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1 Department of Physiology, Division of Medical Sciences, University of Birmingham, Birmingham, UK2 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
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(Received 9 September 2003;
; first published online 5 November 2003)
Corresponding author G. A. Ng: Cardiology Group, Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield Hospital, Leicester LE3 9QP, UK. Email: gan1{at}le.ac.uk
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Introduction |
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Methods |
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The isolated heart preparation with intact autonomic innervation has been previously described (Ng et al. 2001). In brief, adult male New Zealand White rabbits (2.1–2.5 kg, n= 6) were premedicated with Hypnorm (Janssen Pharmaceuticals LtD, Oxford, UK; 0.1 mg kg–1 S.C). General anaesthesia was induced with I.V. Hypnoval (Roche Products Ltd, Welwyn Garden City, UK; 1 mg kg–1) and maintained with pentobarbitone sodium (Sagital, Rhône Mérieux, Harlow, UK; 2 mg every 5 min. I.V.). The rabbit was ventilated, after tracheotomy, at 60 breaths per min using a small-animal ventilator (Harvard Apparatus Ltd, Edenbridge, Kent, UK) with an O2/air mixture. The vagus nerves were isolated and the blood vessels leading to and from the rib cage were ligated and dissected. The rabbit was killed with an overdose of Sagital (60 mg I.V.) together with 500 U heparin I.V. The anterior portion of the rib cage was removed and the descending aorta cannulated. The preparation extending from the neck to thorax was dissected as described before (Ng et al. 2001). The procedures were undertaken in accordance with the Animals (Scientific Procedures) Act 1986 and conformed with the Guide for the Care and Use of Laboratory Animals Published by the US National Institutes of Health (NIH Publication no. 85–23, revised 1985).
Langendorff perfusion
The preparation was perfused via the aortic cannula in the modified Langendorff mode with Tyrode solution of the following composition (mM): Na 138, K 4.0, Ca 1.8, Mg 1.0, HCO3 24.0, H2PO4 0.4, Cl 121, glucose 11. The pH of the solution was maintained at 7.4 by continuously bubbling with 95% O2/5% CO2 mixture and the temperature was maintained at 37°C. A constant perfusion rate of 100 ml min–1 was maintained using a Gilson Minipuls 3 peristaltic pump (Gilson Inc., Ohio, USA). Thebesian venous effluent was drained via a catheter placed at the left ventricular apex. Intraventricular pressure was monitored with a fluid-filled latex balloon connected to a pressure transducer (model MTL0380, AD Instruments Ltd, UK) and inserted into the left ventricle via the left atrium. The volume of the balloon was adjusted to give zero end-diastolic pressure. Perfusion pressure was monitored with a second pressure transducer in series with the aortic cannula. A pair of platinum electrodes (Grass Instruments, Astro-Medical Inc., Slough, UK) was inserted into the right atrial appendage for recording of atrial electrograms.
Autonomic nerve stimulation
Each of the two vagus nerves was supported on separate custom made bipolar silver electrodes (Advent Research Materials, UK: 0.5 mm O.D.) for individual vagus nerve stimulation (VS). For sympathetic stimulation (SS), a quadripolar catheter with 4 electrodes mounted at the end (Biosense Webmaster Inc., Diamond Bar, USA; 2 mm electrode, 10 mm spacing) was inserted into the spinal canal at the 12th thoracic vertebra and the tip of the catheter was advanced to the level of the second thoracic vertebra for stimulation of both sides of the cardiac sympathetic outflow, with the tip electrode acting as cathode and the remaining three electrodes acting as anodes.
Two single channel constant voltage square pulse stimulators (SD9, Grass Instruments) were used – one for VS and one for SS. At a frequency of 5 Hz and 2 ms pulse width, the stimulus output was increased (over a range from 1 to 20 V) to examine the heart rate response of sympathetic, left and right vagus nerve stimulation individually. The stimulus output producing a submaximal response, as described before (Ng et al. 2001), was used subsequently in the study. This was 4.4 ± 1.5 V for sympathetic stimulation and 8.3 ± 2.8 V for both left and right vagus nerve stimulation.
Stimulation was carried out at frequencies of 2 Hz (low), 5 Hz (medium) and 7 Hz (high) with the left and right VS and at 2 Hz (low), 5 Hz (medium) and 10 Hz (high) for SS.
Signal measurements and analysis
All pressure and electrical signals obtained from the preparation were recorded with a PowerLab 800/s system (AD Instruments Ltd) and digitized at 1 kHz using Chart software (AD Instruments Ltd) with the data stored and displayed on a Power Macintosh G3 personal computer (Apple). The stimulus signals were also registered using the same system to record the exact timing and duration of the stimulations. Instantaneous intrinsic sinus heart rate at baseline and after autonomic nerve stimulation was obtained by measuring the beat-to-beat interval of the atrial electrograms.
Statistics
All data are expressed as mean ± standard error. The effects of direct SS or VS on heart rate at different frequencies were analysed using repeated measures ANOVA with Tukey's multiple comparison test for posthoc analysis. Comparison between left and right VS was made with Mann–Whitney test. Two-tailed P-value of less than 0.05 was considered significant.
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Results |
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Steady state heart rate changes. VS was initiated first until heart rate has reached steady state after which SS was commenced. Stimulation of the two sets of autonomic nerves were stopped after a new steady state heart rate was achieved. Figure 1A illustrates a typical experiment where left VS (5 Hz) reduced heart rate from about 150 bpm to 110 bpm. SS (2 Hz) then increased heart rate to reach a steady state level of about 140 bpm. Cessation of autonomic stimulation caused a sharp rise in heart rate followed by a gradual return to prestimulation level.
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The mean data (n= 6) for the effects of background left VS on steady state heart rate achieved with SS are summarized in Fig. 2A. Similar results for right VS are shown in Fig. 2B. SS caused a significant (P P 0.001) frequency dependent increase in heart rate in the absence and presence of VS independent of either left or right VS and of the frequency of VS. Heart rates were significantly lower for right VS compared with left (P P 0.05) at each frequency.
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Figure 1B shows that the increase in heart rate with SS was reduced in the presence of increasing levels of background VS in a typical experiment. This is also suggested in the mean data for steady state heart rates shown in Figs 2A and B for both left and right VS. For quantitative analysis, the increase in heart rate with various frequencies of SS were calculated in each experiment at each level of background VS and the mean data plotted in Fig. 2C for left VS and Fig. 2D for right VS. The reduction in the positive chronotropic effect of SS in the presence of increasing levels of VS is illustrated in these two figures. The increase in heart rate with low frequency SS was reduced from 37.0 ± 3.5 bpm (no VS) to 18.0 ± 4.2 bpm with high frequency left VS (P P 0.001). The heart rate increase with high frequency SS was reduced from 87.1 ± 6.4 bpm (no VS) to 34.9 ± 6.1 bpm with high frequency left VS (P P 0.001). There was no significant difference in the increase in heart rate at the various levels of SS between left and right VS at the various stimulation frequencies.
Algebraic sum of heart rate changes with sympathetic and vagal stimulation
The possible interaction between the two autonomic branches was analysed by simple addition of the changes in heart rate obtained with SS and VS individually (i.e. the algebraic sum) and comparing this with the change in heart rate obtained experimentally during concomitant SS and VS. In Fig. 3A (left VS) and Fig. 3B (right VS), the open symbols represent the calculated algebraic sum for each combination of SS and VS whilst the filled symbols represent the experimentally obtained heart rate change for the corresponding combination. The experimentally obtained changes in heart rate during concomitant SS and VS at each combination of frequencies were all lower than the algebraic sum (P P 0.05 for all except low frequency SS with background low left and right VS).
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As reported previously (Ng et al. 2001), there is a delay or latency in the heart rate response to SS, which decreases with increase in stimulation frequency, and is thought to be related to the kinetics of the second messenger system (Levy et al. 1993). The effect of VS on this latency period was examined in this study. Latency was measured as the time period from the beginning of SS to a 1% increase in heart rate. Figure 4A shows beat-to-beat heart rate in a typical experiment during low frequency SS without and at the various levels of background VS. It can be appreciated that there was a greater delay in heart rate increase with the same level of SS at higher levels of background VS. This is clearly shown in expanded scale in Fig. 4B. Figure 4C shows the mean data for the latency period at different combinations of SS and VS. Latency was decreased significantly (P P 0.05) with increases in SS in the absence of and at each of the various levels of VS. At low frequency SS, latency period was 2.1 ± 0.2 ms with no background VS. Increasing levels of background VS prolonged the latency period with the same low frequency SS up to 4.2 ± 1.0 ms at high frequency background VS which was significant (P P 0.05). This was also true for medium frequency SS (P P 0.05). However, for high frequency SS, although there was a trend towards an increase in latency period from 1.2 ± 0.2 ms without VS to 2.0 ± 0.4 ms with high frequency background VS, this change did not reach statistical significance (P= 0.069). Figure 4D shows the corresponding data for background right VS. Again, significant decrease in latency period was observed with increasing levels of SS without VS and with all levels of background VS. Similar to the results with left VS, increasing levels of right VS prolonged latency period significantly with low and medium frequency SS whilst the change in latency period from 1.3 ± 0.2 ms (no VS) to 2.0 ± 0.4 ms (high frequency VS) with high frequency SS did not reach statistical significance (P= 0.060).
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Steady state heart rate changes. The effect of background SS on the heart rate response to VS was examined in a similar manner to the above mentioned protocol in a reciprocal fashion, with SS first, achieving a steady state heart rate followed by VS. Figure 5A illustrates a typical experiment where SS (2 Hz) increased heart rate from about 150 bpm to 190 bpm. Left VS (5 Hz) then decreased heart rate to about 140 bpm. Cessation of autonomic stimulation caused a sharp rise of heart rate followed by a gradual return to prestimulation values.
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The mean data (n= 6) for the effects of background SS on steady state heart rate achieved with left VS are summarized in Fig. 6A. Similar results for right VS are shown in Fig. 6B. Both right and left VS caused significant (P P 0.001) frequency dependent decreases in heart rate in the absence and presence of background SS independent of stimulation frequency. Heart rates achieved with low and medium frequency VS were comparable between the two vagal nerves but were significantly (P P 0.05) lower during high frequency stimulation with right vagus nerve compared to the left, in the absence of and at all frequencies of background SS.
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Figure 5B shows that the decrease in heart rate with left VS was potentiated in the presence of increasing levels of background SS in a typical experiment. This is also suggested in the mean data for steady state heart rates shown in Figs 6A and B for both left and right VS. The decrease in heart rate with low, medium and high frequencies of VS were calculated in each experiment at the various levels of background SS and the mean data plotted in Fig. 6C (left VS) and Fig. 6D (right VS). The enhancement in the ability of VS to decrease heart rate in the presence of increasing levels of SS is illustrated in the two figures. Low frequency left VS decreased heart rate by 20.5 ± 3.7 bpm without background SS and by 43.0 ± 6.2 bpm with high frequency SS (P P 0.001). High frequency left VS decreased heart rate by 65.7 ± 7.2 bpm without background SS and by 119.3 ± 11.3 bpm with high frequency SS (P P 0.001). This potentiation of heart rate slowing at increasing frequencies of background SS was evident in both left and right VS. There was a trend for the heart rate change with right SS to be greater compared to the left, with and without background SS but this difference did not reach statistical significance.
Algebraic sum of heart rate changes with vagal and sympathetic stimulation
In Fig. 7A (left VS) and Fig. 7B (right VS), the open symbols represent the calculated algebraic sum for each combination of VS and SS whilst the filled symbols represent the experimentally obtained heart rate change for the corresponding combination. The experimentally obtained changes in heart rate during concomitant VS and SS at each combination of frequencies were all lower than the algebraic sum (P P 0.05 for all except low frequency left and right VS with background low frequency SS).
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Effects of background vagus nerve stimulation on sympathetic stimulation
The inhibition of the chronotropic effects of sympathetic stimulation by background vagus nerve stimulation occurred in a frequency dependent manner with increased inhibition at increasing frequency of vagus nerve stimulation. This occurred in a similar manner with left or right vagus nerve stimulation.
The antagonism of the chronotropic effect of the sympathetic nerves by background vagal stimulation, which is in agreement with previous work by Levy & Zieske (1969), can be the result of pre- and postsynaptic mechanisms (Levy, 1971). The levels of noradrenaline (NA) released during sympathetic stimulation are reduced by acetylcholine (Loffelholz & Muscholl, 1969) binding to M3 receptors on presynaptic sympathetic nerve terminals (Kobayashi et al. 1987; Manabe et al. 1991). Post-synaptic mechanisms relate to the muscarinic receptor mediated inhibition of adenylate cyclase activity (Hartzell, 1988) by the inhibitory G-protein, Gi. The ion currents that are phosphorylated in a cAMP dependent manner and consequently inhibited in this way include the hyperpolarization activated current (If), delayed rectifier current (IK) and the L-type calcium channel (ICa,L). Effects on these currents will directly or indirectly affect pacemaker action potential generation and, hence, heart rate (Irisawa et al. 1993). The inhibition of adrenergically stimulated ICa,L is nitric oxide/cGMP-dependent (Han et al. 1994, 1995), via cGMP-stimulated phosphodiesterase II (Han et al. 1998; Sasaki et al. 2000). In addition, vagal stimulation, with the release of acetylcholine, has direct electrophysiological effects on membrane potential via the acetylcholine-activated K current [IK(ACh)], which would affect pacemaker action potential generation (Medina et al. 2000).
Not only was the overall effect on heart rate blunted with background VS, but the time taken for sympathetic stimulation to produce a 1% increase in HR was also prolonged. To our knowledge, this is the first study to show that background vagal stimulation inhibited the rate of rise in heart rate produced with sympathetic stimulation. This prolongation of latency was only significant at low and medium frequency stimulation of the sympathetic nerves. But this was not the case during high frequency SS. At high SS, there was no significant change in latency in the presence of low, medium and high frequency VS, even though the overall effect on HR was profoundly inhibited. In this instance, sympathetic nerve stimulation was able to ‘overcome’ the inhibition of the vagus nerve, at least with respect to latency. This suggests that the presynaptic release of noradrenaline by SS is sufficient at high SS but its postsynaptic effect cannot overcome the inhibition of vagal stimulation since the peak effect is blunted. One possible reason for this could be that during high frequency SS, stimulation of ß-adrenergic system directly links to ICa,L via the stimulatory G-protein (G
-subunit) as suggested by Yatani & Brown (1989). Perhaps more importantly, it is possible that muscarinic stimulation is not able to inhibit this direct Gs-dependent stimulation of the ICa,L, although it will still be capable of reducing cAMP-dependent stimulated ion currents involved in the antagonism of the overall chronotropic effect of SS. Further studies are required to delineate these mechanistic pathways.
The effect of background sympathetic nerve stimulation on vagus nerve stimulation
In contrast to the results seen with the inhibition of chronotropic effects of sympathetic stimulation in the presence of background vagal stimulation, this inhibition was not seen in the reverse direction. In this study, the negative chronotropic effect of vagus nerve stimulation was not inhibited but rather enhanced in the presence of background sympathetic stimulation. These results are in agreement with others (Revington & McCloskey, 1990; Yang & Levy, 1992) who showed that the dominant direction of inhibition was the vagal inhibition of the effects of sympathetic stimulation rather than the other way round. However, Potter (1985) showed in the anaesthetized dog in vivo that sympathetic nerve stimulation reduced the chronotropic effect (Potter, 1985) and time course of the heart rate change (Yang et al. 1994) during vagal stimulation. It was subsequently shown that this antagonism was due to the concurrent release of neuropeptide Y (Warner & Levy, 1989) binding to neuropeptide Y2 receptors (Smith-White et al. 2002) on presynaptic vagal neurones, inhibiting the release of ACh (Potter, 1987). This effect was not observed in the present study but as the frequency of background SS increased, the negative chronotropic effect of vagal stimulation increased, indicating the lack of inhibition of vagus nerve stimulation with background SS. Instead the chronotropic effect of VS was augmented. We interpret this as a combination of the direct effects of muscarinic receptor stimulation of IK(ACh) and the indirect inhibition of cAMP-dependent phosphorylated ion channels mentioned above by the inhibitory Gi-protein. An alternative explanation could be that the intensity of sympathetic stimulation used in the current study, which was less than that used in the study by Potter (1985, 1987) and thus was insufficient to elicit the effects from neuropeptide Y (Lundberg & Hökfelt, 1986).
We have previously shown in the innervated isolated heart preparation (Ng et al. 2001) that the decrease in heart rate with vagus nerve stimulation was instantaneous, with no significant latency period as that seen with sympathetic stimulation. In this study, there was no appreciable effect of background sympathetic stimulation on the time course of heart rate response with vagus nerve stimulation (results not shown).
The effectiveness of left and right vagus nerve stimulation and accentuated antagonism
From the present study it was shown that right vagus nerve stimulation was more potent in reducing heart rate than the left vagus nerve in the absence of sympathetic stimulation, in agreement with previous studies (Loeb et al. 1981; Lang & Levy, 1989; Ng et al. 2001). It was not possible, however, to show that right VS was more potent in reducing the effects of SS than left VS. Left and right VS reduced the effect of SS to a similar extent. Additionally, the decrease in heart rate from left VS and right VS, in the presence of background SS, was not significantly different, although there was a trend for right VS to produce a larger decrease in HR. This suggests that vagal stimulation predominates over sympathetic stimulation and exerts significant inhibition over sympathetic stimulation, an effect which was more obvious at increasing frequency of sympathetic stimulation and with increasing frequency of vagal stimulation.
It is common practice in studies investigating heart rate, to stimulate left or right sided sympathetic and/or vagus efferent pathways to the heart. The right vagus nerve is usually chosen as it has been shown to have a larger chronotropic effect (Shipley & Greiser, 1945; Loeb et al. 1981). This suggests that there may be greater innervation of the sinoatrial node from the right vagus nerve (Ardell & Randall, 1986). Evidence from the rat agrees with this interpretation. Vagal fibres originating from the right dorsal motor nucleus and right nucleus ambiguus innervated the sinoatrial nodal region to a greater extent than the left, whereas fibres from the left dorsal motor nucleus and left nucleus ambiguus projected to a greater extent to the atrioventricular node region than the right side (Cheng et al. 1999; Cheng & Powley, 2000).
Limitations and further studies
In the present study, the whole sympathetic outflow from within the spinal cord was stimulated. This would have incorporated both left and right efferent pathways to the heart, whilst left and right vagus nerves were stimulated separately. This may have implications on some of the data described above whereby isolated right and left sided sympathetic stimulation may have produced different results. There is scope to extend the current studies to study the effect of right or left sympathetic stimulation in isolation either with stellate ganglion stimulation or bilateral stimulation before and after destruction of the stellate ganglion on one side. This will also allow the different ipsilateral and contralateral combinations of interactions between sympathetic and vagus nerve stimulation to be studied.
The possibility of the involvement of other autonomic mediators (Potter & Ulman, 1994), namely neuropeptide Y, vasoactive intestinal polypeptide and substance P, in the interaction between sympathetic and vagal stimulation may also be studied with the use of specific inhibitors and also specific blockers for other recepetors. These studies are difficult to be performed in vivo in the intact animal due to the difficulty with controlling loading conditions and the presence of haemodynamic reflexes and circulating humoral factors; which can be circumvented with an isolated preparation. We have previously demonstrated the selectivity of the response to nerve stimulation in the innervated isolated heart preparation in that the effects were abolished with specific adrenergic and muscarinic antagonists (Ng et al. 2001). In addition, there was no tonic autonomic activity in the absence of nerve stimulation and there was no cross-contamination of responses during either sympathetic or vagal stimulation. The innervated isolated heart preparation thus hold enormous potential as an ideal in vitro model, allowing the investigation of the complex mechanisms underlying the effects of sympatho–vagal interactions on cardiac function.
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References |
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