Cardiac response to norepinephrine and sympathetic nerve stimulation following experimental subarachnoid hemorrhage

Journal of the Neurological Sciences 198 (2002) 43 – 50 www.elsevier.com/locate/jns

Cardiac response to norepinephrine and sympathetic nerve stimulation following experimental subarachnoid hemorrhage Elisabeth Lambert a,*, Xiao-Jun Du b, Elodie Percy b, Gavin Lambert a a

b

Human Neurotransmitter, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia Experimental Cardiology Laboratories, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia Received 31 December 2001; accepted 5 March 2002

Abstract This study aimed to investigate the cardiac response to sympathetic stimulation and norepinephrine exposure following subarachnoid hemorrhage (SAH). Cardiac functional response was assessed 3 days following an injection of 300 Al of homologous blood in the cisterna magna using an in situ perfused, innervated rat heart model. Sympathetic nervous activity was indirectly assessed from measurements of arterial plasma and tissue norepinephrine concentration and cardiac h-receptor density. In in situ perfused hearts, sympathetic nerve stimulation (2, 4 and 8 Hz, 1 min duration) induced a frequency-dependent increase in left ventricular pressure (VP), with the response being more pronounced in the SAH group of animals at the higher frequency ( P < 0.05). However, the concomitant release of norepinephrine was identical in the two groups of animals. Increasing doses of norepinephrine (10 9 to 10 5 M) added to the perfusate induced a dosedependent increase in VP and its first derivative (dP/dt). Both responses were greater in the SAH animals compared to the sham rats ( P < 0.01). ECG recordings from SAH animals presented a higher incidence of different types of arrhythmias, both at rest and when submitted to electrical stimulation or norepinephrine exposure. No difference was found between groups in left ventricle norepinephrine content, plasma norepinephrine nor left ventricle h-receptor density. In conclusion, hearts from animals following acute experimental SAH exhibit enhanced sensitivity to norepinephrine infusion and sympathetic nerve stimulation, and are more prone to develop arrhythmias. However, hypersensitivity of the heart may not be explained by changes in norepinephrine release or by h-receptor density. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Arrhythmia; Cerebrovascular disorders; Ventricular function; Rat

1. Introduction Cardiovascular complications are often observed in patients following acute cerebrovascular disturbances. Indeed, following stroke, patients may present with cardiac arrhythmias, myocardial necrosis, ECG alterations and changes in circadian rhythm of blood pressure [1]. Elevated plasma levels of norepinephrine [2] and alterations in heart rate variability [3,4] in such patients implicate activation of the sympathetic nervous system in the aetiology of these disturbances. Similarly, cardiac complications are also observed in patients following subarachnoid hemorrhage (SAH). Indeed, ECG abnormalities, such as depressed or elevated ST segments, QT prolongation, T-wave abnormalities and cardiac arrhythmias, similar to those seen in

*

Corresponding author. Tel.: +61-3-8532-1345; fax: +61-3-8532-1100. E-mail address: [email protected] (E. Lambert).

patients with myocardial ischemia, are observed in as many as 50– 70% of patients following SAH [5,6]. A reversible form of cardiac injury may occur in patients with neurogenic pulmonary edema following SAH [7]. Impaired left ventricular hemodynamic function in this situation may contribute to cardiovascular instability, pulmonary edema formation, and complications from cerebral ischemia. Accumulating evidence suggests that these cardiac disturbances reflect underlying cardiac pathology and dysfunction [8,9]. The observation that h receptor-blockade reverses ECG changes, prevents myocardial necrotic lesions, and reduces mortality [10] suggests that the cardiac disturbances that occur following SAH arise as a result of increased sympathetic nervous activity with subsequent elevation in levels of circulating catecholamines. Indeed, increased concentrations of plasma and urinary norepinephrine and its metabolites, and elevated rates of norepinephrine spillover to plasma have been documented in patients following SAH [11– 14]. Some studies have failed to find a relation between ECG

0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 0 7 3 - 4

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changes and high plasma norepinephrine concentrations [12,15,16]. It would seem that at this juncture the mechanism(s) responsible for the generation of the cardiac disturbances seen following SAH remain to be elucidated. The aim of the present study was to gain some insight into the potential sympathoadrenergic mechanism underpinning the cardiac complications that occur following SAH. Using an animal model of SAH combined with an in situ heart perfusion system we evaluated cardiac function, norepinephrine release from the heart and ECG activity in response to both direct sympathetic nerve stimulation and norepinephrine infusion, and h-receptor density 3 days following experimental SAH.

2. Methods Experiments were performed on 22 male Sprague – Dawley rats (380 –420 g) bred and housed at the Baker Medical Research Institute. All procedures were performed in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific purposes and the relevant ethics committee of the Baker Medical Research Institute approved the protocol. All rats were housed under controlled temperature and humidity and a 12:12-h dark light cycle with free access to food and water. 2.1. Surgical method Subarachnoid hemorrhage was induced (n = 11) under anesthesia with sodium pentobarbitone (60 mg/kg, i.p.). Rats were placed on a stereotaxic table with their head in a nose down position. Homologous blood (0.3 ml) was withdrawn from a femoral artery and was injected into the cisterna magna over f 1 min. Animals were placed in an incubator/humidity crib set at approximately 28 jC and closely monitored throughout their recovery. Animals were returned to their home cage and examined twice daily until the experimental day that was scheduled 3 days post-SAH. Sham surgery (n = 11) comprised induction of anesthesia and placement on the stereotaxic table as outlined above. The atlantooccipital membrane was exposed but not pierced, a femoral artery blood sample was taken and discarded.

pump. To achieve a similar perfusion flow rate of 5 ml/min/ g heart weight, perfusion flow rates were set at between 4 and 8 ml/min, according to estimated heart weights. Perfusion pressure was maintained at 40 – 45 mm Hg. After ligation of the pulmonary vessels and the superior vena cava, the right atrium was cannulated in order to collect coronary effluent. Therefore, in this preparation, the left ventricle was filled with effluent and sealed. This is different from the isolated Langerdorff heart preparation in which the left ventricle is open and empty. A transducer catheter (Millar Instruments, Houston, USA) was inserted into the left ventricle via the apex to record left ventricular pressure and its first derivative, dP/dt. Heart rate was derived from the left ventricle pressure signal. The flow pressure was measured using a TranStar transducer (Medex, Hilliard, USA) and left ventricular pressure was recorded using a PowerLab recording unit (Neomedix Systems, Warriewood, NSW, Australia). The epicardial ECG was obtained using an electrode inserted superficially into the left ventricle wall. All parameters were monitored throughout the periods of nerve stimulation and exogenous norepinephrine infusion. 2.3. Nerve stimulation In the in situ perfused heart model, the cardiac efferent innervation remains intact. The left cervicothoracic stellate ganglion, with cardiac sympathetic nerves attached, was dissected and placed on electrodes for subsequent electrical stimulation. Nerve stimuli (2 ms and 0.8 mA) were generated by a Model SD-9 stimulator (Grass Instruments, Quincy, USA) and delivered at 2, 4 and 8 Hz (1-min duration each), in random order, separated by a 10-min interval. Nerves were constantly superfused with warm perfusate except when stimulation was performed. Left ventricle effluent was collected for a period of 1 min before and during nerve stimulation and immediately placed on dry ice for subsequent catecholamine determination. The neuronal reuptake inhibitor desipramine (0.3 AM, Sigma, St Louis, USA) was added to the perfusate, thereby the quantification of evoked norepinephrine release was quantified from determination of norepinephrine washout without the potential confounding effects of norepinephrine reuptake. 2.4. Norepinephrine stimulation

2.2. In situ heart perfusion Investigations were performed using an in situ, perfused, innervated heart preparation as previously described [17]. Briefly, the chest was opened and 1 ml of blood was quickly taken from the descending aorta for subsequent catecholamine analysis. The ascending aorta was cannulated to start coronary perfusion in situ. Krebs – Henseleit solution: [containing (in mmol/l) Na + 148, K + 4.0, Ca2 + 1.85, Mg2 + 1.05, HCO3 25, PO4 0.5, glucose 11 and EDTA 0.027, and was gassed with 95% O2 and 5% CO2 (pH 7.4)] was perfused with the flow rate being controlled by a roller

Following nerve stimulation, all hearts were permitted to recover for at least 20 min. Five increasing doses of norepinephrine (10 9, 10 8, 10 7, 10 6, 10 5 M) were administrated via the perfusate solution for a period of 3 min with each dose separated by 3 min. 2.5. Analysis of ventricular arrhythmias We used an arrhythmia scoring system as previously described by Du et al. [18]. The ranking scores are arbitrary numerical grades of different sorts of ventricular arrhyth-

E. Lambert et al. / Journal of the Neurological Sciences 198 (2002) 43–50

mias recorded in each preparation. The scaling applied was as follows: 0 = no arrhythmia, 1 = 1 –5 ventricular premature beats (VPB), 2 = 6 – 15 VPB, 3 = 16– 30 VPB, 4 = more than 30 VPB, 5 = single episode of ventricular tachycardia (VT) of less than 5 s duration, 6 = combined VT with a duration of between 5 and 20 s, and 9 = combined VF with a duration of longer than 20 s. When multiple forms of arrhythmias occurred in one heart, only the highest single score was used. Duration of analysis was as follows: control, 3 min; nerve stimulation: 1 min from the onset of stimulation; norepinephrine infusion: 3 min from the start of infusion. 2.6. Catecholamine analysis Left ventricle effluent, plasma samples and left ventricles were stored at 80 jC until assay. Norepinephrine was extracted from superfusate, plasma and tissue with alumina adsorption, separated by high performance liquid chroma-

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tography and the amounts quantified by electrochemical detection according to previously described methods [19]. The chromatographic system consisted of a Model 480 High Precision Pump, Model Gina autosampler, Model STH 585 column oven, Chromeleon 3.03 Chromatography Data System (Dionex, Germering, Germany), Model 5100A coulometric detector equipped with a Model 5021 conditioning cell and a Model 5011 analytical cell (Environmental Sciences Associates, MA, USA) and a 25-cm Altex Ultrasphere column (ODS 4.6 mm  25 cm, 5 m particle size, Beckman Instruments, CA, USA). Analysis was performed at 24 jC with the operating potentials set at + 0.35 V for the guard cell and 0.35 and + 0.29 V for detectors 1 and 2, respectively. All measurements were made using the oxidising potential applied at detector 2, and compounds of interest were identified by their retention behavior compared to that of authentic standard solutions. The intra- and interassay coefficients of variation were F 2% and F 11%, respectively.

Fig. 1. Example of a recording of ventricular pressure (VP), its first derivative dP/dt, ECG and heart rate (HR) before and after electrical stimulation in a shamoperated animal.

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Fig. 2. Heart rate (HR), ventricular pressure (VP), dP/dt and norepinephrine release responses to electrical stimulation. (Open bars = Sham, n = 11, stripped bars = SAH, n = 11.) Note that stimulation at all frequencies (from 2 to 8 Hz) induced significant increases in all parameters (compared to control). #: P < 0.05 SAH vs. Sham.

2.7. b-Adrenergic binding assay Examination of left ventricle h-receptor density was performed in six animals from each group. Approximately 100 mg of the left ventricle was homogenized using a Potter Elveijheim homogenizer in a binding buffer comprising 50 nmol/l Tris –HCl, 10 nmol/l MgSO4, pH 7.4 and 0.25 mol/l sucrose. The homogenate was centrifuged at 1000  g for 30 min at 4 jC. The resulting pellet was washed once in cold binding buffer and resuspended in the buffer at a final protein concentration of 3 Ag/ml. Protein concentration was determined using the Bradford method. The binding assay involved incubating membrane proteins (40 Ag) with a 40 pmol/l [125I] ( )iodocyanopindolol (2200 Ci/mmol, NEN, Boston MA, USA,) for 1 h at varying concentrations of the h-receptor agonist ( F )iso proterenol (10 10 to 10 4 mol/l, Sigma, St Louis, USA) in a total volume of 200 Al. The assay was performed in duplicate at 22 jC. Samples were then filtered using What-

Fig. 3. Heart rate (HR), ventricular pressure (VP) and dP/dt responses to increasing doses of norepinephrine. (Open circles = Sham, n = 11, solid circles = SAH, n = 11). #: P < 0.05, SAH vs. Sham.

man GF/C filters, followed by washes with 16 ml of the binding buffer. The dried filters were counted in a g-counter (Packard Model 5410 Ria Star, Meriden, USA), analysed using ALLFIT and the results expressed as fmol/mg protein.

E. Lambert et al. / Journal of the Neurological Sciences 198 (2002) 43–50 Table 1 Incidence of ventricular premature beats (VPB) and ventricular fibrillation (VF) at rest and during sympathetic nerve stimulation and norepinephrine infusion in sham operated (n = 11) and SAH (n = 11) animals 3 days postinduction of subarachnoid hemorrhage VPB% Sham Control Nerve stimulation 2 Hz Nerve stimulation 4 Hz Nerve stimulation 8 Hz Norepinephrine 10 9 M Norepinephrine 10 8 M Norepinephrine 10 7 M Norepinephrine 10 6 M Norepinephrine 10 5 M #

0 18.2 18.2 9 36.4 36.4 72.7 72.7 72.7

VF% SAH #

42 16.6 50 75# 33.3 58.3 83.3 92 58.3

Sham

SAH

0 0 0 0 0 0 0 0 0

0 0 8.3 16.6 8.3 8.3 8.3 33.3 33.3

P < 0.05 vs. sham group by Fisher exact test.

2.8. Statistics Values are expressed as mean F standard error of the mean (SEM). The effects of the different electrical stimulations on left ventricle pressure, heart rate, dP/dt and norepinephrine release were compared to the baseline period using a one-way repeated measures analysis of variance when results passed the normality test. Non-Gaussian data was analysed using Friedman’s repeated measures analysis of variance on ranks. Student’s unpaired t-test was used to compare results between groups. A split plot (nested) repeated measure analysis of variance was used to compare the effects of cumulative doses of norepinephrine. The total sums of squares (SS) were divided into between groups SS and within groups SS. Between group comparisons were made using the F ratio of the between group mean square divided by the rows x groups interaction. A comparison of

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the different control periods was also made between groups. Arrhythmia scores were compared using the Mann –Whitney rank sum test for between group comparisons. The Fisher exact test was used to compare the incidence of arrhythmia between groups. P < 0.05 was considered significant.

3. Results 3.1. Left ventricle function and norepinephrine release during nerve stimulation Baseline cardiac function was very similar between the two groups of animals. As illustrated in Fig. 1, cardiac nerve stimulation induced a frequency-dependent increase in heart rate, ventricular pressure and dP/dt as well as a concomitant increase in norepinephrine release in both groups (Fig. 2, P < 0.05 at any frequency). There was no difference in the magnitude of these responses between the two groups for heart rate, dP/dt and cardiac norepinephrine release. However, the 8-Hz stimulation resulted in a greater response in ventricular pressure in the SAH group of rats compared with their sham counterparts (Fig. 2, P < 0.005). Following nerve stimulation at 8 Hz, coronary perfusion pressure was increased only in the SAH group of animals (40 F 1 vs. 44 F 1 mm Hg in SAH animals and 43 F 2 vs. 45 F 3 mm Hg in the sham group). 3.2. Left ventricle function during norepinephrine infusion Norepinephrine infusion resulted in a dose-dependent increase in heart rate, ventricle pressure and dP/dt in both groups of animals. The response in left ventricle pressure in the SAH animals was greater than that of the sham animals

Fig. 4. Arrhythmia score in SAH and sham animals under control (Con) conditions and in response to sympathetic nerve stimulation and norepinephrine infusion. #: P < 0.05 vs. sham group by Mann – Whitney rank sum test.

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(F1,100 = 7.2, P = 0.009). Heart contractility, as indicated by alterations in dP/dtmax and dP/dtmin, was also significantly greater during norepinephrine infusion in the SAH animals (Fig. 3, F1,100 = 13.7, P < 0.001 for dP/dtmax and F1,100 = 4.3, P = 0.041 for dP/dtmin). In response to norepinephrine infusion, coronary perfusion pressure increased by similar degrees in both groups of animals (42 F 2 vs. 49 F 3 mm Hg at 10 5 M norepinephrine in sham animals and 40 F 1 vs. 47 F 1 mm Hg at 10 5 M norepinephrine following experimental SAH). 3.3. Arrhythmia During the control period the electrical activity of the hearts from the sham operated animals was very stable and none exhibited any arrhythmic episodes. In contrast, in approximately one third of cases, the hearts from the SAH group exhibited spontaneous ventricular premature beats (Table 1, P < 0.05 vs. sham). At rest, there occurred no instances of spontaneous ventricular fibrillation in the SAH rats. Whereas sympathetic nerve stimulation induced a modest increase in ventricular premature beats in the sham group, in SAH animals ventricular premature beats were evident in 50% of cases at 8 Hz ( P < 0.05 vs. sham) and ventricular fibrillation in one heart at 4 Hz and two hearts at 8 Hz. During electrical stimulation at 8 Hz, the arrhythmia score was greater in the SAH group of animals (Fig. 4, P < 0.05). Increasing doses of norepinephrine induced ventricular premature beats in over 70% of heart preparations. During norepinephrine infusion, ventricular fibrillation developed in four cases, all of which were in hearts derived from SAH animals. Arrhythmia scores were greater in SAH animals during norepinephrine infusion (Fig. 4, P < 0.05 at 10 6 M). 3.4. Plasma and tissue norepinephrine levels and cardiac breceptor density There occurred no difference in body and heart weights nor the ratio of left ventricle mass/body weight between the two groups of animals. While the arterial plasma norepinephrine level tended to be higher in the SAH group, the content of norepinephrine and the h-receptor density in the

Table 2 Body and heart weight and indices of whole body and cardiac sympathetic activity in sham operated (n = 11) and SAH (n = 11) animals 3 days postinduction of subarachnoid hemorrhage

Body weight (g) Heart weight (g) Left ventricle/body weight (mg/g) Plasma norepinephrine (pg/ml) LV norepinephrine (pg/mg) LV h-receptor density (fmol/mg of protein) Kd

SHAM

SAH

349 F 8 1.30 F 0.04 2.6 F 0.1 197 F 15 458 F 40 58 F 2 1.99 7

349 F 8 1.26 F 0.04 2.6 F 0.1 268 F 50 432 F 86 60 F 4 1.63 7

left ventricle was not different between the two groups. In addition, the affinity of h-receptors also remained unchanged in SAH verses sham animals (Table 2).

4. Discussion Electrocardiographic abnormalities are commonly observed in patients following SAH. In this study, using an isolated perfused heart preparation in animals following experimentally induced SAH, we noted the occurrence of ECG disturbances in a substantial proportion of animals examined. While the hearts from SAH animals exhibited an enhanced sensitivity to adrenergic stimulation, the mechanism responsible for the generation of these ECG abnormalities remains difficult to elucidate. Left ventricle h-receptor density and norepinephrine content were not influenced by SAH. In this study, while norepinephrine infusion elicited ECG disturbances in both sham and SAH-treated animals, direct sympathetic nerve stimulation resulted in a greater incidence of ventricular premature beats and higher arrhythmia score only in SAH animals. Accumulating evidence suggests that the ECG abnormalities that occur following SAH reflect underlying cardiac pathology and dysfunction [8,9]. Indeed, in early studies [20], elevated levels of creatinine-phosphokinase were observed in as many as 50% of patients following SAH. Myocardial damage is in fact commonly seen in patients following acute cerebral lesions [21] with contraction band necrosis being observed in the majority of patients with acute brain hemorrhage [22]. Following experimental SAH in rats, the presence of myocardial contraction band lesions is evident [23]. The mechanism responsible for such cardiac damage is believed to involve activation of the sympathetic nervous system secondary to the accompanying elevation in intracranial pressure. Transmurally located foci of myocardial injury have been described in patients presenting with other acute intracranial lesions such as intracranial bleeding, meningitis or ischaemic oedema [21]. In each of these conditions, intracranial pressure is exacerbated. Similarly, intracranial pressure is substantially elevated in a variety experimental models of SAH [23 – 25]. Interestingly, cardiac lesions are not observed in patients with slowly progressing intracranial tumours unless coexisting complications such as bleeding into the tumour or inflammatory oedema occur [21]. The link between catecholamines and ECG abnormalities following SAH remains controversial [8,12 – 16]. Naredi et al. [14] recently noted remarkably high rates of spillover of norepinephrine to plasma in patients following nontraumatic SAH. The elevated rates of spillover persisted for at least 7 days and electrocardiographic disturbances were observed in all subjects except those few with normal rates of whole body norepinephrine spillover to plasma. Elevated myocardial tissue levels of norepinephrine may lead to repolarisation disturbances and render the heart vulnerable to

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ventricular dysrhythmias [26]. Moreover, high catecholamine concentrations in both man and pigs have been linked to myocardial damage [21,27,28]. In agreement with Elrifai et al. [29], in the present study, we found no relationship between arterial or left ventricular norepinephrine concentration and arrhythmia score 3 days following experimental SAH. In the study by Elrifi et al. [29], while circulating catecholamines were elevated, cardiac norepinephrine levels bore no association with the concentration of norepinephrine in plasma. In the present report we noted a tendency for plasma norepinephrine levels to be approximately 30% higher in the SAH group of animals yet they were not as high as those previously described in conscious animals following experimental SAH [30]. Whether the concurrent use of anesthetics in the current report compromised our plasma norepinephrine measurements remains unknown. The pathophysiology responsible for the complex sequence of autonomic and cardiovascular events that occurs following SAH is not completely understood. There exists direct evidence for cardiovascular and autonomic uncoupling in acute brain injury, with complete uncoupling during brain death [31]. In addition, some studies suggest that elevated levels of circulating catecholamines, coupled with an abnormal sensitivity of the cerebral vasculature to these catecholamines, may be involved in the genesis of cerebral vasospasm, predisposing patients to cerebral ischaemia and neurological deterioration. Indeed, in animal models of SAH, super-sensitivity of the cerebral vasculature to norepinephrine, 3 days after experimental SAH, has previously been described [32,33]. Similarly, following SAH, the present study also shows that the heart is more sensitive to stimulation by norepinephrine, with both ventricular pressure and myocardial contractility being augmented by norepinephrine infusion. Given our combined observations of similar left ventricle tissue norepinephrine content and hreceptor density in SAH and sham-treated animals it is difficult to elucidate the mechanism by which cardiac responsiveness to norepinephrine is increased. Sympathetic nervous activation in animal models of SAH has been documented [30], and in clinical SAH, sympathetic hyperactivity persists for at least 7 days after the trauma [14]. Chronic exposure of the rat myocardium to norepinephrine would be expected to result in a down regulation of total receptor density and elicit a functional desensitisation of myocardial h adrenoreceptors [34]. Given our observations of unaltered cardiac norepinephrine content and h-receptor density, in the scenario of experimental SAH this does not occur. Rather, our observation of increased arrhythmia score and left ventricle function in response to norepinephrine or nerve stimulation following experimental SAH indicate the occurrence of some degree of h-receptor sensitization. Previous work from our group has demonstrated that in this perfusion model, nerve stimulation-mediated functional and arrhythmic responses are mediated almost exclusively by the h-adrenoreceptor [18]. Clearly, other possible mechanisms such as enhanced h-adrenoreceptor coupling to stimulatory

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G proteins and activation of adenylate cyclase following SAH needs to be explored.

Acknowledgements This work was supported by a Block Institute Grant and a CJ Martin Fellowship (GL) from the National Health and Medical Research Council of Australia.

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