Key result
OSI 9719 significantly prolongs action potential duration and increases myocardial contraction force.
Why the study?
Identifying the activity properties of newly synthesized compounds is needed to select adequate research methodologies, motivating an investigation into the relationship between the chemical structure of 25 1,4-dihydropyridine derivatives and their effects on guinea pig papillary muscle contraction force and action potential duration.
In experimental models, most 1,4-dihydropyridine derivatives exhibit negative inotropic effects without altering action potential duration, with the exception of OSI 9719.
Contraction force assessment outperforms AP duration for screening 1,4-dihydropyridine effects in guinea pig myocardium; leaves open translation to human compound selection.
Background. Identification of activity properties of new synthesized compounds is important to help choose the adequate research methodology. The goal of this experimental research was to determine the relationship between the chemical structure of 25 compounds of 1,4-dihydropyridine derivatives and their effects on the contraction force of guinea pig papillary muscles and the action potential (AP) duration. Methods. AP recordings were obtained with standard microelectrodes that were made from borosilicate glass capillaries, filled with 2.5 M KCl and connected to the high-input impedance amplification system. 1.0 Hz stimulation frequency was used. The contraction of papillary muscles was recorded by using a force transducer. Both signals (inotropic response and AP) were digitised by an A/D converter and registered by a computer specialised program. Results. The results have shown that most of 1,4-dihydropyridine derivatives possessed the negative inotropic action and had the negligible impact on the AP duration. It was identified that 1,4-dihydropyridine compound OSI 9719 (2-propoxyethyl-4-difloemethoxyphenyl-2-methyl-5-nitro-1,4-dihydropyridine-3carboxylate) had a prolonged duration of AP and simultaneously increased the force of contraction (p < 0.05). It was shown that the efficiency of 1,4-dihydropyridine derivatives depends on the nature (diflormethoxy-, propoxy-, ethoxycarbonyl-, amine, atom chlorine, ethylene glycol-, isopropoxy-) of the substituents and their spatial isomerisation in the phenyl and 1,4-dihydropyridine rings and the concentration of the compounds. Conclusion. Evaluation of the contraction force of guinea pig papillary muscles is a more informative method than evaluation of the action potential duration, conducting experimental research of the activity properties of 1,4-dihydropyridine derivatives.
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Barsys et al. (2015) studied this question. 25 compounds of 1,4-dihydropyridine derivatives (including OSI 9719) was evaluated on Contraction force and action potential duration of guinea pig papillary muscles (p=<0.05). 1,4-dihydropyridine derivative OSI 9719 significantly prolonged action potential duration and increased contraction force in guinea pig papillary muscles (p < 0.05).
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