Simulation Of Acetylcholine Cardiac Overload Caused By Soman, A Cholinesterase Inhibitor

 

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Subject:    Simulation Of Acetylcholine Cardiac Overload Caused By Soman, A Cholinesterase Inhibitor
 Date:        Mon, 23 Apr 2001 07:49:36 -0400
From:        Stephen Tvedten <steve@getipm.com>
Organization:     Get Set Inc. (www.getipm.com)

To:     Paul Helliker <phelliker@cdpr.ca.gov>
          Director, State of California, Department of Pesticide Regulation 

cc:    Christine Whitman whitman.christine@epa.gov

Dear Mr. Helliker, I thought you might like to read an article entitled:

Session S52.4
Simulation Of Acetylcholine Cardiac Overload Caused By Soman, A Cholinesterase Inhibitor 
C.K. Zoltani, S.I. Baskin

ARL and USA Medical Res. Inst. Chem. Defense Aberdeen Proving Grounds, MD, USA

Organophosphonates (OP's) are considered to be chemical threat agents. It was mandated of these labs to investigate the mechanisms, treatment and possible counteractions to these threats. OP's are known to produce not only atrial bradyarrhythmia, but also serious conduction cardiac arrhythmias that can lead to death. Simulation of these types of arrhythmias on various cardiac structures may provide a rational understanding of which structure would most contribute to the pathologic cardiac picture and thus should allow for improved therapy. OP produced acetylcholine (ACh) overload of the heart was simulated by its effect on the sino atrial (SA) node, the Purkinje fiber and the ventricle of the rabbit. The observed pathology as a function of ACh concentration was studied in terms of the divergence of the membrane currents and the action potential from baseline. The models used were those of the Oxford and Calgary groups. Cases were run on SGI workstations and the Origin2000 at the ARL MSRC. ACh concentrations were varied from 1.0E-8 to 1.0E-4M. Changes in the membrane currents i(K,ACh), i(f) and i(Ca,L) were determined. Separate runs with changes in the potassium conductivity and channel gating as a function of ACh concentration were performed. Bradycardia of the SA node was noted at 1.0E-6M of ACh and complete cessation of automaticity occurred at 1.0E-4M. The ventricles exhibited tachycardia and development of a notch in the phase 1 region of the action potential as the ACh concentration increased. At a concentration of 1.0E-5M incipient fibrillation and a sharp decline in contractility was observed. In the Purkinje fibers, the action potential ceased at approximately 1.0E-5M. Good agreement with published experimental data for lower ACh concentrations was found. The study suggests that the search for antidotes, beside ACh scavengers, drug antagonists that influence the magnitude of the i(K,ACh) may be most fruitful as potential (OP) anomalous rectifiers.

A HREF="http://cinc.mit.edu/Program/s52-4.htm

Well Mr. Helliker, Zane Gard, M.D., once told me that basically whenever he had a patient that suffered a heart attack, he found the trigger was exposure to one of your "registered" POISONS. I read with interest your comments to Fairfax, CA, clearly stating that you would not let the people protect themselves from such "registered" exposures. I hope that you discover at some point in your career that you work for the people and not the POISON "industry". Zig Ziglar once noted: "Hardening of the attitudes is the most deadly disease on the face of the earth." I think this "disease", is far worse on the hearts of the innocent than hardening of the arteries.

Respectfully, Stephen L. Tvedten

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