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The average daily gain of lambs of experimental group averaged 188.7 ± 0.57 g., and in the control group — 152.0 ± 0.78 g. or 19.5 % favor the experimental group. Our findings correspond to the data of some authors, the results of experiments carried out in good years for fodder and climatic conditions. In addition, we studied the effect of standardized feeding on chemical composition and biological value of milk, as well as the body's resistance lambs fed on mother's milk in a lactation period of the year. In our opinion, the study of this problem makes it possible to predict the natural resistance of the organism growing lambs left on to replenish the herd.
The content of dry matter in milk, as well as its components — fat, total protein, casein, and lactose, was in all cases more in the milk of experimental groups than in the control group (table 3).
At six months of age in lambs, that is, if the beat of the mothers received differences at birth survived, and the difference between groups was 5.16 kg., it is said that during the grazing lambs with their mothers, they used the same in the same amount of feed. In addition, since the beginning of the birth, feeding biologically high-grade food means lambs of the experimental group had greater average daily gain. On this basis, we believe that the
difference between the comparison groups has found credible evidence.
Table 3. - Physico-chemical properties of experimental ewes milk
№ Indicators Groups
Control Experienced
1 Dry substance, % 12.79 ± 0.15 15.54 ± 0.24
2 Fat, % 4.82 ± 0.16 5.20 ± 0.09
3 Total protein, % 3.52 ± 0.04 4.16 ± 0.17
4 Casein, % 2.86 ± 0.04 3.40 ± 0.18
5 Lactose, % 4.46 ± 0.03 5.19 ± 0.13
Conclusions
We believe that the organization of the normalized feeding karakul sheep since the beginning of winter, before the beginning of the spring period, make it possible to keep the body weight of ewes in the middle of fatness and get the required amount of high-grade milk. This can contribute to obtaining a larger litter. In the future, it can serve as a means for farmers to increase of production and conservation of highly Karakul sheep, as well as constitute a major factor in the economic sector.
References:
1. Bobokulov N. Ethological bases and histological methods of increasing the efficiency of Karakul Uzbekistan. - Tashkent, 2014. - 208 p.
2. Bazarov C. Improving breeding and genetic basis of breeding of karakul sheep suras under Kyzylkum. Doctoral Dissertation. - Samarkand, 2015. - 24 p.
3. Viktorov P. A technique and organization of zootechnical tests/Menkin V. K. - M.: Agropromizdat, 1991. - P. 38-65.
4. Standards and ration feeding farm animals. Reference Manual/Kalashnikov A. P., Fisinin V. I., Shcheglov V. et al., Ed. Kalashnikov A. P., Fisinin V. I., Shcheglov V. V., Kleimenova N. I. et al. dop. pererabot 3. - M.: Agropromizdat, 2003. - 456 p.
5. Mikhaylenko A. K. Environmental aspects of the formation of physiological, biochemical, immunogenetic status and productivity of animals in ontogeny. Doctoral Dissertation. - Stavropol, 2010. - 30 p.
6. Merkuryeva E. K. Genetics with the basics of biometrics/G. V. Shangin-Berezovsky. - M.: Kolos, 1983. - 400 p.
7. Ovsyannikov A. I. Basics of experimental work in animal husbandry. - M.: Kolos, 1976. - 302 p.
8. Razhamuradov Z. T. Physiological aspects of the supply of wool of goats at pasture year-round content in the conditions of Northern Tajikistan. Abstract of doctoral dissirtatsii. - village Dubrovitsy, 1992.
9. Risimbetov T. K., Kuzimbaev J., Schuklina Z. P. New technology in the cultivation of karakul lambs//Collection of scientific works KazNIIK. - Kainar, Alma-Ata,1981. - T. 6. - P. 61-65.
10. Yusupov S. Y., Saliev V. X., Bazarov S. R. Milking ewes Karakul of different colors and types of constitutional conditions in the Kyzyl-kum//Collection of scientific works VNIIK. -Tashkent, 1991. - Vol. 2. "Technology issues Karakul". - P. 3-4.
Zaynabiddinov Anvar Erkinjonovich, post-graduate, Sadykov Institute of Bioorganic Chemistry, Uzbek Academy of Sciences, Tashkent, Uzbekistan E-mail: azaynobiddinov@bk.ru Usmanov Pulat Bekmuratovich, Doctor of science, professor, Sadykov Institute of Bioorganic Chemistry, Uzbek Academy of Sciences, Tashkent, Uzbekistan
Effect of 15-hydroxyazomethine and 15-acetoxyazomethine, diterpenoid alkaloid atisine derivatives, on postrest potentiation in rat papillary muscle
This work was supported by a grant FA-F6-T083 from the Coordinating Committee for Development of Science and Technology under the Cabinet of Ministers of the Republic of Uzbekistan
Abstract: We studied the effects of diterpenoid alkaloids 15-acetoxyazomethine and 15-hydroxyazomethine on post-rest potentiation behavior in rat papillary muscle. The results show that 15-AAA produced a concentration-dependent biphasic effect on post-rest potentiation (PRP) and at low concentrations (< 5 ^mol/l) enhanced it, whereas, at higher concentrations
(> 5 ^mol/l) slightly depressed it. One possible explanation for the biphasic effect of 15-AAA is as follows: at low concentration it by activation of SR Ca 2+ load, may result in an increase the amount of Ca 2+ available for release, resulting in enhancement of PRP; at higher concentration, it by inhibition of Ca 2+ influx and impairment of SR function may result in a decrease the amount of Ca 2+ released by SR, resulting in depression of PRP. In contrast, 15-HAA at all concentrations more strongly than 15-AAA depressed PRP, presumably, due to its more pronounced the negative inotropic effect. These results shows that 15-AAA and 15-HAA has dual effects on PRP through a complex modulation of Ca 2+ handling in cardiac cell, which may involve the modification of Ca 2+ transport through sarcolemmal membrane and on the level of SR. These findings suggest that a large portion of negative inotropic effect of 15-AAA and 15-HAA may, at least, are related to the inhibition of Ca 2+ influx and, in part, to the subsequent impairment of SR function resulted in decreased the amount of Ca 2+ being taken up and released by SR leading to depression of contractility.
Keywords: Alkaloids, post-rest potentiation, sarcoplasmic reticulum.
Introduction
15-hydroxyazomethine atisine (15-HAA) and 15-acetoxy-azomethine atisine (15-AAA), derivatives of diterpenoid alkaloid atisine, isolated from Aconitum plant species, have a pronounced antiarrhythmic effect [1]. Previously we demonstrated that 15-HAA and 15-AAA exerted significant negative inotropic effects and markedly depressed the contraction force in the electrically stimulated rat papillary muscles [2]. In these preliminary studies the negative inotropic effects of these alkaloids were found attenuated by lidocaine and reduced after inactivation of Na+-channels by elevated extracellular KCl concentration (24 mmol/l). Furthermore, these alkaloids significantly inhibited the contraction force induced by elevation in extracellular Ca 2+ concentration, which was mainly mediated by Ca 2+ influx via L-type Ca 2+ channels. Together these results suggested that the negative inotropic effect of 15-AAA and 15-HAA probably were provided by mechanism similar to that of some class 1 antiarrhythmic drugs, which by inhibition of Na+ channels and subsequent impairment of Ca 2+ handling reduced the intracellular concentration of Ca 2+ ([Ca 2+]i) and depressed the contraction force [3; 4]. It is considered that the reduction in [Ca 2+]i produced by these drugs mediated mainly by Na+/Ca 2+ exchanger which when the Na+ channels were blocked and the intracellular concentration of Na+ reduced will decrease Ca 2+ influx, and enhance Ca 2+ efflux and thereby may reduce [Ca 2+]i [5]. This is compatible with our results obtained in the previous study, namely that the 15-AAA and 15-HAA significantly inhibited the contraction induced by low Na+ solution and ouabaine, which mainly are due to the Ca 2+ entry via Na+/Ca 2+-exchanger [6]. These results suggested that the inhibition of Ca 2+ influx via Na+/Ca 2+ exchanger by 15-AAA and 15-HAA also may be involved in their negative inotropic effect. However, it is widely accepted that the Ca 2+ entry through Na+/Ca 2+ exchanger may contribute not only to control of [Ca 2+]i but have a significant effect on the amount of Ca 2+ being taken up and released by the sarcoplasmic reticulum (SR) [7; 8]. Considering this we assumed that inhibition of Ca 2+ influx through Na+/Ca 2+ exchanger by 15-AAA and 15-HAA could also reduce the Ca 2+ content in SR, resulting in depression of the contraction force thus inducing the negative inotropic effect. Therefore, to examine the effect of 15-AAA and 15-HAA on storage and release functions of SR their effects on post-rest potentiation (PRP) of contraction force in rat papillary muscle were studied.
Materials and methods
Experimental protocol and conditions for preoperative care were approved by the animal use committee of our institution. Adult male Wistar rats weighing 200-250 g. were anaesthetized with sodium pentobarbital (50 mg kg-1, i. and then sacrificed by cervical dislocation. The papillary muscles from the left ventricles of the rat hearts about 0.5-0.8 mm in diameter and 1-3 mm. in length were dissected and mounted in a tissue bath (STEIRT, HSE, Germany)
of 3 ml. volume and superfused continuously with Krebs solution. The Krebs solution contained (in mmol/l) NaCl 118, KCl 4.7, MgSO41.2, KH2PO4 1.2, glucose 10, NaHCO3 24, CaCl2 2.54. The solution was continuously gassed with O2/CO2 mixture (95 %/5 %) CO2 to provide a pH of 7.4 and was kept at 37 °C. The preparation was mounted horizontally in the tissue bath with one end attached to a hook and the other end attached to an force transducer (Type F30, Grass, Quincy, Mass., USA). Each preparation was stretched to a length at which maximum developed force was evoked and allowed to equilibrate for at least 1 h prior to experiments. The preparations were field-stimulated at a rate of 0.1-5 Hz. by two platinum electrodes with rectangular wave pulses of 10 ms. duration at twice the threshold voltage delivered from an electronic stimulator (ESL-2, Russia). Contractions were recorded on a chart recorder (TZ 4620, Czech Rep.) and after conversion to digital form stored on a personal computer. To examine the effects of 15-HAA and 15-AAA on storage and release functions of SR we studied their effects on post-rest potentiation (PRP) of contraction. The contraction during PRP was studied after a rest period ofvariable duration, and at [Ca 2+]i of 0.5 mmol/l because its study is more sensitive at a low [Ca 2+]o. The results of these experiments are reported as relative potentiation which was quantified by normalizing peak amplitude of the first potentiated contraction (B1) to the steady state contraction recorded immediately before the rest interval (B0): B1/B0.
All drugs were purchased from Sigma-Aldrich Chimie (Sigma, St. Louis, Mo, USA.). All values are presented as mean ± SD. Student's t test was used to compare test and control values and values of P < 0.05 were considered significant. Statistical analysis was performed using OriginPro 7.5 software (OriginLab Co., U. S.A).
Results and discussion
Post rest behavior is a tool to study the activity of SR, because it reflects the ability of the SR to store and release Ca 2+ [9; 10]. In rat papillary muscle, the first contraction after a period of rest (B1) is increased due to accumulation of Ca 2+ in SR beyond that accumulated with regular stimulation, therefore, it is more significant than the last beat before the rest (B0). In our experiments in rat papillary muscle stimulated at steady state frequency (0.1 Hz.), the amplitude of the B1 after the rest period always increased compared with amplitude of steady-state contraction before the rest (B0). The ratio B1/B0, which reflects the relative PRP and was used as an index of SR activity, increased with increasing duration of the rest period until a plateau was reached at 30-s rest. As it is illustrated in Fig. 1A, the amplitude of B1 after rest was 189.7 ± 6.2 % in comparison with amplitude of B0 (taken as 100 %), providing a ratio B1/B0 1.89 ± 0.10. After application of 5 ^mol/l 15-AAA both B0 and B1 increased by 20.6 ± 4.9 % and 76.6 ± 8.1 %, respectively, of control obtained before 15-AAA (Fig. 1B). The increase in B0, induced by 15-AAA, can be explained by its positive inotropic effect, which by increasing B0 should simultaneously increase the B1,
because the state of this contraction almost linearly depends on the state of preceding contraction B0 [11]. However, the 15-AAA caused more pronounced increase in B1 than B0, providing the ratio B1/B0 2.20 ± 0.18. Taking into account that the ratio B1/B0 reflect the Ca 2+ storage and release functions of SR [12; 13], its increase suggest that 15-AAA enhances the PRP possible by modulation of these function of SR. This is in agreement with thefinding that relative potentiation caused by 15-AAA was not affected by propranolol and nifedipine, indicating that enhancing effect of 15-AAA is not related to stimulation of ^-adrenergic receptors and activation of L-type Ca 2+ channels (data not shown). It should be noted that positive inotropic effect produced by 15-AAA also was resistant
to propranolol and nifedipine [2]. To further examine the effect of 15-AAA on the loading and releasing functions of SR we used caffeine, which by enhancing Ca 2+ release and inhibiting its reuptake processes, impaired either SR release function or the capacity of SR to load Ca 2+ during the rest period [14]. As it can be seen in Fig. 2A, caffeine in the concentration of 8 mmol/l significantly decreased the ratio B1/B0, indicating that PRP was completely abolished due mainly to depletion of the SR Ca 2+ store. Application of 15-AAA (5^mol/l) on the background of developed caffeine effect did not provide recovery of normal muscle response on post-rest test (Fig. 2A), suggesting that the enhancing effect of 15-AAA depends on the Ca 2+ storage or release function of SR.
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Fig. 1. Effect of 15-AAA on post-rest contractile behavior in rat papillary muscle: A) Typical tracings representing developed post-rest contraction after 30 s rest period; B) Enhancing effect of 5^mol/l 15-AAA on post-rest potentiation of contraction; C) The relative potentiation of contraction (the ratio B1/B0) before and after administration of 5 ^M 15-AAA. Results are reported as mean ± SEM (n = 5) (* — P < 0.05, compared to control)
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Fig. 2. Influence of caffeine on enhancing effect of 15-AAA on relative potentiation of contraction in rat papillary muscle. Effect of 15-AAA (5^M) in the presence of 8 mmol/l (A) and 3 mmol/l (B) caffeine. Results are reported as mean ± SEM (n = 5) (* — P < 0.05, compared to control)
This assumption is supported by results obtained in conditions when PRP was partially reduced by 3mM caffeine, as evidenced by the reduction in the ratio B1/B0. As it can be seen in Fig. 2B the ratio B1/B0 reduced by caffeine (3mmol/l) to 1.4 ± 0.12, after application of 15-AAA (5 ^mol/l) again increased to 1.74 ± 0.14. These results indicate that when the PRP partially preserved, 15-AAA is still able to enhance it, suggesting that this effect of 15-AAA probably is associated with modification of either Ca 2+ storage or release functions of SR. To obtain a better insight into the mechanisms by which 15-AAA
enhanced PRP, we further investigated its effects in the presence of cyclopiazonic acid (CPA), a selective inhibitor of SR Ca 2+-ATPase (SERCA2). In our experiments application of 30 ^mol/l CPA significantly decreased both B0 and B1, as well as, the ratio B1/B0, indicating that PRP was complete abolished (Fig. 3A). This effect of CPA is due mainly to inhibition ofthe Ca2+ loading in the SR and subsequent depletion of Ca 2+ store available for release [15; 16]. Application of 15-AAA (5^mol/l) on top of 30 ^mol/l CPA, when PRP completely abolished, it did not provide recovery of PRP (Fig. 3A).
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Fig. 3. Influence of CPA on enhancing effect of 15-AAA on relative potentiation of contraction in rat papillary muscle. Effect of 15-AAA (5|M) in the presence of 30 |imol/l (A) and 5 |imol/l (B) CPA. Results are reported as mean ± SEM (n = 5) (* — P < 0.05, compared to control)
However, in the presence of 5 ^mol/l CPA, when the PRP partially preserved, according to the ratio B1/B0 (1.5 ± 0.11), application of 15-AAA (5 ^mol/l) still increased it to 1.72 ± 0.12. These results shows that when PRP was partially preserved 15-AAA still is capable to enhance contraction after rest. This suggest again that enhancing effect of 15-AAA is associated with SR function and presumably is due to modulation of Ca2+ release function or the capacity of SR to load Ca 2+ during the rest period. Based on these data we conclude that the enhancing effect of 15-AAA could be explained
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either by increase in Ca2+ accumulation in SR during the rest period or by increase in Ca 2+ available for release from SR.
In contrast, to low concentration, which enhanced PRP, high concentrations of 15-AAA (> 5 ^imol/l) significantly depressed the steady-state contraction as well as the first contraction after rest. As it can be seen in Fig. 4, in the presence of 30 ^mol/l 15-AAA, both B0 and B1 significantly decreased to 12.3 ± 2.6 % and to 18.1 ± 3.4 %, respectively, from control values, obtained in absence of 15-AAA.
□ Control I—I 15-AAA (30 Mmol/1)
■ 15-HAA (30 Mmol/1) *
Fig. 4. Effect of high concentrations 15-AAA and 15-HAA on post-rest potentiation of contraction in rat papillary muscle. A), B) Representative tracings of the effects of 15-AAA and 15-HAA, both at 30 |imol/l; C) Effect of 15-AAA and 15-HAA (both at 30 |imol/l) on relative potentiation of contraction. Results are reported as mean ± SEM (n = 5) (* — P < 0.05, compared to control)
The decrease in B0 caused by high concentration of 15-AAA, presumably is due to its negative inotropic effect, which is attributed to its Na+-channel blocking properties [2]. It is well known, that the blockade of the Na+-channels in cardiac cells may secondarily alter Ca2+ transport so that a decreased Ca2+ influx would reduce [Ca2+] and, thus, suppress cardiac contractility [7; 12]. So, if this effect of 15-AAA is mainly due to a decrease in Ca2+ influx, the decrease in B0 should accompanied by a similar decrease in the B1, without significant changes in the ratio B1/B0. However, as it can be seen in Fig. 4A, despite the significant decrease in the absolute amplitude
of B1 the ratio B1/B0 reduced only to 1.47 ± 0.15, indicating that relative potentiation still well preserved. This shows that the depression of B1 by high concentration of 15-AAA, at least in part, can be explained by its simultaneous inhibition of Ca2+ influx and impairment ofSR function. Together, these results suggest that 15-AAA has dose-dependent biphasic effect on PRP a possible explanation for which is as follows: at low concentration (< 5 ^mol/l), it by activation of SR Ca2+ load, may result in an increase of amount of Ca2+ available for release, resulting in enhancement of PRP; at higher concentration (> 5^mol/l), it by inhibition of Ca2+ influx and impairment of
SR function may result in a decrease the amount of Ca2+ being taken up and released by SR, resulting in depression of PRP. Almost similar effect on post-rest behavior, to that caused by 15-AAA at high concentrations, observed with 15-HAA, which at all concentrations induced only negative inotropic effect [2]. As it can be seen in Fig. 4B, application of 30 ^mol/l 15-HAA significantly decreased B0 and B1 from control values to 7.3 ± 2.1 % and to 10.2 ± 4 %, respectively, providing the ratio B1/B0 1.39 ± 0.13. Comparison of the effects of 15-AAA and 15-HAAA has shown that 15-HAA reduced both B0 and B1, as well as, the ratio B1/B0, more stronger that 15-AAA. This difference may be due to the more pronounced negative inotropic effect of 15 -HAA and to the superimposed positive inotropic effect of 15 -AAA which could limit its inhibitory action. Considering that suppression of B0 and B1 by 15-HAA was accompanied with significant reduction in the ratio B1/B0 this its effect can be attributed in part to impairment of the SR function. Thus, these results shows that 15-AAA and 15-HAA has dual effects on PRP through a complex modulation of Ca2+ handling in cardiac cell, which may involve the modification of Ca 2+ transport through sarcolemmal membrane and on the level of SR. Together, these findings suggest that a large portion of negative inotropic effect of 15-AAA and 15-HAA may, at least, reflect interference with intracellular Ca 2+ transport mechanisms and in part an impairment of SR function.
Conclusion
Our results have shown that both 15-AAA and 15-HAA specifically affected the PRP in rat papillary muscle. 15-AAA produced a concentration-dependent biphasic effect and at low concentrations (< 5 ^mol/l) enhanced PRP, whereas, at higher concentrations (> 5 ^mol/l) slightly decreased it. One possible explanation for the biphasic effect of 15-AAA on PRP is as follows: at low concentration it by activation of SR Ca 2+ load, may result in an increase amount of Ca 2+ available for release, resulting in enhancement of PRP; at higher concentration, it by inhibition of Ca 2+ influx and impairment of SR function may result in a decrease amount of Ca 2+ released by SR, resulting in depression of PRP. Almost similar, but more strong effect on post-rest behavior, produced 15-HAAA, which is due mainly to its more pronounced the negative inotropic effect. These findings suggest that 15-AAA and 15-HAA have dual effects on PRP through a complex modulation of Ca 2+ handling in cardiac cell, which may involve the modification of Ca 2+ transport on the level of sarcolemmal membrane and SR. We conclude that a large portion of negative inotropic effect of 15-AAA and 15-HAA may, at least, is related to the inhibition of Ca 2+ influx and, in part, to the subsequent decreases in the amount of Ca 2+ being taken up and released by SR, resulting in depression of contractile force. Further studies will be required to clarify these points.
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