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Cardiovascular Research 1999 43(4):930-938; doi:10.1016/S0008-6363(99)00103-0
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Copyright © 1999, European Society of Cardiology

Cardiac transplantation does not effect ischaemia-induced arrhythmias in rats

P. Guo1, M.K. Pugsley2, S.L. Yong and M.J.A. Walker*

Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, 2l76 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

* Corresponding author. Tel.: +1-604-822-9531; fax: +1-604-822-9578 mwalker{at}nortran.com

Received 22 September 1998; accepted 4 February 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
Objective: In many species arrhythmias induced by myocardial ischaemia appear to be in part dependent upon cardiac sympathetic nerves. However, previous experiments in rats did not suggest that myocardial or other catecholamines are involved in ischaemic arrhythmogenesis in this species. The aim of this study was to investigate this further using transplanted hearts. Methods: We transplanted ’donated’ hearts onto the abdominal aorta of recipient rats and, at varying periods after transplantation, subjected donated and recipient hearts to occlusion of the left anterior descending (LAD) coronary artery. Donated and recipient hearts were tested at various times after transplantation for responsiveness to drugs acting upon aspects of the autonomic nervous system. The intention of this latter study was to assess the status of innervation and receptors simultaneously in both donated and recipient hearts. Results: Donated (transplanted) hearts showed responses consistent with denervation and receptor supersensitivity. Changes varied with the duration of the transplant. Over the same period recipient hearts did not change in responsiveness to drugs. When subjected to coronary artery occlusion, transplanted hearts responded to occlusion with the same frequency and severity of arrhythmias as recipient and other control hearts, regardless of the duration of transplant, or sensitivity to drugs. Conclusions: The results of these experiments suggest that cardiac innervation is not an important factor in the genesis of ischaemia-induced arrhythmias in rats.

KEYWORDS Heart transplant; Coronary occlusion; Ischaemic arrhythmias; Autonomic drugs; Cardiac innervation

See Editorial of this article by X.-J. Du and A.M. Dart (pages 832–834) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
Extensive evidence has been accumulated for a number of different species subject to coronary occlusion which suggests that arrhythmias induced by myocardial ischaemia are due in part to activation of the sympathetic system and the release of the sympathetic neurotransmitter, noradrenaline [1,2]. The evidence appears strong enough to warrant accepting the hypothesis that noradrenaline release and activation of adrenoceptors is an important factor in ischaemic arrhythmogenesis; both alpha and beta adrenoceptors appear to be involved [3–9].

Despite evidence to support the above hypothesis in some species, such evidence in rats is more equivocal. Thus, while there is evidence which suggests that cardiac noradrenaline is involved in ischaemic arrhythmogenesis in the rat, an equal weight of evidence suggests that this is not the case. Evidence for and against an involvement of cardiac noradrenaline has been obtained by the use of selective blocking drugs, or removal of components of the sympathetic system by a combination of surgery and drugs [10–12]. The evidence for adrenoceptor involvement in ischaemic arrhythmogenesis in anaesthetized rats obtained by the use of beta blocking drugs is open to alternative explanations. Thus the antiarrhythmic effects of beta blockers against ischaemia-induced arrhythmias in anaesthetized rats can be explained on the basis of their ability to elevate serum potassium concentration [5,6,13]. Blockade of peripheral β2 receptors elevates serum potassium concentrations and such elevated potassium concentrations are antiarrhythmic [14,15].

Isolated rat hearts subject to coronary occlusion and regional ischaemia have the same type and severity of arrhythmias as hearts in intact conscious rats subject to the same type of coronary occlusion [16,17]. As well, it has been shown that a functionally intact sympathetic nervous system is not a sine qua non for the occurrence of arrhythmias in rats [13,16,18]. These results argue strongly against the hypothesis that central activation of the cardiac sympathetic system plays a critical role in ischaemic arrhythmogenesis in the rat. However, it has been suggested that the important arrhythmogenic stimulus is not the activation of the sympathetic system by the central nervous system but local ischaemia-induced release of cardiac noradrenaline [10,16].

In an attempt to further clarify the situation in rats, we performed heterotopic abdominal rat heart transplantation and subjected both the transplanted (donated) heart as well as recipient heart to the same type of occlusion of the left anterior descending (LAD) coronary artery. The recipient heart remained innervated whereas the donated hearts were subjected to decentralization and degeneration of nerve endings depending upon the duration of the transplant. We compared the incidence and severity of the arrhythmias induced by occlusion in transplanted hearts with those which occurred in normal hearts, both in rats subjected to transplantation, and in a separate group of control rats. In addition, various drugs acting at various loci in the autonomic nervous system were used to probe the status of innervation and adrenoceptors in both donated and recipient hearts.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 Acknowledgments
 References
 
2.1 General animal surgery
All experiments used male Sprague-Dawley rats weighing between 200–250 g at the time of transplant. Experiments were conducted in accordance with requirements of the Animal Care Committee of the University of British Columbia. Separate groups of control rats were subjected to coronary occlusion after sham transplantation. Both donated, recipient and control hearts were subjected to occlusion of the left coronary main artery (while anesthetized) in a manner previously described and used in many previous experiments [15,16,19].

Recipient rats subjected to transplantation received hearts from animals of the same strain (isograft). Both donated and recipient hearts were tested over a period of days following transplantation for sensitivity to various autonomic and cardiovascular drugs. The purpose of this pharmacological study was to establish the responsiveness of both donated and recipient hearts to drugs which activate or block the sympathetic nervous system at different loci.

2.2 Cardiac transplantation technique
A modified version of Ono’s heart transplantation technique [20,21,22] was performed under halothane (1.5%) in oxygen anaesthesia. Donated hearts from pentobarbitone (50 mg/kg, i.p.) anaesthetized rats were initially arrested by injection of 10 ml of sterilized, ice-cold, heparinized (100 U/ml) Ringer’s lactate solution into the inferior vena cava. The aorta was transected 3 mm above its cardiac origin and the pulmonary vein ligated concurrently. The superior and inferior vena cava were also ligated. The donated right lung was ligated and removed together with the lower lobes of the left lung. Thus, heart together with a single upper lobe of left lung were excised from a donor rat and placed in oxygenated, cold, sterile saline (0.9%) solution until transplanted.

The abdominal aorta and inferior vena cava of the recipient animal were temporarily clamped using microsurgical clamps. Cessation of blood flow allowed for an end-to-side anastomosis of the root of the donor aorta to the side of the recipient’s abdominal aorta using 8.0 Ethicon sutures. The entire procedure was performed in less than 30 min. Blood flow to the transplanted heart occurred upon release of the microsurgical clamps. In the transplanted heart, blood flow passes into the coronary arteries via the anastomosed aorta and returns to the right atrium to be pumped via the right ventricle and the pulmonary artery into the residual lobe of the lung. The blood returns to the left atrium and ventricle to be subsequently pumped through the donor aortic root into the recipient’s abdominal aorta. The cardiac output of the donated heart was therefore its coronary flow which is expected to be approximately 25% of the normal cardiac output. Following re-establishment of blood flow and contractility in the transplanted heart, minor bleeding at the anastomosis site was stopped by the application of direct pressure to the site using a cotton swab. If necessary, additional sutures were used to stop excessive bleeding. The transplanted heart was closed within the abdominal cavity with a single continuous suture (3.0 Ethicon surgical silk). Ampicillin (50 mg/kg/day, im) was administered for 3 days following surgery.

Only animals which survived transplantation and were in good health and in which the transplanted heart continued to beat well were used for subsequent experiments. Beating in transplanted hearts was evaluated by palpation and abdominal ECG leads.

2.3 Coronary artery occlusion
A standard procedure was used to produce coronary occlusion of the left main ‘LAD’ coronary artery in all hearts using artificially-ventilated, pentobarbitone (50 mg/kg, ip) anaesthetized rats as previously described [19]. In order to perform occlusion in donated (transplanted) hearts the previous abdominal incision was opened and a ligature placed immediately below the bifurcation of the left main coronary artery. When coronary occlusion was performed in control or recipient hearts the heart was exposed by means of an intercostal incision at the level of the fifth and sixth ribs. In all hearts, the site of placement of the occluder was identical. In some experiments occluders were placed in both donated and recipient hearts within the same animal. In other animals occluders were only placed in the donated or recipient heart.

Following transplantation animals were randomized to one of four concurrent study groups. Transplanted hearts were separated into a trial experiment whereby animals in this group were occluded one hour after transplantation, (trial group 1, n=12), or were randomly assigned to the experimental study groups where hearts were occluded either on day 2 (group 2, n=10), day 5 (group 3, n=10) or day 10 (group 4, n=10), post transplantation. Prior to occlusion, a blood sample (0.5 ml) was taken in order to measure serum K+ levels. ECG, arrhythmias, blood pressure, heart rate and mortality were monitored for 4 h after occlusion, unless animals succumbed to the resulting arrhythmias before completion of the observation period. Arrhythmias, consisting of premature ventricular beats (PVB), ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded and summarized according to an Arrhythmia Score (AS) [23]. The arrhythmia score is a Gaussian distributed variable that describes the occurrence of PVBs, and the number and duration of episodes of VT and VF. Premature ventricular beats were defined as single QRS complexes which occurred before any identifiable P wave. Doublets (bigeminal) or triplets (trigeminal), and variations in the single QRS complex, were not classed as distinct arrhythmias but rather were summed for each group as PVBs [23]. Ventricular tachycardia was defined as four or more consecutive PVBs and not subclassified according to rate. A VT was classified by characteristic changes in ECG morphology such as loss of the P-wave but distinguishable QRS complex, elevation in heart rate and fall in mean blood pressure [23]. Ventricular fibrillation was defined as a chaotic ECG pattern in which no distinguishable QRS complexes could be discerned accompanied by a precipitous fall in blood pressure. Animals were not defibrillated and if VF did not spontaneously revert, the animal died. At the end of the observation period a second blood sample was taken from surviving animals. Hearts were then removed, and perfused via the Langendorff technique with cardiogreen dye (1.0 mg/ml) to reveal underperfused tissue (occluded zone). The hearts were then lightly patted dry with a Kimwipe® (to remove only excess perfusate) and weighed. Rats were only included in the study provided: (1) mean arterial blood pressure did not fall below 25 mmHg for more than 2 min before or after occlusion; (2) pre-occlusion ECG had a well defined P, QRS and T-wave, was in normal sinus rhythm, and the S-T segment was below the R-wave peak; (3) there was no VT or VF and less than 15 PVB before occlusion; (4) serum K+ concentrations were between 2.9 and 3.9 mM before occlusion; (5) occlusion produced an increase in R-wave and elevation of the S-T segment [19] and (6) occluded zone size was between 25 and 50% of total ventricular weight.

2.4 Drug responsiveness of normal and transplanted hearts
In order to test responses of donated and recipient hearts to various drugs rats were subjected to treatment with various autonomic and cardiovascular drugs. Animals were anaesthetized with pentobarbitone (50 mg/kg, ip) and the right external jugular vein cannulated for drug administration. Two (lead II) ECG’s were set-up using needle electrodes inserted under the skin. Independent ECG’s were observed for each heart. Drugs were injected as bolus intravenous (iv) injections and heart rate responses of the donated and recipient hearts detected by means of abdominal (donated) and chest (recipient) ECGs. Heart rate was calculated based on the average R–R interval using 10 consecutive beats. Thus responses of both recipient and donated hearts to drugs which acted directly, or indirectly, upon cardiac β-receptors or adrenergic nerves were assessed. Drugs were saline vehicle (0.2 ml); adrenergic agonists [isopropylnoradrenaline (IPNA, 0.1 µg/kg) and noradrenaline (NA, 0.1 µg/kg)]; the ganglion stimulant, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 0.1 µg/kg); the ganglion blocker, hexamethonium (5.0 mg/kg); the cholinergic agonist, acetylcholine (ACh, 1.0 µg/kg); the smooth muscle relaxant, nitroprusside (20 µg/kg), the cholinergic antagonist, atropine (1.0 mg/kg) and the beta blocker, propranolol (10 µg/kg). Doses were chosen on the basis of previous experiments and were chosen to produce a 25% change in heart rate for agonists and effective blockade for antagonists. Drug injection volume was always less than 0.2 ml, followed by 0.2 ml of saline wash in.

2.5 Statistics
Statistical significance was taken at p<0.05, unless otherwise indicated, using the NCSS statistical package [24]. Results between groups were compared using ANOVA and Duncan’s multiple comparison test. All reported values are mean(±SEM). The statistically significant differences between group incidence of arrhythmias (ventricular tachycardia and ventricular fibrillation) were compared using Mainland’s contingency tables [25]. The number of premature ventricular beats (PVBs) were normalized by log10 transformation before using parametric statistical analyses.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 Acknowledgments
 References
 
The physiological and pharmacological status of donated and recipient hearts was assessed prior to occlusion in terms of heart rate and responses to drugs.

3.1 Heart rate and drug responsiveness of transplanted and recipient hearts
The resting heart rates of donated and recipient hearts under anaesthesia before and for 4 h after occlusion are shown in Fig. 1. Early after transplantation (2 days) the resting rate of donated hearts (236±9 beats/min) was significantly lower (p<0.01) than that of recipient hearts (338±11 beats/min) but this difference became less as the age of the transplant increased. After ten days (d) transplantation the rate of the donated heart (356±7 beats/min) was slightly, but still significantly (p<0.05), less than that of the recipient (376±10 beats/min). The heart rate of the recipient heart after occlusion consisted of a short-lived initial rise then a fall, followed by a slow and steady rise (see Fig. 1, panel A insert). In transplanted hearts there was a similar increase in heart rate 4 h after occlusion in the hearts transplanted for 2 and 5 d but not in those which were 10 d old.


Figure 1
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  		Fig. 1 Heart rates in donated and recipient hearts before and after coronary artery occlusion at various times after transplantation. Heart rate values for recipient (unfilled symbols, panel A) and donated (filled symbols, panel B) hearts are shown at 2 days (triangles), 5 days (circles) and 10 days (squares) post-transplantation. The inset in panel A shows the early initial heart rate response (0–30 min) of the recipient heart to occlusion 2 days (triangles), 5 days (circles) and 10 days (squares) after transplantation. Error bars have not been shown for sake of clarity.

 
There were notable differences between the transplanted and donated hearts in terms of their sensitivity to drugs as summarized in Table 1. Sensitivity differences depended on the type of drug. Thus the directly acting agonists noradrenaline and isopropylnoradrenaline (IPNA) increased the heart rate in donated hearts more than in recipient hearts (p<0.05). Tachycardic drug responses to IPNA was marked in both types of hearts at all times after transplant. The control drug for the vasodilation induced by IPNA was nitroprusside which induced tachycardia in all recipient, but not in donated hearts. Noradrenaline always increased the rate of the donated heart (p<0.05) but often slowed the recipient heart, presumably as a result of reflex bradycardia due to the pressor effect of noradrenaline Stimulation of autonomic ganglia directly by DMPP or indirectly by activation of a reflex arc following hypotension induced by nitroprusside caused a much greater tachycardia in recipient hearts than donated hearts (p<0.01). In keeping with the importance of innervation in recipient hearts was the slowing induced by administration of the ganglion blocking drug, hexamethonium (p<0.05). On the other hand hexamethonium produced no effects on donated hearts. Acetylcholine, however, reduced heart rate in both donated as well as recipient hearts.


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  		Table 1 Response of donated hearts compared with recipient hearts to drugsa

 
Propranolol reduced heart rate in both donated and recipient hearts with the decrease being greatest in the recipient hearts, 2 and 5 d after the transplant operation. On the other hand 10 d transplanted hearts appeared to be very sensitive to the bradycardic actions of propranolol indicative perhaps of their sensitivity to circulating catecholamine levels.

3.2 Arrhythmic and other responses to coronary occlusion
Table 2 summarizes the responses of transplanted and donated hearts to coronary occlusion in a trial group (1 h after transplantation) and in the experimental study groups (2, 5 and 10 d after transplantation) of the donated heart. In the trial group (Table 2, panel A) coronary occlusion was performed 1 h after completing heart transplant surgery in both the donated and recipient hearts. Occlusion was first performed in the donated heart followed 30 min later by occlusion of the recipient heart. Arrhythmia incidence was then monitored for 240 min. When the donated heart was subjected to occlusion prior to the recipient heart the occurrence of ventricular fibrillation was not a problem since the recipient heart maintained the cardiac output and hence blood pressure. On the other hand when the recipient heart was occluded first the occurrence of ventricular fibrillation usually resulted in either failure of the donated heart to beat or death of the animal, since none of the animals were subject to defibrillation. In this initial experiment there was a statistically significant differences in VPB incidence between the two groups of hearts (p<0.05). However both the incidence of VT and VF as well as the arrhythmia score were not different between the two groups of hearts (Table 2, panel A).


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  		Table 2 Incidence of ventricular arrhythmias in donated and recipient hearts produced by coronary occlusiona

 
In order to evaluate arrhythmia incidence between transplant and recipient hearts and ensure equal group sizes, the experiment whose results are shown in Table 2, panel B, was performed. This table contains data from donated and recipient hearts subject to coronary occlusion in separate animals. As can readily be seen in Table 2, panel B, the overall incidence of all types of arrhythmias were similar in the various groups. In addition, arrhythmia scores were the same for the different groups.

An examination of the time profiles for the incidence of VPBs (Fig. 2) and the number of individual incidents of VT and VF arrhythmias (Figs. 3 and 4Go) suggest that a majority of arrhythmias first occur in both groups between 5 and 90 min after occlusion with a slight variability in peak depending upon arrhythmic type, experimental group and day post-transplantation. This is a commonly observed time period for the development of arrhythmias using the rat coronary occlusion model [19]. When the PVB incidence was examined over the 0–90 min post-occlusion time period for the day 2, 5 and 10 recipient heart groups the median time to peak PVB incidence was 8.3±1.7 min. Analysis of the data for the median time to peak PVB incidence for the donated heart group was 10.5±1.5 min post-occlusion. These results suggest that while the PVB incidence between donated and recipient groups may vary at some of the time intervals examined, the time to peak PVB incidence does not vary significantly between groups (see Fig. 2). In Fig. 3 the time to median number of incidents of VT was 6.0±1.8 min for the recipient hearts and 8.2±2.3 min for the donated hearts post-occlusion. Lastly, the median time to VF incidence was 9.0±2.0 min for the recipient hearts and 13±3.0 min for the donated hearts post-occlusion. In this last analysis there was a significant difference in the peak time to onset of arrhythmia incidence between the donated and recipient groups (p<0.05). However, it should be noted that despite this difference in time of arrhythmia occurrence between groups (see Fig. 4 at day 2 and day 5 post transplantation), as well as the time-to-time variability in arrhythmias, the arrhythmia score of Table 2, (a more reliable index of the severity of ischaemic arrhythmias that occur [23] since it accounts for duration as well as number of arrhythmic episodes) does not indicate an overall difference between groups.


Figure 2
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  		Fig. 2 Temporal pattern for arrhythmias after coronary artery occlusion in donated (filled columns) and recipient (open columns) hearts. Results are grouped according to severity of arrhythmias, i.e., incidence of premature ventricular beats (PVBs) for groups at 2, 5 and 10 days after transplantation. Arrhythmia incidence was monitored for 240 min after coronary artery occlusion in all hearts. PVC incidence was log10 transformed.

 

Figure 3
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  		Fig. 3 Temporal pattern for arrhythmias after coronary artery occlusion in donated (filled columns) and recipient (open columns) hearts. Results are grouped according to severity of arrhythmias, i.e., incidence of ventricular tachycardia (VT) for groups at 2, 5 and 10 days after transplantation. Arrhythmia incidence was monitored for 240 min after coronary artery occlusion in all hearts.

 

Figure 4
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  		Fig. 4 Temporal pattern for arrhythmias after coronary artery occlusion in donated (filled columns) and recipient (open columns) hearts. Results are grouped according to severity of arrhythmias, i.e., incidence of ventricular fibrillation (VF) for groups at 2, 5 and 10 days after transplantation. Arrhythmia incidence was monitored for 240 min after coronary artery occlusion in all hearts.

 
It has previously been shown that the incidence and severity of arrhythmias in rats subjected to coronary occlusion are to some extent dependent upon the serum potassium concentration at the time of occlusion as well as upon the size of the occluded zone (ischaemic zone) [15,19]. Serum potassium values did not vary statistically significantly in a meaningful manner between the different groups. Group means (±SEM) ranged from 2.9±0.1 to 4.0±0.2 mM in a manner which did not relate to time, or procedure. Occluded zone (OZ) sizes (expressed as percent of total ventricular weight) were generally larger in recipient hearts (between 35±2 and 40±3%) although they did not vary with the age of the transplant. The mean OZ for all recipient hearts was 38±2% whereas that for donated hearts was 35±1% (p=0.05).

The blood pressure responses to occlusion (data not shown) were very similar in the different groups. Similarly, there were no differences in ECG response (such as the P–R interval, QRS width, or Q–T interval) to occlusion between the different groups. As shown in Fig. 5 the R-wave changes in response to occlusion reached a higher peak in 2 d transplanted recipient hearts but fell more quickly after reaching a peak. A similar pattern occurred in 5 d transplants whereas in 10 d transplants peak responses were similar. However, in these donated hearts the R-wave fell more quickly. On the other hand S-T segment elevations were similar between donated and recipient hearts for 2, 5 and 10 d transplants (data not shown).


Figure 5
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  		Fig. 5 Pattern of R-wave height (in mV) changes for donated (filled columns) and recipient (open columns) hearts induced by coronary artery occlusion. Values are mean (±SEM) for hearts occluded 2, 5, and 10 days after transplantation.

 
3.3 Status of donated and recipient hearts
In terms of weight and appearance, hearts from control (1.5±0.5 g) and recipient (1.6±0.2 g) animals were identical whereas the weight of transplanted hearts fell with the age of transplant (to 1.2±0.5 g after 10 d). While a full histological examination was not performed it was apparent, from careful visual and microscopic inspection, that donated hearts showed no gross signs of inflammation or rejection. A complete cessation of palpable heart beats was defined as a criterion for rejection; however, rejection of the isograft heart in rats does not occur, on average, until 18 d after transplantation [26].


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
Acknowledgments
 References
 
These experiments show that arrhythmias induced by coronary occlusion in transplanted rat hearts are similar in severity and incidence to those in intact hearts. Such evidence would suggest that an intact sympathetic innervation is not necessary for ischaemia-induced arrhythmogenesis in this species. However, such a conclusion is premised on the assumption that the transplanted heart is truly denervated with respect to cardiac neurotransmitters, particularly noradrenaline. Furthermore, it is assumed that the transplanted heart is physiologically identical to the intact heart and that the process of transplantation does not increase the sensitivity of the donated heart to the arrhythmogenic stimulus of ischaemia.

With respect to such considerations, donated hearts were obviously performing less work than recipient hearts, and not under autonomic control. Presumably, a lack of cardiac work was responsible for the lighter weights of donated hearts. The loss of weight in donated hearts has been commented on many times and is presumed to be a result of atrophy; thus, this non-physiological mode of heart transplantation is not recommended for use in functional heart studies [27]. Whether this relative dystrophy influences the arrhythmic response to ischaemia is not known. On the other hand the process of rejection is associated with infiltration of the donated tissue with inflammatory cells such as leukocytes [28–30]. Such inflammatory cells have been associated with arrhythmogenesis during myocardial ischaemia and infarction [31]. However, the rejection process increases with the duration of the transplant but in this study there was no change in the incidence of arrhythmias with transplant duration. Thus, it is unlikely that invasion of transplanted hearts with cells of the immune system constituted an arrhythmogenic process which compensated for a loss with innervation. Studies with long-term survivors of orthotopic and heterotopic cardiac transplantation exemplify this in that it was shown that arrhythmias were no more common in donated hearts than in normal hearts [32].

With respect to the physiological and pharmacological status of donated hearts most of the changes seen were those expected to result from decentralization and denervation. As might be expected as a result of decentralization, donated heart rates fell after transplantation and also failed to show a reflex increase in heart rate in response to injections of the vasodilator, nitroprusside. The ganglion stimulant DMPP produced a very limited response in the donated heart compared with the recipient heart. This is to be expected if DMPP releases both locally effective noradrenaline from intact sympathetic cardiac nerves and circulating adrenaline from the adrenal medulla.

Donated hearts were presumed to contain adrenoceptors since they all showed positive chronotropic responses to isopropylnoradrenaline and noradrenaline. Responses to isopropylnoradrenaline might be expected to be heightened in recipient animals because of additional reflex tachycardia and direct stimulation of cardiac beta adrenoceptors. The tachycardic effects following noradrenaline administration were less in recipient hearts than in donated hearts presumably as a result of reflex bradycardia in the former following a rise in blood pressure. A marked reduction in heart rate was observed in the 10 day post transplant donated hearts after administration of propranolol. This effect may be indicative of a developing sensitivity of these hearts to circulating catecholamines.

In conclusion, the heterotopic model of cardiac transplantation used in this study provided a means by which to examine the actions of the autonomic nervous system and arrhythmias in heart transplantation. Thus, our results show that ischaemia-induced arrhythmias in the rat are independent of cardiac autonomic nervous system innervation in this species.

Time for primary review 50 days.


   Acknowledgments
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
References
 
We wish to thank the B.C. Medical Services Foundation, the Heart and Stroke Foundation of B.C. and Yukon, and the Medical Research Council of Canada for financial support of the above project.


   Notes
 
1 Department of Pharmacology, Amgen Co., Thousand Oaks, CA, 91320, USA. Back

2 Department of Pharmacology and Toxicology, XOMA Ltd., Berkeley, CA, 94710, USA. Back


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 

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