Mechanisms of Cardiac Muscle Insensitivity to a Novel Acetylcholinesterase Inhibitor C-547

Abstract

We compared the effects of the novel acetylcholinesterase (AChE) inhibitor C-547 on action potential configuration and sinus rhythm in the isolated right atrium preparation of rat with those of armin and neostigmine. Both armin (10(-7), 10(-6), and 10(-5) M) and neostigmine (10(-7), 10(-6), and 5 x 10(-6) M) produced a marked decrease in action potential duration and slowing of sinus rate. These effects were abolished by atropine and are attributable to the accumulation of acetylcholine in the myocardium. The novel selective AChE inhibitor C-547 (10(-9) to 10(-7) M), an alkylammonium derivative of 6-methyluracil, had no such effects. The inhibition constant of C-547 on cardiac AChE is 40-fold higher than that on extensor digitorum longus muscle AChE. These results suggest that C-547 might be employed to treat diseases such as myasthenia gravis or Alzheimer disease, without having unwanted effects on the heart.

Non‐quantal release of acetylcholine from parasympathetic nerve terminals in the right atrium of rats

“…1) and also significantly reduced the decrease of APD 50 induced by armin (Figs 1 and 2A). A similar action of atropine was shown in the neostigmine experiments (Abramochkin et al 2009). Therefore, the effects of AChE inhibitors are ascribed to activation of muscarinic receptors induced by accumulation of ACh, but not to the additional effects of inhibitors.…”

“…Nothing is known about non‐quantal release of ACh in the myocardium. In our recent studies, we observed cardiotropic effects of AChE inhibitors that are very similar to the effects of exogenous ACh (Abramochkin et al 2008, 2009). In the present study, we provide the first evidence of non‐quantal secretion of ACh from the parasympathetic nerve terminals in the rat heart.…”

“…We have recently demonstrated that application of neostigmine (10 −7 , 10 −6 and 5 × 10 −6 m ) produces an analogous concentration‐dependent decrease of APD 50 and APD 90 and slowing of the sinus rate (Abramochkin et al 2009).…”

Specific inhibitory effects of the alkylammonium derivative 6-methyluracil on acetylcholinesterase of smooth and striated muscles in rats

“…We have also found that compound no. C 547 inhibits AChE in the myocardium at concentrations, which are two orders of magnitude higher than those that completely inhibit AChE in the skeletal muscles [8]. C 547 contains in its structure quaternary nitro gen that troubles its transition across the blood-brain barrier; therefore, the most probable area of its appli cation is treatment of syndromes of pathological mus cular weakness and smooth muscle atonia.…”