Inhibition of cardiac vagal component of baroreflex by group III and IV afferents.

Inhibition of cardiac vagal component of baroreflex by group III and IV afferents P. N. McWILLIAM AND T. YANG Department of Cardiovascular Studies,

University

MCWILLIAM, P. N., AND T. YANG. Inhibition of cardiac vagal component of baroreflex by group III and IV afferents. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H730-H734,1991.-The action of electrically evoked activity in somatic afferent fibers on the sensitivity of the baroreceptor reflex was examined in decerebrate cats. The sensitivity of the reflex was expressed as the difference between the maximum prolongation of R-R interval in response to carotid sinus pressure elevation and the mean of 10 R-R intervals immediately before pressure elevation. The control value of R-R interval prolongation was 192 t 50 ms. Stimulation (10 Hz) of group I and II fibers of the right peroneal nerve (evoked volleys recorded from the sciatic nerve) had no effect on R-R interval prolongation (171 t 45 ms). Recruitment of group III fibers (10 Hz) conducting at 23.6 t 0.65 m/s reduced the prolongation of R-R interval to 52 t 14 ms. Recruitment of group IV fibers (10 Hz) conducting c2.5 m/s further reduced the prolongation of R-R interval to 1.0 t 8.0 ms. It is concluded that the inhibition of the cardiac vagal component of the baroreceptor reflex produced by electrical stimulation of the peroneal nerve is mediated by afferent fibers of groups III and IV.

of Leeds, Leeds LS2 9JT, United Kingdom

MATERIALS

AND

METHODS

The experiments were performed on decerebrate cats. The animals were initially anesthetized with halothane (Fluothane, ICI, 5% in 02). The trachea was cannulated and the animal ventilated using a Starling “Ideal” pump. Oxygen was added to the inspired air to bring the inspired oxygen fractional concentration (FIN,) to at least 0.4. End-tidal PCO~was maintained at 30 mmHg. Catheters were placed in the left femoral artery and vein. The animal’s esophageal temperature was maintained at 3739°C by circulating hot water through the operating table. During the experiments the animals received a constant intravenous infusion (6 ml kg-‘. h-l) of a solution comprising 125 ml Haemaccel (Hoechst), 125 ml distilled water, 2.1 g NaHC03, and 0.5 g glucose (1). The external carotid arteries were cannulated with double-lumen catheters. The lingual arteries and other minor arteries of the carotid sinus region, except the internal carotid artery, were ligated and snares placed around the common carotid arteries caudal to the sinus baroreceptor reflex; vagus; somatic afferents region. Therefore, by tightening the snares and injection of Ringer-Locke solution through one lumen, it was possible to stimulate the carotid sinus baroreceptors and ELECTRICAL STIMULATION of somatic nerves can cause to measure the change in sinus pressure via the second profound changes in the cardiovascular system including lumen. The animal was decerebrated at the midcollicular both depressor and pressor effects (5). Low-threshold level using a suction probe (2.0 mm, OD), all structures group III fibers are reported to produce depressor effects, rostra1 to the section being removed from the cranium. whereas high-threshold group III and group IV fibers During the decerebration and for the remainder of the elicit pressor effects (4). Somatic nerve stimulation also experiment the IV ventricle was perfused with an artifiproduces changes in the baroreceptor reflex. Low-intencial cerebrospinal fluid (0.3 ml/min) via a double-lumen sity sciatic nerve stimulation in the cat is reported to catheter inserted through the dura mater of the foramen augment the reflex vagal bradycardia evoked by intramagnum and secured in place with cyanoacrylate glue; venous phenylephrine, whereas high-intensity stimulathe second lumen was used to monitor cerebrospinal fluid tion is reported to block such vagal bradycardia (16). pressure. This perfusion excluded blood and other debris The groups of afferent fibers producing these effects on of the decerebration from the remaining intact portions the baroreceptor reflex were not clearly identified, al- of the central nervous system. Once the decerebration though group IV fibers were implicated in inhibition of was complete, anesthetic was discontinued and the anithe reflex. Others have reported an inhibition of the mal was paralyzed with vecuronium bromide (0.1 mg/kg baroreceptor reflex in the cat on stimulation of the sciatic iv every 20 min) (17). nerve (10) or the lateral popliteal nerve (2). Similarly The right sciatic and peroneal nerves were exposed via sciatic nerve stimulation is reported to inhibit the baro- a lateral incision. A paraffin pool was created over the receptor reflex in the dog (9) and rat (14). However, in nerves by securing skin flaps to a rigid frame. Bipolar these four latter studies no augmentation of the reflex silver stimulating electrodes were applied to the cut was reported nor were the group(s) of afferent fibers central end of the peroneal nerve in the popliteal fossa, responsible for inhibition of the baroreflex identified. and the compound action potential evoked by electrical The aim of the present study was to identify which stimulation was recorded with bipolar silver recording group or groups of somatic afferent fibers inhibit the electrodes applied to the sciatic nerve close to the hip cardiac vagal component of the baroreceptor reflex in joint. By a gradual increase in the amplitude and width the cat. of the stimulus, different groups of nerve fibers could be H730

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recruited. Fibers having conduction velocities in the range 72-120 m/s were classified as group I, 30-72 m/s as group II, 2.5-30 m/s as group III, and ~2.5 m/s as group Iv (see DISCUSSION). R-R intervals were measured from the electrocardiogram. The reflex response to baroreceptor stimulation was quantified in terms of the prolongation of R-R interval, i.e., the difference between the longest R-R interval after sinus pressure elevation and the means of 10 R-R intervals immediately before sinus pressure elevation. Baroreceptors were stimulated at random during the ventilatory cycle, and no attempt was made to time baroreceptor stimulation to occur during the expiratory phase of the central respiratory cycle, since phrenic nerve activity was not recorded. The effects of repetitive electrical stimulation (5-10 Hz) of different groups of afferent fibers in the peroneal nerve on the baroreceptor induced prolongation of R-R internal were then assessed. Baroreceptors were stimulated within 1 s of the onset of nerve stimulation. All values are means t SE. RESULTS

Evoked volleys. Supramaximal stimulation of the peroneal nerve evoked a compound action potential in the sciatic nerve with distinct volleys corresponding to activity in fibers of groups I-IV (Fig. 1). By a gradual increase in the amplitude and width of the stimulus, it was possible to recruit these different groups in a clear sequential manner. The volleys from group I and II fibers became maximal (amplitude and shape became constant) before the group III threshold was reached. Similarly the group III volley became maximal before the group IV threshold was reached. Indeed a relatively large increment in stimulus parameters was required to recruit the group IV volley. The peak of the group III volley conducted at 23.6 t 0.6 m/s (n = 7), whereas the peak of the group IV volley conducted at 1.1 t 0.1 m/s. The effects of repetitive stimulation of just group I and II fibers, or groups

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I-III, or groups I-IV on the baroreceptor-induced prolongation of R-R interval were then compared. When the effects of group I and II fibers were examined, the stimulus parameters used were not merely those at which the group I and II volleys were seen to become maximal but, rather, the maximum stimulus that could be used without recruiting group III fibers. This was to ensure that any effect attributed to the recruitment of group III fibers was not merely due to further recruitment of group II fibers. Similarly, when the effects of group I-III fibers were studied, the stimulus parameters were set to just below the group IV threshold, with signal averaging being routinely employed to ensure that the group IV threshold was not exceeded. Response to sinus pressure elevation. When carotid sinus pressure was increased, there was an immediate prolongation of R-R interval, with the longest interval occurring two to four beats after the rise in sinus pressure (Fig. 2A). With low pressure in the carotid sinuses (left 41 & 8 mmHg, right 34 t 5 mmHg, n = 7), systolic arterial pressure was 160 t 4 mmHg, diastolic pressure was 97 t 4 mmHg, and R-R interval was 333 t 16 ms. Elevation of sinus pressure (left to 140 t 11 mmHg, right to 159 t 16 mmHg) produced a maximum R-R interval of 519 t 42 ms, a prolongation of 185 k 38 ms. These immediate prolongations of R-R interval were abolished by atropine (1 mg/kg iv). Effect of nerue stimulation. Stimulation of group I and II fibers of the right peroneal nerve had no significant effect on the prolongation of R-R interval following baroreceptor stimulation. Prolongation of R-R interval in the control situation was 192 t 50 ms, and the prolongation of R-R interval by baroreceptor stimulation 0.55 + 0.12 s after the onset of peroneal nerve stimulation (10 Hz) was 171 t 45 ms (P > 0.05, paired t test, n = 5). In all animals stimulation of group I and II fibers produced reflex excitation of motoneurons as evidenced by the recording from the sciatic nerve of evoked activity with variable latency that increased if the recording electrodes

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1. Three oscilloscope traces showing evoked volleys recorded from sciatic nerve in response to electrical stimulation of peroneal nerve. Conduction distance was 66 mm. A: evoked volleys in group I and II fibers. B: recruitment of group III fibers with a peak at 3.2 ms, indicating a conduction velocity of 20.6 m/s; note change in vertical gain from A. C: recruitment of group IV fibers with a peak at 65 ms, indicating a conduction velocity of 1.0 m/s; note the change in both vertical gain and time base from B. FIG.

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’ Is ’ 2. Inhibition of R-R interval prolongation by group III fibers. A: control response to baroreceptor stimulation; mean control R-R interval 316 ms; longest R-R interval after baroreceptor stimulation 508 ms, i.e., a prolongation of 192 ms. B: same stimulus to baroreceptors as in A but delivered -1 s after onset of stimulation (5 Hz) of group IIII fibers of peroneal nerve. Reflex prolongation of R-R interval was only 40 ms. ECG, electrocardiogram; CSP, carotid sinus pressure; FAP, femoral arterial pressure. FIG.


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300

200 Prolongation of R-R interval

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FIG. 3. A comparison of prolongations of R-R interval (mean k SE) in control conditions (C) and during stimulation (10 Hz in 6 animals, 5 Hz in 1 animal) of group I and II fibers only, group I-III fibers, and finally group I-IV fibers of right peroneal nerve (n = 7 animals).

were moved closer to the stimulating electrodes. Muscle contraction, however, was prevented by the administration of vecuronium bromide (see MATERIALS AND METHODS).

In contrast to the lack of effect of group I and II fibers, recruitment of group III fibers significantly reduced the prolongation of R-R interval on baroreceptor stimulation (Fig. 2). Prolongation of R-R interval in the control situation was 149 t 19 ms, and prolongation of the R-R interval by baroreceptor stimulation 0.71 t 0.05 s after the onset of nerve stimulation (5-10 Hz) was 52 2 14 ms (P < 0.005, paired t test, n = 7). Recruitment of group IV fibers in the peroneal nerve produced a greater inhibition of the cardiac vagal component of the baroreflex. R-R interval prolongation in the control situation was 160 t 23 ms but only 1.0 t 8.0 ms (P < 0.001, paired t test, n = 7) when the baroreceptors were challenged 0.72 t 0.03 ms after the onset of nerve stimulation (5-10 Hz). Analysis of variance showed that the recruitment of group IV fibers had a significantly greater inhibitory effect on the prolongation of R-R interval than stimulation of just groups I-III (P < 0.05, Fig. 3). In the light of this greater inhibitory effect when group IV fibers were recruited, the evoked compound action potentials were carefully scrutinized to confirm that group IV fibers really were responsible and that the increased stimulus had not simply recruited more group III fibers. In each experiment the group III volley became

maximal well before the group IV threshold was reached. Similarly there was a range of stimulating voltages over which the group III inhibitory effect remained constant before the additional inhibitory effects of group IV fibers were seen. In all situations where the effects of nerve stimulation on R-R interval prolongation were assessed,other factors known to influence R-R interval, i.e., arterial systolic pressure, arterial diastolic pressure, initial carotid sinus pressure, change in carotid sinus pressure, and final carotid sinus pressure, were found to be not significantly different in the control and experimental situations (P > 0.05, paired t test, Fig. 4). The carotid baroreceptors were challenged within 1 s of the onset of nerve stimulation and before any changes in arterial blood pressure occurred (Fig. 2). Longer periods of nerve stimulation did produce increases in heart rate and blood pressure but only when group III or III and IV fibers were activated (Fig. 5). Where the effects of group III and III plus IV fibers were compared (Fig. 3), then the same frequency of stimulation was used in any one animal. This was usually 10 Hz, but in some animals activation of group III fibers with this frequency completely inhibited the prolongation of R-R interval on baroreceptor stimulation so that it was impossible to see any additional effect when group IV fibers were recruited. In such circumstances the frequency of stimulation was reduced to 5 Hz. No augmentation of the reflex prolongation of R-R interval was ever seen but no attempt was made to stimulate only low-threshold group III fibers. The results indicate that electrical stimulation of group III and IV fibers of the peroneal nerve inhibits the cardiac vagal component of the baroreflex. The pronounced bradycardia observed on cessation of nerve stimulation (Fig. 5) would indicate that this inhibitory effect on the cardiac vagal component of the baroreflex lasts only fractionally longer than the period of nerve stimulation. DISCUSSION

The results of this study show clearly that electrical stimulation of group III and IV afferent fibers of the peroneal nerve reduces the baroreceptor induced prolon400

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FIG. 4. Histograms showing values (mean t SE) of various parameters immediately before sinus pressure elevation together with final carotid sinus pressures in control situation (solid bars) and during peroneal nerve stimulation (hatched bars, groups I-III, 10 Hz). In each case control values are not significantly different from those during stimulation (P > 0.05, n = 7 animals). L init, L final, R init, R final, left and right initial and final carotid sinus pressures respectively; Syst, Diast, systolic and diastolic arterial pressures (left-hand axis). R-R int, R-R interval (right-hand axis).

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200 Arterial blood 1 pressure hn Hg) 0J Stimulation groups I-IV 10 Hz lnnnnnnAAn(nnAAnnnAn) Time

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FIG. 5. Increase in heart rate and arterial blood pressure caused by stimulation (groups I-IV, 10 Hz) of right peroneal nerve for 10 s. Note that there is a delay of at least 2 s before arterial blood pressure increases and that there is a marked bradycardia on cessation of stimulation.

gation of R-R interval, i.e., the same stimulus to the baroreceptors produces a smaller reflex response during peroneal nerve stimulation. The conclusion to be drawn from this finding is that stimulation of group III and IV fibers of the peroneal nerve reduces the sensitivity of the baroreceptor reflex. It is perhaps not unexpected that changes in the sensitivity of the baroreceptor reflex are mediated by group III and IV fibers and that group I and II fibers have no effect because the increase in heart rate and blood pressure on sciatic nerve stimulation in the cat is mediated by group III and IV fibers (4). Similarly the increase in heart rate and arterial blood pressure as a result of muscle contraction produced by ventral root stimulation is mediated by group III and IV fibers (12). The lack of effect of group I and II fibers in the present study is consistent with a number of previous studies where group I and II fibers have been repeatedly found to be without effect on the cardiovascular system (3, 4, 6, 7, 12). There are minor discrepancies in the published values for the upper limit of the conduction velocity of group III fibers. Matthews (11) places the boundary between group II and III fibers at 24 m/s, although others (13) report the lower limit for group II fibers as 30 m/s and the upper limit for group III fibers at 15 m/s. In the present study the group III volley was always quite distinct (Fig. I), with the peak conducting at 23.6 t 0.6 m/s. The peroneal nerve is not a pure muscle nerve but a mixed nerve innervating both muscle and joints and possibly even skin, although the skin of the lower leg is mainly innervated by the caudal sural nerve. It innervates muscles of the lateral aspect of the lower leg including peroneus brevis, peroneus longus, and tibialis anterior; it provides a branch to the ankle joint and branches to the area of the toes. Therefore, although it is most likely that the group III and IV fibers which have an inhibitory effect on the baroreceptor reflex originate in skeletal muscle, a contribution from group III and IV afferents innervating ligaments, joint capsules, and possibly even bone cannot be excluded. This study shows that marked changes in baroreceptor sensitivity can occur with relatively low rates of peroneal

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nerve stimulation, e.g., 5 Hz (Fig. 2). Previous studies (2, 9, 10, 16) employed much higher frequencies of stimulation (typically 100 Hz) that may be considered to be unphysiological. The fact that stimulation at 5 and 10 Hz can produce such marked changes in the cardiac component of the baroreceptor reflex is felt to be of significance to cardiovascular regulation during exercise because these frequencies are well within the range of discharge frequencies of group III afferent fibers (up to 35 Hz) seen during muscle contraction (8). We chose to assessbaroreceptor sensitivity in terms of the prolongation of R-R interval. Alternatively we could have assessedit in terms of changes in heart rate, but there is a growing realization that changes in R-R interval are more appropriate than changes in heart rate in reflecting alterations in vagal efferent outflow. This stems from the work of Parker et al. (15), who showed that in anesthetized dogs the relationship between R-R interval and the frequency of vagal stimulation is linear, whereas the relationship between heart rate and frequency of vagal stimulation is hyperbolic. The consequence of this finding is that an increment in the firing of vagal efferent fibers would prolong R-R interval by a fixed value independent of the initial R-R interval; the change in heart rate would, however, depend on the initial heart rate. The experimental protocol, whereby sinus pressure was elevated within 1 s of the onset of peroneal nerve stimulation, was deliberately chosen so that the sensitivity of the baroreceptor reflex could be assessedbefore any change in arterial blood pressure resulting from peroneal nerve stimulation. Thus the discharge from aortic arch baroreceptors and its reflex effect on vagal outflow would not have altered. The consequence is that it is possible to discuss the baroreflex relatively simply, i.e., a stimulus, in terms of a change in carotid sinus pressure, and a response, in terms of prolongation of RR interval. A change in the response despite a constant stimulus would therefore indicate a change in the sensitivity of the reflex. That atropine abolished the immediate prolongation of R-R interval indicates that these changes in R-R interval reflex alterations in vagal efferent outflow. Recordings from the sciatic nerve showed that stimulation of the peroneal nerve resulted in the reflex activation of motoneurons, and in the absence of vecuronium there was contraction not only of muscles in the right hindlimb but also in the contralateral limb and in the forelimbs. Administration of vecuronium (0.1 mg/kg iv every 20 min) completely prevented muscular contraction as evidenced by an absence of electromyographic activity. This dosage is reported to have no effect on bradycardia resulting from vagal stimulation (l7), and we saw no evidence of depression of reflex vagal bradycardia evoked by baroreceptor stimulation. Thus the inhibition of the cardiac vagal component of the baroreceptor reflex can be attributed directly to the electrical activation of group III and IV afferent fibers of the peroneal nerve and not to secondary activation of muscle afferents resulting from muscle contraction.


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It is a pleasure Jean Kaye. Address reprint Received

5 July

to acknowledge requests

the skilled

technical

assistance

INHIBITION of

to P. N. McWilliam.

1990; accepted

in final

form

24 October

1990.

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and metabolic stimuli. Circ. Res. 61, Suppl. I: 60-65, 1987. 9. KOZELKA, J. W., G. W. CHRISTY, AND R. D. WURSTER. Somatoautonomic reflexes in anesthetised and unanesthetised dogs. J. Auton. Nerv. Syst. 5: 63-70, 1982. 10. KUMADA, M., K. NOGAMI, AND K. SAGAWA. Modulation of carotid sinus baroreceptor reflex by sciatic nerve stimulation. Am. J. Physiol. 228: 1535-1541, 1975. 11. MATTHEWS, P. B. C. Muscle Receptors and Their Central Actions. London: Arnold, 1972. 12. MCCLOSKEY, D. I., AND J. H. MITCHELL. Reflex cardiovascular and respiratory responses originating in exercising muscle. J. Physiol. Lond. 224: 173-186, 1972. 13. MITCHELL, J. H., AND R. F. SCHMIDT. Cardiovascular reflex control by afferent fibers from skeletal muscle receptors. In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ BZood Flow. Bethesda, MD: Am. Physiol. Sot., 1983, sect. 2, vol. III, pt. 2, chapt. 17, p. 623-658. 14. NOSAKA, S., N. NAKASE, AND K. MURATA. Somatosensory and hypothalamic inhibitions of baroreflex vagal bradycardia in rats. Eur. J. Pharmacol. 413: 656-666,1989. 15. PARKER, P., B. G. CELLER, E. K. POTTER, AND D. I. MCCLUSKEY. Vagal stimulation and cardiac slowing. J. Auton. Nerv. Syst. 11: 226-231,1984. 16. QUEST, J. A., AND G. L. GEBBER. Modulation of baroreceptor reflex by somatic afferent nerve stimulation. Am. J. Physiol. 222: 12511259,1972. 17. SUTHERLAND, G. A., I. B. SQUIRE, A. J. GIBB, AND I. MARSHALL. Neuromuscular blocking and autonomic effects of vecuronium and atracurium in the anaesthetized cat. Br. J. Anaesth. 55: 1119-1126, 1983.


Responses of group IV and group III muscle afferents to thermal stimuli.

Effects of hypoxia on the discharge of group III and IV muscle afferents in cats.

Sensitization of group III and IV muscle afferents in the mouse after ischemia and reperfusion injury.

Group III and IV muscle afferents: role on central motor drive and clinical implications.

IV muscle afferents is not the sensory signal for perception of effort.

IV muscle afferents limit the intramuscular metabolic perturbation during whole body exercise in humans.

IV muscle afferents impair limb blood in patients with chronic heart failure.

Brain noradrenergic neurons in the locus coeruleus: inhibition by blood volume load through vagal afferents.

Depression of the recurrent inhibition of extensor motoneurons by the action of group II afferents.

Reflex inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular receptors with vagal afferents in dogs.

Determination of vagal baroreflex sensitivity in normal subjects.

IV.

Antinociception produced by electrical stimulation of vagal afferents: independence of cervical and subdiaphragmatic branches.

Inhibition by angiotensin II of baroreceptor-evoked activity in cardiac vagal efferent nerves in the dog.

Responses of inspiratory neurons of the dorsal respiratory group to stimulation of expiratory muscle and vagal afferents.

Gut vagal afferents differentially modulate innate anxiety and learned fear.

Antinociception and cardiovascular responses produced by intravenous morphine: the role of vagal afferents.

Inhibition by cocaine of the baroreflex in the rat.

Protection by halothane of the vagal baroreflex system from transient global cerebral ischemia in dogs.

Endogenous vascular endothelial growth factor produces tonic facilitation of cardiac vagal baroreflex via fetal liver kinase-1 in medulla oblongata.

Hypersensitivity of Vagal Pulmonary Afferents Induced by Tumor Necrosis Factor Alpha in Mice.

EXPRESS: Voltage-dependent sodium (NaV) channels in group IV sensory afferents.

Modulation of single vagal efferent fibre discharge by gastrointestinal afferents in the rat.

Capsaicin-sensitive vagal stimulation-induced gastric acid secretion in the rat: evidence for cholinergic vagal afferents.