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1 Division of Cardiovascular Physiology and Pharmacology, School of Medicine2 Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education3 School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710061, China
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Abstract |
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(Received 24 April 2004;
accepted after revision 1 October 2004; first published online 4 October 2004)
Corresponding author W. J. Zaing: School of Medicine, Department of Pharmacology, Division of Cardiovascular Physiology and Pharmacology, School of Medicine, Ki'an Jiaotong University, Xi'an, 710061, China. Email: zwj{at}mail.xjtu.edu.cn
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Introduction |
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The present study investigates and compares the direct negative effects of ACh on the electromechanical characteristics of guinea-pig atrial and ventricular tissue and myocytes.
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Methods |
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For this experiment, guinea-pigs of both sexes weighing 200–300 g (supplied by the Experimental Animal Center of Xi'an Jiaotong University, China) were used in accordance with recommended guidelines on the care and use of laboratory animals issued by the Chinese Council on Animal Research. The study was approved by the ethical committee of Xi'an Jiaotong University. The guinea-pigs were killed by a blow to the head. The hearts were rapidly removed, and atrial tissues and papillary muscles from the right ventricle were isolated. Muscles of uniform size (length 6–8 mm, diameter <1 mm) were pinned in a special perfusion chamber (2 ml) and perfused at 10 ml min–1 with a modified Tyrode solution oxygenated with 100% O2. The composition of the modified Tyrode solution was as follows (mM): NaCl, 147; KCl, 5.4; MgCl2, 1.05; Tris, 10; CaCl2, 1.8; glucose, 11.1; pH adjusted to 7.40 with HCl. The temperature was maintained at 36.0–37.0°C and the pH was maintained at 7.30–7.40 throughout the experiments.
Determination of force of contraction
The multicellular preparations were set up in the perfusion chamber with one end of the tissue pinned to the chamber floor and the other end attached (via a silk suture) to the force transducer. The resting tension was adjusted to 5 mN, after which the preparations were stimulated using a programmable stimulator (SEN-3201, Nihon Kohden, Tokyo, Japan) at 1 Hz for 5 ms with an intensity 50% greater than threshold. Equilibrium was maintained for 60 min before the start of the experiment. The developed tension was recorded with a force–displacement transducer connected to a two-channel physiological recording system (LMS-2 A, Nihon Kohden).
Electrophysiological measurements
Transmembrane action potentials were recorded from atrial and ventricular tissues with standard glass microelectrodes filled with 3 M KCl (tip resistance 10–30 M
) coupled to a high-input-impedance amplifier (MEZ 8201, Nihon Kohden). The amplified signals were then fed to an A–D converter and processed by a computer. Resting membrane potential, amplitude of action potential (APA), overshoot, action potential duration (APD), and action potential duration at 50 and 90% repolarization action potential (APD50, APD90) were stored and measured using a system for the automatic acquisition and processing of cardiac action potentials (RM-6281 software; The Fourth Military Medical University, Xi'an, China).
Cell isolation
Myocytes were enzymatically dissociated from guinea-pig hearts. During the procedure, all solutions were oxygenated with 100% O2 and maintained at 37°C. Guinea-pigs of both sexes, weighing 200–300 g, were injected with heparin (400 IU, I.P.) as an anticoagulant and killed by a blow to the head. The chest was opened and the heart removed. The aorta was cannulated and the heart retrogradely perfused at constant pressure (70 cmH2O) via the aorta and coronary arteries with normal Tyrode solution in a Langendorff apparatus. The composition of the Tyrode solution was as follows (mM): NaCl, 135; KCl, 5.4; MgCl2, 1; NaH2PO4, 0.33; glucose, 10; Hepes, 10; CaCl2, 1.80; pH adjusted to 7.35 with NaOH. After the blood had been washed out, the heart was perfused with Ca2+-free Tyrode solution for 3–5 min. Subsequently, the heart was perfused with 30 ml Ca2+-free Tyrode's solution containing 6 mg of collagenase (type II, Yakult, Japan), 0.1 mg of protease (type XIV, Sigma, St Louis, MO, USA) and 30 mg BSA. The solution was recirculated for 10 min, after which the enzymes were washed out by perfusion with 50 ml of high-K+, low-Cl– solution containing (mM): KCl, 25; KH2PO4, 10; taurine, 20; L-glutamic acid, 70; MgCl2, 3; EGTA, 0.5; Hepes, 10; glucose, 10; pH adjusted to 7.35 by addition of KOH. Afterwards, the atrium and the ventricle were cut into pieces (1 mm3), the cells were dispersed in KB solution and the undigested tissue was removed by filtration through nylon mesh. After 30 min, the cells were transferred to Tyrode solution (the cellular perfusing solution; Zang et al. 1993) comprising (mM): NaCl, 136.9; KCl, 5.4; MgCl2, 1; Hepes, 5; NaH2PO4, 0.33; glucose, 10; CaCl2, 1.80; pH adjusted to 7.40 with NaOH. The cells were kept at room temperature for at least 1 h before being used in experiments.
Cell contraction
Contractions of single myocytes were elicited by an extracellular voltage field at a rate of 0.5 Hz using 5 ms square pulses with a constant voltage (50% above threshold). Cell contraction was quantified by measuring the displacement of each end of the cell. A video edge-detection system (IonOptix Corporation, Milton, MA, USA) was used to track the motion of the cell edges. The signal from the detector was sent to a strip chart recorder and to a VCR video recorder for storage and off-line analysis. The shortening of each cell was measured, and is expressed here either in micrometers displacement or as a percentage of cell length.
Chemicals
Acetylcholine chloride, protease (type XIV) and Hepes were purchased from Sigma, and collagenase (type II) was purchased from Yakult. Other reagents (e.g. the constituents of the Tyrode solution) were obtained from pharmaceutical and chemical companies in China. All reagents were of ANALAR grade or the highest purity available. Stock solution (1 mM) of ACh chloride was prepared daily and later diluted in Tyrode solution to the desired concentration.
Statistical analysis
Data are expressed as mean values ± S.E.M. and were analysed using standard software (SPSS, V10.0, SPSS Inc.). Comparisons were made using Student's t test or a paired t test as appropriate. Probability values of P < 0.05 were considered indicative of statistical significance. In our experiments, single doses of acetylcholine were applied to the atria tissue and papillary muscles, but cumulative dose–response curves were not obtained, because the effects of acetylcholine showed desensitization.
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Results |
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Acetylcholine (0.01–100 µM) exerted a concentration-dependent direct inhibitory effect on the force of contraction in guinea-pig atrial and ventricular myocardia. The maximum decrease from baseline values in the force of contraction was 100% in atrial myocardium and 48.2% in ventricular myocardium (a dose–response curve is shown in Fig. 1A). ACh at 0.185 and 1.076 µM exerted half-maximal effects in the atrium and ventricle, respectively. Figure 1A also shows that the direct negative inotropic effects of ACh at 0.01–100 µM in the guinea-pig atrium were greater than in the ventricle (P < 0.01, atrium versus ventricle).
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Comparative effects of 1 µM ACh on force of contraction in atrial and ventricular myocardia
Acetylcholine at 1 µM inhibited the contractile force of the atrial and the ventriclular tissue significantly, by 80.0 ± 3.5% (P < 0.001 versus control, n = 8) and 21.4 ± 1.8% (P < 0.01 versus control, n = 7), respectively. Furthermore, the negative inotropic effect of ACh on atrial myocardium was greater than that on ventricular myocardium (P < 0.001, atria versus ventricles). Additionally, there was a desensitization phenomenon during ACh exposure and a rebound after washout in both groups. After washout, the force of contraction rose to 127.8 ± 4.8% (P < 0.001, n = 8, atrial myocardium) and 115.5 ± 3.9% (P < 0.01, n = 7, ventricular myocardium) of the baseline values.
Comparative effects of 1 µM ACh on contraction in atrial and ventricular cells
Acetylcholine at 1 µM inhibited the shortening of atrial and ventricular cells significantly, by 69.4 ± 4.5% in atrial myocytes (P < 0.001, n = 14) and by 19.0 ± 3.7% in ventricular myocytes (P < 0.001, n = 15; Fig. 2). However, the direct negative inotropic effects of ACh on atrial myocytes was greater than on ventricular myocytes (P < 0.001, atrial versus ventricular cells). These results were similar to the effects of ACh on the contractile forces of isolated myocardia (Fig. 3), with desensitization and rebound phenomena also being observed in contraction. After washout, the amplitude of cell contraction was increased to 128.19 ± 4.72% (P < 0.001, n = 14, atrial myocytes) and 110.34 ± 2.80% (P = 0.002, n = 15, ventricular myocytes) of the baseline values. About 33.3% of ventricular cells (5/15) were not affected by 1 µM ACh, in contrast to the reproducible effects of ACh on isolated ventricular muscle.
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Acetylcholine at 0.001 µM did not influence the action potential parameters in atrial (P > 0.05, n = 6) or ventricular cells (P > 0.05, n = 5). At 0.01–100 µM, however, ACh application resulted in a dose-dependent shortening of the APD in both atrial and ventricular myocardia (Fig. 1B); maximally by 48.2% in atrial myocytes and 10.6% in ventricular myocytes. The values of concentration for 50% of the maximal effect (EC50) was 0.391 µM in the atrium and 1.144 µM in the ventricle. Furthermore, ACh at 1–100 µM decreased APA in atrial cells and reduced their excitability but had no effect on the APA of the ventricular cells.
Figure 1B also indicates that ACh at 0.01–10 µM shortened the APD of the atrium greater than that of the ventricle (P < 0.01, atrium versus ventricle), which suggests that atrial myocardium is more sensitive to ACh than ventricular myocardium in guinea-pigs. From the results shown in Fig. 1C, the tendencies of the decrease of contraction and the shortening of APD produced by ACh in the atrial and ventricular myocardia were in accord.
Comparative effects of 1 µM ACh on action potentials in atrium and ventricle
Table 1 shows that ACh at 1 µM significantly shortened the APD of both atria and ventricles, by 30.6 ± 2.0 (P < 0.01, n = 6) and 5.27 ± 2.81% (P < 0.05, n = 6), respectively (P < 0.01, atrium versus ventricle). Moreover, the APA of the atrium was reduced by 1 µM ACh from 89.5 ± 5.80 to 71.70 ± 4.40 mV (P < 0.01, n = 6), whereas that of the ventricle was not influenced by ACh. On the other hand, ACh slightly hyperpolarized the resting membrane potentials (an increase of 0.5–1.5 mV) of the atrium and ventricles, although not significantly relative to controls. In addition, there was also a desensitization phenomenon during ACh exposure and a rebound after washout in both groups. Specimen recordings from the atrium and ventricle are shown in Fig. 4.
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Discussion |
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Previous studies on concentration-dependence
There are a few reports on the direct effects of ACh on guinea-pig heart. Zhang et al. (1998) showed that ACh decreased the contractile force of guinea-pig atria in a dose-dependent manner, whereas there was no effect on contractile function of the ventricular trabeculae. Stimulation of muscarinic ACh receptors with carbachol reduces the APD and has a positive inotropic effect in papillary muscles from both ventricles, with both effects being concentration dependent and atropine sensitive (Arreola et al. 1994); ACh applied at 0.03–0.3 µM to isolated guinea-pig ventricular papillary muscle resulted in a significant shortening of APD and the contractile force showed no change or only a slight decrease, while ACh applied at 5 µM reduced APD50 and APD90 whilst the contractile force was slightly increased (Yang et al. 1989); in the presence of 10 µM physostigmine (a cholinesterase inhibitor), ACh produced concentration-dependent negative and positive inotropic effects in the presence and absence of the phosphodiesterase inhibitor IBMX (3-isobutyl-1-methyl xanthine, 100 µM), with half-maximal effective concentrations of 1.36 and 46 µM, respectively (Korth et al. 1987). The above-mentioned studies did not compare the effects on the atria and the ventricles systemically, and the results are controversial. Our study is the first to compare the effects on the atria and the ventricles systemically, with the results showing that ACh exerted concentration-dependent direct negative effects not only on the atria but also on the ventricles in guinea-pigs.
The direct negative effect of ACh was greater in guinea-pig atria than in the ventricles. Dose–response curves (Fig. 1) show that the atria are more sensitive to ACh than the ventricles in guinea-pigs, which might be explained by: (1) there being more muscarinic receptors distributed in the atria than in the ventricles (Brodde et al. 2001; Dhein et al. 2001; Wang et al. 2001; Krejci & Tucek, 2002); (2) acetylocholine sensitive potassium current (IK,ACh) being greater in the atria than in the ventricles (McMorn et al. 1993); (3) the vagal innervation density being lower in the ventricles than in the atria (Loffelholz & Pappano, 1985; Cremers et al. 1997); or (4) ACh having a higher affinity in the atrium than in the ventricle, since there are comparable muscarinic receptor densities (atrium versus ventricle) in guinea-pigs (Wei & Sulakhe, 1978).
The phenomena of desensitization and rebound were observed frequently in contractile force and APD in both multicellular tissue and single cardiac myocytes. Desensitization is possibly attributable to a mechanism such as muscarinic receptor endocytosis, G protein phosphorylation, G protein-coupled receptor kinase phosphorylation, or potassium channel down-regulation (Zang et al. 1993; Dobrev et al. 2001; Ferguson, 2001; Shui et al. 2001). Rebound of the contraction may involve an increase in the intracellular Na+ concentration with subsequent activation of the Na+–Ca2+ exchanger and a rise in the intracellular Ca2+ transient (Korth & Kuhlkamp, 1985; Saeki et al. 1997; Protas et al. 1998; Endoh, 1999; Dhein et al. 2001). However, the exact underlying mechanisms are still unclear.
Contraction and APD
Our results are the first to show, in guinea-pigs, that ACh-induced decreases in the force of contraction and shortening are consistent with the changes in APD in both the atria and the ventricles (Fig. 1C), which further supports the hypothesis that the decrease in basal contractile force by muscarinic receptor agonists is due to shortening of the APD.
It has been reported that ACh has no effect on the contractile forces of ventricular cells from ferrets (Dobrzynski et al. 2002) and rats (McMorn et al. 1993) when the contractions are triggered by voltage-clamp pulses of constant duration. This also supports the hypothesis that the direct negative inotropic effect of muscarinic agonists in cardiac muscle is attributable to shortening of the APD. It was also found that, in 19% of ferret ventricular cells, the decrease in twitch shortening might have been partly attributable to an apparent decrease in Ca2+ current (Boyett et al. 1988). In ferret papillary muscle the direct effect is associated with a paradoxical effect on intracellular Ca2+; muscarinic stimulation in ferret ventricular muscle attenuates the mobilization of Ca2+ ions, whereas it increases the myofibrillar sensitivity to Ca2+ (Endoh, 1999; Dhein et al. 2001).
The decrease in basal contractile force of muscarinic receptor agonists is probably attributable to at least one of the following mechanisms: (1) the shortening of the APD by activation of potassium channels via direct effects of the G protein ß
-subunits (Medina et al. 2000) reducing the time window for calcium current (ICa); (2) a decrease in Na+–Ca2+ exchange current (INa/Ca) (Dobrzynski et al. 2002); (3) a direct decrease in Ca2+ current (Boyett et al. 1988); or (4) the inhibition of mobilization of intracellular Ca2+ ions, thereby causing cumulative depletion of intracellular stores of Ca2+ (Endoh, 1999; Dhein et al. 2001; Zhang et al. 2003). This needs to be confirmed in guinea-pig atrium and ventricle.
Single myocytes and isolated myocardium
In our experiments on isolated ventricular cells, about 33.3% of them did not respond to ACh. One possible reason for this is that the ACh-sensitive potassium channel (KACh) was not distributed evenly in guinea-pig ventricle such that the membrane of some ventricular cells contained KACh whereas others had no (or insufficient) KACh (Dobrzynski et al. 2001). Another possible reason is that cells from different regions of the ventricles have differing responses to ACh. For example, different reactions amongst the three layers of the ventricular myocardium (endocardium, midmyocardium and epicardium) have been recorded electrophysiologically (Litovsky & Antzelevitch, 1990; Yang et al. 1996), and there are differences between working myocardium and the conduction system (Mubagwa & Carmeliet, 1983).
Vagal stimulation and exogenous addition of ACh
Several studies have shown that bath-applied acetylcholine produces different effects from vagal stimulation in cardiac tissue (e.g. Bywater et al. 1989); in the isolated rat heart, acetylcholine, but not vagal stimulation, decreased left ventricular contractility (Takahashi et al. 2003). From the results of the present study, it appears that exogenous acetylcholine might produce different effects from vagal stimulation. Vagal stimulation may be more representational of physiological conditions than exogenous application of acetylcholine. However, there are many influential factors related to vagal stimulation in vivo or in vitro. For example, there are some neuropeptides colocalized with ACh or noradrenaline (NA) in cardiac autonomic nerves, such as neuropeptide Y, substance P and calcitonin gene-related peptide (Morris et al. 1986). Vagal stimulation induces release of some other substances as well as ACh from vagal postganglionic axons, e.g. somatostatin (Bywater et al. 1989). Additionally, there is an interaction between sympathetic and parasympathetic nerves in vivo (Dhein et al. 2001). Therefore, the result of vagal stimulation could be complex, although ACh is the main neurotransmitter of the vagus.
In conclusion, exogenous ACh exerted direct inhibitory effects including decreased force of contraction and shortening of APD in both atrium and the ventricle of guinea-pigs in a concentration-dependent manner. The negative effect was larger on atrial tissue and myocytes than on ventricular tissue and myocytes, while the effect of 1 µM ACh on single cardiac cells was similar to that on isolated myocardium. In addition, not all ventricular myocytes responded to ACh. The present experiments further confirm that ACh plays an important role in modulating the function of not only the atria but also the ventricles.
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) and ventricular strips (•). Ordinate: negative inotropic effect of ACh as a percentage of the maximal force of contraction (–
Fc (%)). Abscissa: logarithm of molar concentration of ACh. B, negative effect on electrically driven guinea-pig isolated atrial samples (
), n = 8; atrial myocyte (
), n = 7; ventricular myocyte (