© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Sympathetic modulation of hypoxic pulmonary vasoconstriction in intact dogs
Laboratory of Cardiovascular and Respiratory Physiology, Free University of Brussels, Brussels, Belgium
* Corresponding author. Department of Intensive Care, Erasmus University Hospital, Lennik Road 808, B-1070 Brussels, Belgium. Tel.: +32 (2) 555.44.10; fax: +32 (2) 555.46.98.
Received 17 July 1996; accepted 27 December 1996
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Abstract |
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Background: The effects of the sympathetic nervous system on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We studied the effects of adrenergic receptor blockade and epidural blockade on HPV in 32 pentobarbital-anaesthetised intact dogs. Methods: Pulmonary arterial flow–pressure relationships were determined in hyperoxia and hypoxia, at baseline and after
-blockade (phentolamine 2 mg/kg + 50 µg·kg–1·h–1), β-blockade (propranolol 2 mg/kg), β-blockade, epidural blockade (lignocaine 20 mg/kg), and β- plus epidural blockade. Results: At reference flow of 3.5 l·min–1·m–2, the mean hypoxic response (hypoxia-induced increase in transpulmonary pressure gradient, each n=8) changed from 6.0±0.9 to 3.5±1.0 mmHg after -blockade, from 5.8±0.9 to 7.3±0.7 mmHg after β-blockade, from 4.1±0.8 to 9.0±1.4 mmHg after β-blockade, and from 3.4±1.0 to 4.3±0.9 mmHg after epidural blockade (all P<0.05), and was not affected by epidural blockade after β-blockade. Conclusions: In pentobarbital-anaesthetised dogs, (1) HPV is attenuated by - and enhanced by β-, β- and epidural blockade, and (2) epidural blockade has no significant adrenergic-unrelated effect on the pulmonary vasculature.
KEYWORDS Dog, anesthetized; Pulmonary circulation; Hypoxia; Flow–pressure relationships; Autonomic nervous system; Adrenergic receptors
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1 Introduction |
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Drugs affecting the sympathetic nervous system (SNS) are widely used in patients with cardiovascular and pulmonary diseases [21]. Their effects on hypoxic pulmonary vasoconstriction (HPV), a major mechanism in the prevention of arterial hypoxaemia, however, remain controversial [13, 19, 23].
-Adrenergic blockade has been reported to abolish, to attenuate, or not to affect HPV [2, 3, 7–9, 12, 16, 31, 32, 34, 44, 47, 46, 51]. β-Adrenergic blockade has been more consistently reported to enhance HPV [3, 34, 44, 47, 51]. As an effect of global SNS inhibition, HPV was abolished, attenuated, unaffected, or enhanced after chemoreceptor denervation, surgical sympathectomy, ganglionic blockade, chemical sympathectomy and adrenergic receptor blockade [33, 38, 47]. In the few studies investigating the effects of central neural blockade, HPV was found to be suppressed, unaffected, or enhanced [26, 41, 45]. Differences between the effects of adrenergic and neural blockade could result from several factors. Central neural blockade can inhibit sympathetic but also parasympathetic and other efferent pathways [41]. Circulating catecholamine levels increase after adrenergic receptor blockade, but remain unchanged or decrease after spinal blockade [43]. In the systemic circulation, SNS stimulation has been reported to cause vasoconstriction which is not mediated by -receptors [50].
Considering the widespread use of epidural anaesthesia and the clinical importance of HPV, we therefore investigated the effects of epidural blockade on hyperoxic and hypoxic pulmonary vessels. The objectives of the study were to determine (1) the effects of - and β-adrenergic receptors blockade on HPV, (2) the effects of epidural blockade on HPV, and (3) whether epidural blockade has additional effects over - and β-receptors blockade (e.g., by inhibiting other than - and β-adrenergic pathways). The study was done in intact dogs, allowing the expression of control mechanisms affecting the pulmonary circulation. Pulmonary vascular tone was assessed by flow–pressure curves, to discriminate between passive (flow-dependent) and active (tone-dependent) changes in vascular resistance [36]. Hypoxic response was defined as the difference between hypoxic and hyperoxic pulmonary vascular tone.
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2 Methods |
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2.1 Preparation
All experiments were performed in accordance with the ‘Guiding Principles in the Care and Use of Animals’ approved by the Council of the American Physiological Society. Experiments were done in 32 mongrel dogs (15–36 kg, mean 26), anaesthetised with sodium pentobarbital (30 mg/kg i.v.), intubated and ventilated mechanically (tidal volume 16 ml/kg, respiratory rate 12.5/min), and prepared as described previously [6]. Briefly, femoral and pulmonary arterial catheters were inserted for measurement of systemic and pulmonary haemodynamics and for sampling of arterial and mixed venous blood. Vascular pressures were monitored and recorded continuously, and read at end-expiration. Cardiac output was measured with the thermodilution method, using three 10-ml injections of ice-cold saline delivered at the beginning of expiration. (Thermodilution was used to avoid thoracotomy, and yielded a variation coefficient less than 5%.) Cardiac output was controlled by inflating a balloon inserted in the inferior vena cava or by opening a femoral arterio-venous fistula to respectively decrease or increase venous return. Arterial (a) and mixed venous (v) blood gases were measured immediately after drawing the samples. Arterial pH was maintained between 7.35 and 7.40 with sodium bicarbonate. Thrombus formation was prevented with heparin, and temperature was kept at 37–38°C with an electric heating pad. Anaesthesia was maintained with pentobarbital (3 mg/kg) and paralysis was obtained with pancuronium (0.2 mg/kg) before each hyperoxic flow–pressure curve determination (paralysis was used to prevent the respiratory efforts sometimes occurring during hypoxia). The epidural catheter was inserted at the beginning of the experiment, through the vertebral arch of the second coccygeal vertebra. It was advanced until the tip was near the L4 vertebra, as confirmed by autopsy at the end of the experiment.
2.2 Measurements
Five-point pulmonary arterial flow–pressure curves were generated in hyperoxia and in hypoxia (inspired oxygen fraction, FiO2, respectively 0.40 and 0.10), at baseline and after administration of the adrenergic blocking agent. For each curve, the first point was obtained after complete deflation of the intracaval balloon and opening of the arterio-venous fistula, the second point after clamping the fistula, and the third to fifth points after stepwise inflations of the balloon. Haemodynamic variables (cardiac output, heart rate, systemic and pulmonary vascular pressures) were collected at each point. Arterial and mixed venous blood gases were measured at the first and last points of the curve (high flow and low flow). Measurements at each point were delayed until haemodynamic stabilisation. Generation of a complete 5-point curve typically required 20–30 min.
2.3 Adrenergic blockade
-Adrenergic blockade was obtained with an intravenous 2 mg/kg phentolamine bolus and a 50 µg·kg–1·h–1 phentolamine infusion (n=8). β-Adrenergic blockade was obtained with a slow intravenous 2 mg/kg propranolol bolus (n=8). Combined - and β-adrenergic blockade was obtained with addition of phentolamine and propranolol (n=8). Effectiveness of the adrenergic blockade was tested by administration of the corresponding agonist before and after administration of the blocking drug. -Adrenergic stimulation was done with intravenous phenylephrine 5 µg/kg, and β-adrenergic stimulation with intravenous isoprenaline 1 µg/kg. Epidural blockade was obtained with 20 mg/kg lignocaine, using a 2% solution (n=8). The procedure was expected to interrupt all motor, sensitive, and sympathetic pathways up to the cervical level. Effectiveness of the epidural blockade was confirmed by the typical decrease in systemic arterial pressure and by the absence of cardiovascular and motor response to tail clamping [41, 42]. If necessary, epidural anaesthesia was delayed until pentobarbital and pancuronium no longer prevented motor responses. In summary, each blocking procedure was thus applied to one group of 8 dogs. The third group, after combined - and β-adrenergic blockade, moreover received additional epidural blockade (cf. infra). Phenylephrine was given to the 2 groups treated with phentolamine, and isoprenaline to the 2 groups treated with propranolol.
2.4 Data analysis
Slight but significant changes were observed in the pulmonary artery occluded pressure, which could interfere with the interpretation of flow–pressure data. (Occluded pressure is measured downstream from a small balloon inflated in the pulmonary artery, and is taken to be similar to left atrial pressure). The difference between arterial and occluded pressure (Ppa–Ppao), or transpulmonary pressure gradient, was therefore selected to describe the pulmonary circulation. To take into account changes in baseline values, the hypoxic response was defined as the difference between Ppa–Ppao values at FiO2 of 0.10 and 0.40. Hypoxic response data are given at reference flow of 3.5 l·min–1·m–2, selected as a value still reached after adrenergic and after epidural blockade. Pulmonary arterial flow–pressure relationships were clearly linear at visual examination, and linear correlation coefficients were above 0.95 (P<0.05) in most cases. Individual linear regressions were therefore used to obtain pressure values at flows ranging from 1.5 to 3.5 l·min–1·m–2. Results were expressed as means±s.e. Variables displayed in tables and figures were analysed by a repeated-measures analysis of variance with 3 factors (flow, FiO2 and drug) [55]. Changes in hypoxic response were analysed by a repeated-measures analysis of variance with two factors (flow and drug) [55]. P-values <0.05 were accepted as indicating statistical significance.
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3 Results |
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Baseline haemodynamics and blood gases were comparable in the 4 groups. Hypoxia decreased the arterial and mixed venous oxygen tensions (PaO2 and PvO2) to about 5.3 and 4.3 kPa, respectively. Hypoxia was associated with increases in cardiac output, pulmonary arterial pressure, and Ppa–Ppao. The individual variability in HPV was substantial, as usually reported, but the initial hypoxic response was not different between groups (P=0.18). Clamping the arterio-venous fistula and inflating the vena caval balloon allowed the cardiac output to decrease from 4–6 to 1–2 l·min–1·m–2 at baseline, and from 3–6 to 1–2 l·min–1·m–2 after
β-adrenergic or epidural blockade. The reduction in cardiac output was associated with decreases in all intravascular pressures, in PaCO2 and in PvO2. In dogs treated with phentolamine (n=16), phenylephrine increased mean systemic arterial pressure by 39±3 mmHg at baseline, by 3±1 mmHg after phentolamine administration, and by 0±1 mmHg at the end of the experiment. In dogs treated with propranolol (n=16), isoprenaline increased heart rate by 100±9 beats/min at baseline, by 2±2 beats/min after propranolol administration, and by 5±2 beats/min at the end of the experiment.
Phentolamine increased heart rate, decreased systemic arterial pressure, and decreased PaO2 (Table 1). Phentolamine shifted the pulmonary arterial flow–pressure curves downwards, and attenuated the pressor response to hypoxia (Fig. 1). At the reference flow of 3.5 l·min–1·m–2, the hypoxic response decreased from 6.0±0.9 to 3.5±1.0 mmHg (P<0.01).
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Propranolol decreased heart rate, did not affect systemic pressure, and increased pulmonary arterial pressure (Table 2). Propranolol shifted the pulmonary arterial flow–pressure curves upwards, and enhanced the pressor response to hypoxia (Fig. 2). At reference flow, the hypoxic response increased from 5.8±0.9 to 7.3±0.7 mmHg (P<0.05).
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Combined phentolamine and propranolol decreased cardiac output, heart rate, and systemic arterial pressure, but did not affect pulmonary arterial pressure or Ppa–Ppao difference (Table 3). Combined phentolamine and propranolol did not affect the pulmonary arterial flow–pressure curve in hyperoxia, but enhanced the pressor response to hypoxia (Fig. 3). At reference flow, the hypoxic response increased from 4.1±0.8 to 9.0±1.4 mmHg (P<0.001).
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Epidural lignocaine decreased cardiac output, heart rate, and systemic arterial pressure, and increased pulmonary arterial pressure and Ppa–Ppao difference (Table 4). It shifted the pulmonary arterial flow–pressure curves upwards, and enhanced the pressor response to hypoxia (Fig. 4). At reference flow, the hypoxic response increased from 3.4±1.0 to 4.3±0.9 mmHg (P<0.05).
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After pretreatment with phentolamine and propranolol, additional epidural lignocaine further decreased cardiac output, heart rate, and systemic arterial pressure, increased pulmonary wedge pressure, and did not change pulmonary arterial pressure or Ppa–Ppao difference (Table 5). Additional lignocaine did not affect the pulmonary arterial flow–pressure curves (Fig. 5) or the hypoxic response at reference flow (7.7±1.4 to 7.8±1.6 mmHg).
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4 Discussion |
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Epidural anaesthesia and analgesia have been reported to improve respiratory function and postoperative outcome in high-risk patients [56], but their effects on the pulmonary vasoreactivity to hypoxia remain unclear [26, 41, 45]. The cardiovascular effects of epidural blockade result from preganglionic SNS blockade [21, 22], but the effects of SNS blockade on HPV also remain unclear. We therefore investigated the effects of epidural blockade on HPV, and verified whether they could be explained by adrenergic blockade alone, or whether they implied some additional effect.
4.1 Hyperoxia
During hyperoxia, effects of - and β-adrenergic blockade on pulmonary vessels were comparable to those reported previously: phentolamine decreased and propranolol increased pulmonary vascular tone [13, 19, 23, 37]. Combined - and β-blockade did not significantly affect vascular tone, indicating that - and β-stimulation were comparable in hyperoxia. Different results in other studies can be explained by a difference in either - or β-stimulation. For example, our data show that combined - and β-blockade tended to shift the flow–pressure curve upwards at baseline flow but downwards at low flow (Fig. 3). -Stimulation may thus become dominating at low flow, as a result of the decrease in flow and/or in arterial pressure.
4.2 Isolated - and β-adrenergic blockade
Some studies reported that -blockade did not affect the HPV [8, 32, 34, 47, 46, 51]. Many of them analysed pressure or resistance changes [8, 34, 46, 51], which may be misleading when flow also changes [36]. One of them used unconventional diameter measurements (but found no significant change when flow reduction decreased pressure from 29 to 17 mmHg), and used phentolamine as a single bolus [47]. All other studies reported -blockade to attenuate or to abolish the HPV [2, 3, 7, 9, 12, 16, 31, 44]. Previous studies generally observed β-blockade to enhance the HPV [3, 44, 47, 51]. Malik et al. reported an absence of effect, as they also did for -blockade [34]. The present data confirm that -blockade attenuates and that β-blockade enhances HPV. The HPV attenuation explains why the PaO2 decreased after phentolamine.
4.3 Combined - and β-adrenergic blockade
The effects of complete SNS blockade are much less clear. Inhibition of the hypoxia-induced sympathetic response by chemoreceptor denervation attenuated [1]or enhanced the HPV [38], while chemoreceptor stimulation attenuated the HPV [10, 30, 54]. Surgical sympathectomy attenuated [1, 12, 26, 27, 48, 49]or did not affect [14, 15, 18, 39]the HPV. Spinal blockade abolished [26], did not affect [45]or enhanced [41]the HPV. Ganglionic blockade did not affect [26, 31, 33], or enhanced [47]the HPV. Adrenalectomy attenuated [9], did not affect [12, 35, 39]or enhanced [47]the HPV. Chemical sympathectomy with guanethidine or reserpine attenuated [7, 35]or did not affect [20, 25, 32, 46]the HPV. Chemical sympathectomy with 6-hydroxy-dopamine did not affect the HPV [24, 38, 52]. Combined - and β-receptors blockade did not affect the HPV [33]. In summary, SNS blockade was reported to attenuate, not to affect, and to enhance HPV in respectively 11, 19, and 7 studies.
Many of these discrepancies can be related to some major factors: (a) Studies using a surgical sympathectomy assumed that sympathetic activity could be completely prevented, and that thoracic surgery did not affect the pulmonary vasoreactivity. These assumptions may be incorrect [24, 34], and surgical sympathectomy moreover has delayed effects and can result in catecholamine hypersensitivity [34]. (b) Studies using drugs sometimes failed to test the effectiveness of a pharmacological blockade after giving a bolus or brief infusion of a short-acting drug. In our experience the blocking effect of an intravenous 2 mg/kg phentolamine bolus, for example, decreases by at least 50% after 30 min. (c) Effects of surgical and chemical sympathectomy were commonly reported as post-intervention without pre-intervention data. The mere fact that HPV still occurred after the surgical or pharmacological intervention was interpreted as an unchanged situation (unchanged HPV), whereas HPV in fact could have decreased or increased. (d) Changes in pulmonary vascular pressure or resistance were frequently interpreted as vasoconstriction or vasodilation, despite substantial changes in cardiac output. This may be inappropriate, so that active changes in pulmonary vascular tone should be evaluated at constant flow or by flow–pressure curves [36]. False negative reports (unchanged HPV) and false positive reports of HPV attenuation could easily result from any one of these factors. False positive reports of HPV enhancement can only result from the last factor, and are much less likely.
In our study, combined - and β-adrenergic receptor blockade clearly enhanced the HPV. In a similar study in conscious dogs, HPV remained unchanged after - and β-blockade and after ganglionic blockade [33]. The discrepancy probably results from differences in experimental conditions. Barbiturates were reported to attenuate the HPV [53], but not to interfere with the effects of the SNS on the HPV [4, 48]. Barbiturates were also reported to prevent the sympathetic response to haemorrhage [57], but a similar effect in our study would only attenuate and not enhance the effects of SNS blockade. Our results were obtained after elimination of all causes of misinterpretation discussed above, and at constant ventilation and acid–base status. They are consistent with most recent studies on the effects of SNS blockade on HPV [10, 38, 41, 47, 54]. We thus conclude that the substantial enhancement of HPV actually resulted from the combined - and β-adrenergic blockade. This indicates that β-stimulation predominates during moderate hypoxia in pentobarbital-anaesthetised dogs.
4.4 Epidural blockade
The few studies investigating the effects of central neural blockade on HPV have yielded controversial results. Judson et al. reported that HPV was abolished after epidural or spinal blockade with procaine in 3 patients, but cardiac output data were not provided [26]. Reeves et al. reported that HPV persisted after spinal anaesthesia or spinal transection in 10 calves, but cardiac output was not measured, or decreased [45]. Ohmura et al. reported that HPV was enhanced by injection of tetracaine into the cisterna magna in 6 dogs [41]. The procedure caused adrenergic and cholinergic blockade, but HPV is not affected by the parasympathetic system [28]and thus was enhanced by the spinal-like blockade.
In our study, HPV increased after epidural blockade. Epidural blockade changed the pulmonary artery occluded pressure, but only to a small extent (2–3 mmHg) and in the direction of an increase which would tend to attenuate the HPV [29]. Lignocaine probably was reabsorbed in substantial amounts and could contribute to the decrease in cardiac output and in systemic arterial pressure, but it has been shown not to affect the HPV [4, 5]. All haemodynamic changes observed after epidural blockade were comparable to those observed after combined - and β-blockade. The HPV enhancement was smaller after epidural blockade, but so was the initial HPV in this group. Moreover, epidural blockade had no pulmonary vascular effect in - and β-blocked animals. The result was that epidural blockade enhanced the HPV by inhibiting the SNS, and that it had no - or β-unrelated effect on the pulmonary circulation.
4.5 Conclusions
Combined - and β-receptor blockade clearly enhanced the HPV, indicating that β-stimulation predominates in the intact animal during hypoxia. Epidural blockade enhanced the HPV in untreated dogs and had no effect after β-blockade, suggesting that all its effects on the pulmonary circulation are related to the sympathetic blockade. These effects of epidural anaesthesia contrast with those of general anaesthesia: most studies reported that intravenous anaesthetics do not affect HPV, and that inhaled anaesthetics depress HPV [17]. The contrasting beneficial effects of epidural anaesthesia on HPV should thus be taken into account when selecting a mode of anaesthesia in hypoxaemic patients.
Time for primary review 22 days.
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Acknowledgements |
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J.L. Vachiéry and M. Delcroix were fellows of the Erasme Foundation in 1988 and 1989. S. Brimioulle was a recipient of the Foundation for Cardiac Surgery in 1994. The study was supported by grants (nos. 1.5091.89 and 9.4513.94) from the Foundation for Medical Scientific Research (Belgium). Phentolamine was kindly supplied by Ciba-Geigy (Groot-Bijgaarden, Belgium), and propranolol by Zeneca (Destelbergen, Belgium).
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References |
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I. Garutti, L. Olmedilla, and C. D. Spies Searching the Preferred Anesthetic Technique During One-Lung-Ventilation * Response Anesth. Analg., April 1, 2002; 94(4): 1041 - 1042. [Full Text] [PDF]
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 M. Zaugg, M. C. Schaub, T. Pasch, and D. R. Spahn Modulation of {beta}-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action Br. J. Anaesth., January 1, 2002; 88(1): 101 - 123. [Abstract] [Full Text] [PDF]
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V. Von Dossow, M. Welte, U. Zaune, E. Martin, M. Walter, J. Ruckert, W. J. Kox, and C. D. Spies Thoracic Epidural Anesthesia Combined with General Anesthesia: The Preferred Anesthetic Technique for Thoracic Surgery Anesth. Analg., April 1, 2001; 92(4): 848 - 854. [Abstract] [Full Text] [PDF]
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 S. S. Salvi {alpha}1-Adrenergic Hypothesis for Pulmonary Hypertension Chest, June 1, 1999; 115(6): 1708 - 1719. [Abstract] [Full Text] [PDF]
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 H. Duplain, L. Vollenweider, A. Delabays, P. Nicod, P. Bartsch, and U. Scherrer Augmented Sympathetic Activation During Short-Term Hypoxia and High-Altitude Exposure in Subjects Susceptible to High-Altitude Pulmonary Edema Circulation, April 6, 1999; 99(13): 1713 - 1718. [Abstract] [Full Text] [PDF]
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 S. Brimioulle, M. Maggiorini, J. Stephanazzi, F. Vermeulen, P. Lejeune, and R. Naeije Effects of low flow on pulmonary vascular flow-pressure curves and pulmonary vascular impedance Cardiovasc Res, April 1, 1999; 42(1): 183 - 192. [Abstract] [Full Text] [PDF]
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