," says Sachs, "I think [with GsMtx-4] we are getting closer to the cause of the fibrillation."
Sachs et al have begun to synthesize the venom peptide both by molecular biology and chemical synthesis. They have tested the synthetic version of the peptide for efficacy. They will need to test for toxicity: GsMtx-4, in addition to blocking cardiocyte SACs, also blocks SACs in astrocytes, and therefore its effect on nerve function will need to be investigated. Currently, the researchers are looking for a drug company interested in collaborating with them: "We are trying to find a company to make [GsMtx-4] into a useful compound and maybe use it as a model for making small organic molecules that block the same channel, so that you take [the agent] orally instead of by IV."
Heartwire from Medscape © 2001
Cite this: Tarantula venom may inhibit atrial fibrillation - Medscape - Jan 18, 2001.