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Year : 2010 | Volume:  42 | Issue Number:  3

LETTER TO EDITOR

A mathematical model to understand the mechanisms of action of class 1 antiarrhythmic drugs

Jain Dinesh K, Arya Raj K, Jain Ashok K

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1 sachin koomra, 3/14/2011 9:08:34 AM
Sir,
I am a PG student in Pharmacology. I have studied anti-arrhythmic drugs as a special topic. This article is confusing and contrary to well documented concepts in genesis of biopotentials. It appears that the authors lack clarity in concepts about electrophysiology operating in heart. The model is off-track and misleading. It is wonder how the article got published in this leading journal of our fraternity. We had a journal club meeting on this article and I am representing the unanimous decision of our pharmacological society.
It is our earnest appeal to you, if possible, to kindly arrange a second review of the wrong scientific contents of this article and decide future action on this wrong model to safeguard the value of this journal. The facts are as follows.
• The genesis of action potential has been depicted wrongly without any role of slow Na+ Ca++-channels.
• The linking of magnitude of action potential with duration is misleading.
• The magnitude of action potential (+120mv) does not change as described in form of 7,8,and 9 units
Sachin Koomra
2 Ajay Jain, 3/15/2011 6:30:37 AM
I fully agree with Dr Sachin Koomra who has explicitly highlighted the errors in the mathematical model which is grossly misleading. In cardiac muscle action potential (AP), the plateau is strictly due to slow Na-Ca channel; hence, the importance of of Ca-modulating drugs in cardiac functioning. Ca-modulating substances do not affect skeletal muscle APas Ca-channels are not involved. The height of AP is fixed, no matter what; and this is due to the All or None principle. The height does not change and play to the tune of the authors who have displayed their lack of understanding of basic electrophysology in cardiac muscle. All assumptions are purely and wildly guess-work and speculative. I also wonder how this paper got published in this journal; in fact, it is hard to believe it has actually got published. Dr Ajay Jain, New Delhi
3 Pornima Tonpay, 3/25/2011 1:10:17 AM
Based on Editorial comments on submission ref no. IJP_165_11


Sir,

The mathematical model to understand the mechanisms of action of class I

anti-arrhythmic drugs is a conceptually erroneous and distorted model.

The model presented in the paper [1] is a conceptual error with serious violation of fundamental All or None law, which is exhibited faithfully by excitable tissues and upon which the whole model has been made to rest.
The authors’ equilibration of +120 mv action potential (AP) height to10 units’ height implies 1 unit height to represent 12 mv in view of which, mild, moderate and profound blockages of Na+ channels lead to 9 units (108 mv), 8 units (96 mv) and 7 units (84 mv) respectively and raise an erroneous state of varying AP-strengths of 108, 96 and 84 mv height (amplitude) which is a conceptually-erroneous presentation of APs. The AP is invariably of +120 mv (under constant conditions) when Purkinje fibers are stimulated at their resting membrane potential of -90 mv (as depicted in the various figures of the paper).
According to All or None law, if a stimulus is adequate to raise the potential of Purkinje fibers to firing level, a full-fledged AP (of +120 mv) develops irrespective of the strength of the stimulus. This is a fundamental law and property exhibited by excitable tissue (in this case, the Purkinje fibers).
The cardiac muscle and Purkinje fibers also follow the simple law of All or None law (response) faithfully, which remains a fundamental governing law in excitable tissue.
In the cited brief paper [1], this fundamental law has been totally violated and appears to have been even quashed to satisfy a conceptually erroneous view that is based solely on vague, bizarre and unfounded presumptions.
Since this model has been intended to simplify the understanding of class I anti- arrhythmic drugs among students, the sustenance of this brief paper in its present form appears detrimental not only to the basic concepts in the minds of the students but also to the reputation of the journal with far-reaching adverse consequences.
Other serious concerns are:
a. Page-1; para-3: Outward (delayed) rectified K+ current that flows in phase 2 (plateau) “completes” repolarization and NOT “initiates” repolarization as stated by the authors. Initiation of repolarization is due to closure of Na+ channels [2] (observed as an acute dip in the AP) and probably contributed by flow of transient outward K+ current in phase 1, but certainly not by delayed rectified current of phase 2 as erroneously stated by the authors.
b. Currents “flow” and not “open” as has been repeatedly stated in the paper; the use of the term “open” is likely to confuse the readers (students in particular) with channel/gate events.
c. It is claimed to be a mathematical model, but attempting to explain the so-called model in highly vague terms of mild, moderate and profound blockage of Na+ channels does not display any mathematical or numeral figures to present.
d. All the presumptions adhered to in the paper are unfounded and imaginary lacking any scientific evidence in support.
e. A relationship between AP amplitude and AP duration (APD) appears to have been forcibly framed, again to satisfy the distorted viewpoint. This relation does not exist in case of action potentials, although it may be applicable in case of an ECG.
f. No mention of important role of Ca++ channels has been even made in the development of the action potential.

Thus, in view of violation of the fundamental All or None law upon which the whole viewpoint is based and in the larger interest of the student community and reputation of the journal, this model appears to stand seriously flawed and invalid.






References:
1. Jain DK, Arya RK, Jain AK. A mathematical model to understand the

mechanisms of action of class 1 antiarrhythmic drugs. Indian J Pharmacol

2010;42:195-6.

2. Ganong WF. Review of Medical Physiology. 21...


 

 

 

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