The effects of baroreceptor stimulation on central respiratory drive: A review

Respiratory Physiology & Neurobiology 174 (2010) 37–42

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Review

The effects of baroreceptor stimulation on central respiratory drive: A review夽 Simon McMullan ∗ , Paul M. Pilowsky The Australian School of Advanced Medicine, F10A, Macquarie University, NSW 2109, Australia

a r t i c l e

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Article history: Accepted 22 July 2010 Keywords: Barorespiratory Baroreceptor Respiratory rhythm Blood pressure Cardiorespiratory

a b s t r a c t The neural systems that control breathing and the circulation are located in adjacent longitudinal columns in the ventrolateral medulla. They have much in common, in terms of their structure, function, and evolution. In the most part, both systems are affected by the same sensory modalities and receive input from many of the same higher centres. Indeed, such is the parallel organisation of the two systems that stimuli that alter the behaviour of the one almost invariably influence the other. It is well-known that rhythmic respiratory inputs exert powerful effects on parasympathetic and sympathetic outputs. However, the question of whether cardiovascular inputs exert any influence on respiratory rhythmogenesis is more contentious. Here, we review the effects of baroreceptor activation, classically considered a ‘cardiovascular’ stimulus, on respiratory drive. We show that, although subtle, baroreceptor inputs evoke reproducible prolongation of expiration in a range of preparations. The consequences of this reflex are discussed with regard to cardiorespiratory coordination. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Although the influences that the respiratory system exert on cardiovascular output have been known of for over 100 years, evidence that the cardiovascular system can influence the respiratory system has largely been ignored. This review will examine the evidence for cardiovascular modulation of respiratory activity. Medullary networks that coordinate the respiratory and cardiovascular systems are highly conserved across the vertebrate subphylum and have much in common with each other (Taylor et al., 1999). Located in the rostral medulla immediately caudal to the facial nucleus, the neurons that control these two crucial homeostatic functions lie in adjacent overlapping longitudinal columns (reviewed by Alheid and McCrimmon, 2008; Guyenet, 2006; Taylor et al., 1999). In phylogenetically ancient species such as cyclostome fish (e.g. lamprey), the sympathetic ganglia closely resemble clusters of chromaffin cells, and receive no obvious input from spinal sympathetic preganglionic neurons (see Gibbins, 1994; Taylor et al., 2009); in these species central cardiovascular control seems predominantly orchestrated by parasympathetic cranial outputs, perhaps involving communication between vagus and sympathetic ganglia. Similarly, respiratory motor output is entirely subserved by cranial motoneurons, which control the propulsion of water through the gills. Even at this relatively low

夽 This paper is part of a special issue entitled “Central cardiorespiratory regulation: physiology and pathology”, guest-edited by Thomas E. Dick and Paul M. Pilowsky. ∗ Corresponding author. Tel.: +61 2 9812 3552. E-mail address: [email protected] (S. McMullan). 1569-9048/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2010.07.009

level of evolutionary sophistication, autonomic reflexes such as the chemoreceptor (see Randall, 1982) and baroreceptor (Lutz and Wyman, 1932) reflexes are well-developed, and there is strong evidence of cardiorespiratory integration (Taylor et al., 2006, 2009). As fish evolved, the level of organisation of the sympathetic nervous system rapidly increased. Elasmobranch fish (e.g. sharks) have recognisable chains of sympathetic ganglia under neurogenic control (Opdyke et al., 1983), presumably via spinal preganglionic neurons (Gibbins, 1994). As dedicated lung-breathing emerged, the respiratory system also became supplemented by bulbospinal pathways: the relative importance of the muscles innervated by cranial motoneurons becomes overshadowed by the predominant role that trunk musculature, and later the diaphragm, took in powering ventilation. Information pertaining to the internal (e.g. pH, blood oxygen) or external (e.g. skin temperature, noxious inputs) environments, and input from higher centres (e.g. arousal, sleep) all have strong coordinating influences on both respiratory and cardiovascular control systems. Indeed, it is difficult to think of a naturalistic stimulus that selectively influences either. The sensory modalities that particularly influence baseline respiratory outflow in the mammal are pH (and hence CO2 ) and, to a lesser degree, blood oxygen. It is interesting to note that oxygen-sensing is predominant over pH in determining respiratory drive in lower (aquatic) vertebrates. This is likely related to the high variability of oxygen concentration in water compared to air (Burleson, 2009). Both modalities potently activate sympathetic output. Blockade of central respiratory rhythm does not alter the maximal sympathetic responses to hypoxia (Koshiya and Guyenet, 1996), so it seems likely that sympathetic premotor neurons receive direct chemosen-

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sory input, in addition to excitatory and inhibitory drive secondary to enhanced respiratory activity. Blood oxygen and pressure sensation are subserved by vagal afferents in the gills in lower vertebrates (Burleson, 2009), and their evolutionary derivatives in mammals – the chemoreceptors and baroreceptors of the carotid sinus and aortic arch (Burleson, 2009; Sundin et al., 2007). In addition to similarities in structure and evolution, both the respiratory and cardiovascular systems share some strikingly similar functional attributes. For example, both exhibit a basal level of activity that is intrinsically rhythmic. The phasic nature of respiration is one of its more obvious features, but the bursting of nerves related to cardiovascular function is less straightforward and merits further consideration. The irregular bursting of sympathetic nerves results from multiple overlaid rhythms of different frequencies that are out of phase from one other. It is thought that the different frequency components of sympathetic nerve activity reflect inputs from a variety of different sources; one of the most obvious components is a strong respiratory modulation. This feature of cardiovascular control was first proposed in the 1860s, but respiratorymodulated sympathetic nerve activity was not recorded until 60 years later (Adrian et al., 1932; reviewed by Habler et al., 1994). The degree of respiratory modulation is dependent on the strength of respiratory drive (Haselton and Guyenet, 1989), the tissue innervated by the nerve (Habler et al., 1999), and the species of animal and anaesthetic used. Repeated exposure to hypoxia can enhance the strength of respiratory-sympathetic coupling (Dick et al., 2007), suggested as one of the mechanisms that may underlie the pathophysiology of obstructive sleep apnoea. The same mechanism is also suggested to underlie the hypertensive phenotype of the spontaneously hypertensive rat (Simms et al., 2009). Overlaid upon relatively slow rhythms related to central respiratory drive, many sympathetic outputs oscillate at the same frequency as heart rate. The degree of pulse-modulation of nerve activity depends on the blood pressure of the animal and the barosensitivity of the nerve. When isolated from respiratory and baroreceptor-mediated inputs, sympathetic nerve activity continues to occur in bursts. This continued bursting reflects some degree of central cardiovascular coordination; it seems likely that the bursting effect is caused by the synchronous recruitment of postganglionic nerve fibres, which in humans generally fire one action potential per burst, rather than a high level of activity in a restricted number of individual fibres (Macefield and Elam, 2003; Macefield et al., 2002). The frequencies at which bursting occurs in ‘free-running’ sympathetic nerve activity is speciesand tissue-dependent. In rat, vasomotor nerves (Allen et al., 1993; Kocsis and Gyimesi-Pelczer, 2004) and barosensitive sympathetic premotor neurons (Tseng et al., 2009; McMullan, unpublished observation) show a broad band of activity up to around 10 Hz, whereas temperature-related sympathetic nerve activity (e.g. tail and brown fat) exhibit a narrow peak in power between 0.4 and 1.2 Hz (Gilbey, 2007; Huang and Gilbey, 2005; Morrison, 1999). Similar properties of sympathetic nerves have been reported in other species (Barman et al., 1992; Barman and Kenney, 2007; Kocsis and Gyimesi-Pelczer, 2004).

2. Evidence of barorespiratory effects In contrast to the many studies that have demonstrated a clear effect of central respiratory drive on sympathetic nerve activity, the effect of baroreceptor or central sympathetic inputs on respiratory activity is still highly controversial. Although the effects of changes in carotid sinus pressure on respiration were first described in the 1930s (Heymans and Bouckaert, 1930 (see Fig. 1); Schmidt, 1932), many investigators still consider the baroreflex a purely cardiovascular stimulus. This is perhaps based on the lack of any

Fig. 1. Increases in blood pressure evoked by intravenous adrenaline suppress ventilation. Blood pressure (BP) and respiratory (R) responses to intravenous injection of 0.2 mg adrenaline (arrow) in a chloralose-anaesthetised dog before (Plate I) and after (Plate II) section of the carotid sinus nerves. Reproduced with permission from Heymans and Bouckaert (1930).

obvious physiological advantage to barorespiratory interactions in the species most commonly studied, or perhaps the segregation by academe of these overlapping fields into ‘cardiovascular’ and ‘respiratory’ disciplines. However, such thinking represents a teleological error, and ignores a wide range of experimental evidence to the contrary. Many experimental approaches have demonstrated a considerable sensitivity of the central respiratory generator to baroreceptor inputs. Suppression of respiration by prolongation of expiratory duration (TE ) is common in the overwhelming majority of studies, albeit with differences in the magnitude of effects and the extent to which inspiratory duration (TI ) and depth of ventilation are affected. Baroreceptor activation prolongs TI and generally has no effect on phrenic nerve amplitude in the rat (Baekey et al., 2008; Jung et al., 1995; McMullan et al., 2009), but reduces TI (Maass-Moreno and Katona, 1989) and inspiratory depth in the cat (Biscoe and Sampson, 1970; Grunstein et al., 1975; Maass-Moreno and Katona, 1989). A different pattern again is found in the dog; extension of TI , sometimes accompanied by an increase in inspiratory depth (Brunner et al., 1982; Heistad et al., 1975; Heymans and Bouckaert, 1930 (see Fig. 1); Maass-Moreno and Katona, 1989). 2.1. Naturalistic baroreceptor stimulation It is well known that acute reductions in blood pressure, for example during haemorrhage, rapidly increase ventilation, which has been suggested to be baroreceptor mediated (Clement et al., 1981; Heistad et al., 1975; Miserocchi and Quinn, 1980). How-

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ever, interpretation of respiratory effects evoked by reduced blood volume is clearly confounded by effects on peripheral chemoreceptors. At low blood pressure, carotid body perfusion is significantly reduced (McCloskey and Torrance, 1971), causing increased activity in approximately half of the chemoreceptor population (Mitchell and McCloskey, 1974). Indeed, respiratory responses to haemorrhagic hypotension are largely abolished by section of the carotid sinus nerve or selective chemoreceptor destruction (D’Silva et al., 1966). Given the sensitivity of the central respiratory network to chemoreceptor input, changes in respiratory drive evoked by such manoeuvres should not be surprising. Similar concerns regarding potential for inadvertent chemoreceptor activation hamper interpretation of studies in which carotid occlusion is used to unload the baroreceptors (Bishop, 1974). These pitfalls are circumvented by taking the converse approach; to raise central blood pressure and observe the effects on respiratory output. The respiratory effects that follow acute increases in arterial pressure are uniformly bradypnoeic in anaesthetised animals, and are therefore consistent with those reported following haemorrhage. Over 100 years ago Oliver and Schafer (1895) described an initial apnoea that accompanied pressor responses driven by intravenous adrenal extracts. This phenomenon, dubbed ‘adrenaline apnoea’ (Heymans and Bouckaert, 1930), has been reproduced many times (Jung et al., 1995; Kanjhan et al., 1995; McMullan et al., 2009; Potter and McCloskey, 1979), and seems to be largely mediated by a prolongation of TE (Dillon et al., 1991; Jung et al., 1995; McMullan et al., 2009). An elegant alternative to evoking changes in systemic blood pressure is to selectively increase blood pressure at the site of baroreceptive transduction. A major step in dissecting the effects of baroreceptor stimulation from those evoked by chemoreceptor activation was made in a study by Brunner and colleagues (1982), in which the carotid body of the dog was surgically destroyed prior to baroreceptor activation using a blind sac approach. They consistently found that increasing sinus pressure reduced ventilation, predominantly through increases in TE , which were partially buffered by increases in tidal volume (Brunner et al., 1982). These findings have since been replicated by a number of workers (Dove and Katona, 1985; Hopp and Seagard, 1998; Jung and Katona, 1990). Although adrenaline apnoea is consistent in the anaesthetised rat, variable responses can be obtained when other preparations are used: intravenous phenylephrine is reported to increase ventilation in the conscious rat (Walker and Jennings, 1996, 1998), although suppression of ventilation is generally (but not always: Somers et al., 1991) seen in the conscious human (Heistad et al.,

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1972) and goat (Carrithers et al., 1994). Furthermore, if the experiment is repeated using equipressor doses of angiotensin II, we and others have found that baroreceptor-mediated suppression of ventilation became less consistent (McMullan et al., 2009; Potter and McCloskey, 1979). A similar finding is indicated in the human: reanalysis of the data published in Table IV of Heistad et al. (1972) indicates that phenylephrine infusion has more potent hypoventilatory effects than equipressor doses of angiotensin, although this point was not made in the original manuscript. We reanalysed their data using repeated measures ANOVA with Tukey post-test and found significant effects of 40 and 80 ␮g/min infusions of phenylephrine (P < 0.01, 0.05, respectively) on minute ventilation. Infusions of angiotensin II that evoked equivalent effects on blood pressure only evoked hypoventilatory effects at the higher dose (0.5 ␮g/min; P < 0.01). This difference in effects may be related to the reported stimulatory effects of circulating angiotensin II on ventilation (Ohtake and Jennings, 1992, 1993; Potter and McCloskey, 1979), or the different haemodynamic effects of angiotensin compared to phenylephrine (Appleton et al., 1985; Shenker et al., 1988). Alternatively, the effect may be related to the attenuation of baroreflex sensitivity evoked by circulating angiotensin II (Guo and Abboud, 1984; McMullan et al., 2007). Microinjection of angiotensin II at the nucleus of the solitary tract (NTS) attenuates both cardiovascular and respiratory responses to baroreceptor stimulation in the working heart and brainstem preparation (Boscan et al., 2001; Paton and Kasparov, 1999), suggesting that altered central baroreflex sensitivity may indeed be responsible for the difference in effect evoked by these two pressor agents. Suppression of ventilation is consistently seen when blood pressure is raised using other naturalistic approaches. Obstruction of abdominal bloodflow, evoked by inflation of a balloon in the aorta, is reported to reduce respiratory frequency in the cat (Grunstein et al., 1975), pig (Curran and Leiter, 2007) and dog (Heistad et al., 1975; Potter and McCloskey, 1979). The study by Heistad et al. (1975) is particularly interesting, because they also observed a reduction in chemoreflex sensitivity during baroreceptor stimulation. A similar relationship between perfusion pressure and central respiratory drive is visible in the decerebrate artificially perfused rat (Fig. 2; Baekey et al., 2008; Paton and Kasparov, 1999; Pickering and Paton, 2006). In a number of studies the role of the arterial baroreceptors in mediating barorespiratory responses was confirmed by repeating the experiment following barodenervation. In all cases, barodenervation abolished the respiratory responses previously seen (Grunstein et al., 1975; Heymans and Bouckaert, 1930; Potter and McCloskey, 1979; Simms et al., 2009).

Fig. 2. Increases in aortic perfusion pressure evokes a baroreflex reduction in respiratory frequency. Recording from the unanaesthetised decerebrate artificially perfused rat. A 1 s increases in flow (×2, ×3, ×4 baseline rate) evoke baroreflex reductions in HR, thoracic SNA (thSNA) and respiratory rhythm (but not amplitude) that are proportional to the change in perfusion pressure. Modified with permission (Pickering and Paton, 2006).

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Fig. 3. Electrical stimulation of barosensitive nerves reduces respiratory frequency. Recording from the urethane-anaesthetised rat demonstrating changes in arterial pressure (AP), splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PNA) evoked by 1, 3 and 5 second trains of aortic depressor nerve (ADN) stimulation (50 Hz, 3 ms, ×3 threshold). Phrenic nerve frequency (PNf), inspiratory (TI ) and expiratory time (TE ) are derived from PNA. ADN stimulation consistently reduces PNf, primarily through effects on TE .

2.2. Electrical stimulation of barosensitive nerves Electrical stimulation of barosensitive nerves has repeatedly evoked respiratory effects. Earlier studies in the cat (Biscoe and Sampson, 1970) saw inhibition of phrenic motoneurons in response to electrical or naturalistic activation of the carotid sinus nerve. Similar responses have also been reported in response to stimulation of the aortic depressor nerve (ADN) of the rat (Fig. 3; Jung et al., 1989; McMullan et al., 2009), although Hayashi et al. (1993) saw no such effects. Although the ADN of the rat is reported to contain some chemoreceptor afferents (Brophy et al., 1999), the functional significance of the chemoreceptor population seems negligible, and its stimulation is generally interpreted as purely barosensory (Kobayashi et al., 1999). We recently reported that tetanic stimulation of the rat ADN prolongs TI and TE , and that intermittent (1 Hz) ADN stimulation significantly increased the variability of TI . In neither case did ADN stimulation result in any change in the amplitude of phrenic nerve discharge (McMullan et al., 2009). Qualitatively similar effects of ADN stimulation, although of a much stronger magnitude, were observed by Sapru et al. (1981) in the decerebrate rat, in which electrical ADN stimulation caused complete respiratory arrest for the duration of the stimulus. This observation has not, to our knowledge, been replicated by any other laboratory. The reasons for the potency of the respiratory effects reported in that study may be related to the absence of anaesthesia or the decerebration of the animals, or may be related to the stimulus parameters used. Surprisingly, Sapru and colleagues observed motor responses to ADN stimulation, a feature that has not been reported elsewhere: “Respiratory responses to stimulation of these nerves [ADN] produced movements in the decerebrate animals which interfered with monitoring of respiration” (Sapru et al., 1981). Such unusual effects may indicate current spread around the stimulating electrodes, and could indicate that the ADN was not selectively activated in that study. Stimulation of the nearby superior laryngeal nerve is known to evoke long-lasting apnoeic effects (Hayashi and McCrimmon, 1996) similar to those seen by Sapru and colleagues. 3. Barorespiratory pathways The pathways that underlie the barorespiratory response are unclear; barorespiratory effects have been recorded in medullary rhythm-generating neurons (see Baekey and Dick, current issue), which are in close proximity to the barosensitive sympathetic premotor neurons that control vasomotor tone. Sympathetic premotor neurons contain catecholamines (Schreihofer and Guyenet, 1997), enkephalin (Stornetta et al., 2001), glutamate (Stornetta et al., 2002), and a variety of peptide neurotransmitters (e.g. PACAP: Farnham et al., 2008). Many of these transmitters have been identi-

fied in synapses close to functionally identified respiratory neurons (Sun et al., 1994), and their application causes robust respiratory (and often cardiovascular) effects (Arita and Ochiishi, 1991; Miyawaki et al., 2002; MMJ Farnham, personal communication). This suggests that baroreceptor-mediated changes in sympathetic premotor neuron activity could drive changes in respiratory output. However, there is no direct evidence that barorespiratory effects are secondary to changes in activity of sympathetic premotor neurons; selective activation of cardiovascular neurons in the rostral ventrolateral medulla (RVLM) by microinjection of angiotensin II exerts no effects on phrenic nerve activity (Li et al., 1992). Furthermore, barorespiratory responses persist following application of pentobarbital sodium to the ventral medullary surface, likely to inhibit sympathoexcitatory RVLM neurons and baroinhibitory neurons in the caudal ventrolateral medulla (CVLM: Jung et al., 1989). This is an important observation because it suggests that barorespiratory pathways do not involve the NTS–CVLM–RVLM circuit thought to underlie the sympathetic baroreflex and suggests that the apparatus that underlies the barorespiratory reflex lies beyond the medulla. If barorespiratory pathways seem unlikely to directly involve medullary respiratory centres, what neural apparatus mediates the response? It is well-known that the pons plays an important role in gating baroreflexes (Felder and Mifflin, 1988; Hayward and Felder, 1998) and respiratory phase transition (Dutschmann and Herbert, 2006; Haji et al., 2002). Recent work by Baekey et al. (2008) showed that pontine transection attenuated sympathetic, and completely abolished heart rate, baroreflexes, and eliminated the prolongation of TE evoked by baroreceptor activation. However, although many pontine neurons, including those in the parabrachial and KöllikerFuse nuclei, receive baroreceptive inputs (Jhamandas et al., 1991; Jhamandas and Harris, 1992), it seems unlikely that the barorespiratory reflex relays through the pons, as baroreceptor activation still exerts effects on respiratory phase-switching following pontine transection (Baekey et al., 2008). Instead, it seems more likely that inputs from higher centres, including the pons (Baekey et al., 2008) and hypothalamus (Dillon et al., 1991), modulate barorespiratory interactions without directly participating in the reflex arch. 4. Physiological significance The collation of empirical evidence for phase-locking of cardiovascular and respiratory rhythms has only been possible following advances in data analysis and mathematics (Lotriˇc and Stefanovska, 2000; Rosenblum et al., 2002; Schäfer et al., 1998, 1999). The results of this work indicate bidirectionality of cardiorespiratory coupling (Buchner et al., 2009; Rosenblum et al., 2002); that is to say, that heart rate influences respiratory timing. The same conclusion was

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independently reached following examination of an in-silica model of cardiorespiratory synchronization by Kotani et al. (2002), in which synchronization could not be achieved without inclusion of a weak barorespiratory influence. This proposition has since been confirmed by experimental work in the rat, in which cardiorespiratory synchronization was observed during cardiac pacing, and was subsequently abolished by sinoaortic denervation (Tzeng et al., 2007). In humans, the strength of the barorespiratory input is dependent on physical fitness (Schäfer et al., 1998), arousal levels (Wu and Lo, 2010; Zhang et al., 2010), and age (Rosenblum et al., 2002). Coupling appears pronounced in infants; Rosenblum et al. (2002) found that cardiorespiratory coupling was approximately symmetrical in the first days after birth, but that respiratory sinus arrhythmia predominated within 6 months of birth. In at least one case strong barorespiratory coupling during sleep, coincident with vagal bradycardia, has been suggested as a driving factor in a potentially fatal apnoea (Wallois et al., 2008). The functional significance of cardiorespiratory synchronization is unclear in mammals, but has been suggested as a mechanism by which fish can improve the efficiency of breathing. The drawing of water through the gills requires substantial energy output (Hughes and Shelton, 1962), so synchronization of breathing with the heartbeat may be a mechanism that ensures appropriate perfusion of the gas-exchanging surface (Shelton and Randall, 1962). Strong cardiorespiratory synchronization has been observed in a variety of fish species, including elasmobranchs (Lyon, 1926) and teleosts (Shelton and Randall, 1962). Such synchronization is of little obvious value to air-breathers, for whom respiratory effort is metabolically cheap; we speculate that the barorespiratory response may be a vestigial reflex inherited from our aquatic predecessors. 5. Closing remarks The influence of baroreceptor input on ventilation is certainly subtle compared to the better known heart-rate or sympathetic baroreflexes; none the less, it is reproducible in a range of mammalian species, including man. It perfectly exemplifies the blurring of boundaries between ‘cardiovascular’ and ‘respiratory’ neuroscience. Acknowledgements Work in the authors’ laboratory is funded by the National Health & Medical Research Council of Australia (604002, 457080, 457069), Garnett Passe and Rodney Williams Memorial Foundation and Macquarie University. References Adrian, E.D., Bronk, D.W., Phillips, G., 1932. Discharges in mammalian sympathetic nerves. J. Physiol. 74, 115–133. Alheid, G.F., McCrimmon, D.R., 2008. The chemical neuroanatomy of breathing. Respir. Physiol. Neurobiol. 164, 3–11. Allen, A.M., Adams, J.M., Guyenet, P.G., 1993. Role of the spinal cord in generating the 2- to 6-Hz rhythm in rat sympathetic outflow. Am. J. Physiol. 264, R938–945. Appleton, C., Olajos, M., Morkin, E., Goldman, S., 1985. Alpha-1 adrenergic control of the venous circulation in intact dogs. J. Pharm. Exp. Ther. 233, 729–734. Arita, H., Ochiishi, M., 1991. Opposing effects of 5-hydroxytryptamine on two types of medullary inspiratory neurons with distinct firing patterns. J. Neurophysiol. 66, 285–292. Baekey, D.M., Dick, T.E., Paton, J.F., 2008. Pontomedullary transection attenuates central respiratory modulation of sympathetic discharge, heart rate and the baroreceptor reflex in the in situ rat preparation. Exp. Physiol. 93, 803–816. Barman, S.M., Gebber, G.L., Zhong, S., 1992. The 10-Hz rhythm in sympathetic nerve discharge. Am. J. Physiol. 262, R1006–1014. Barman, S.M., Kenney, M.J., 2007. Methods of analysis and physiological relevance of rhythms in sympathetic nerve discharge. Clin. Exp. Pharmacol. Physiol. 34, 350–355.

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