Effect on Left Ventricular Performance of Stimulation of an Afferent Nerve from Muscle

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1 Effect on Left Ventrcular Performance of Stmulaton of an Afferent Nerve from Muscle By Jere H. Mtchell, M.D., Donald S. Menwak, M.D., Kern Wldenthal, M.D., Wllam D. Wlls, Jr., M.D., Ph.D., and Alvn M. Smth, B.A. ABSTRACT The effect on left ventrcular performance of electrcal stmulaton of the cut central end of the quadrceps nerve was studed n open-chest dogs. Stmulaton of the nerve at 2 to 4 tmes threshold for the flexon reflex, whch presumably actvated ntermedate-szed afferent fbers, caused a decrease n heart rate and arteral pressure. Stmulaton at 5 to 25 tmes threshold, whch presumably actvated small-szed, hgh-threshold afferent fbers, ncreased heart rate, arteral pressure, and cardac output. When heart rate, arteral pressure, and cardac output were controlled, actvaton of hgh-threshold afferent fbers caused a sgnfcant ncrease n the maxmal rate of pressure rse, stroke power, and mean rate of ejecton of the left ventrcle wthout an ncrease n the enddastolc pressure. These same fbers may n some way be actvated durng muscular exercse and be partally responsble for the ncrease n left ventrcular contractlty that occurs durng that tme. ADDITIONAL KEY WORDS contractlty of left ventrcle reflex notropc changes of ventrcle It has been proposed that reflexes nvolvng muscle afferent fbers play a role n the responses of the cardovascular system to muscular exercse n cats (1), dogs (2, 3), and man (4-7); however, the physologcal stmul and the receptors concerned reman undefned. It seemed mportant, therefore, to determne whether stmulaton of afferent nerve fbers from muscle can produce cardo- Fron the Paulne and Adolph Wenberger Laboratory for Cardovascular Research, Department of Internal Medcne, and the Department of Anatomy, Unversty of Texas Southwestern Medcal School, Dallas, Texas Ths nvestgaton was supported n part by U. S. Publc Health Servce Grants HE and HE from the Natonal Heart Insttute and by the Dallas Heart Assocaton. Dr. Mtchell s an Establshed Investgator of the Amercan Heart Assocaton. Dr. Wldenthal s a U. S. Publc Health Servce Postdoctoral Research Fellow (F2-HE-31,967). Dr. Merzwak s an Advanced Research Fellow of the Amercan Heart Assocaton. Accepted for publcaton February 1, left ventrcular functon exercse cardovascular reflexes from lmbs dogs vascular responses smlar to those seen durng muscular exercse. Stmulaton of the central end of a mxed nerve from the lmbs has long been known to produce alteratons n blood pressure and heart rate (8). More recently workers n several laboratores have shown that electrcal stmulaton of nerves from muscle from the lmbs produces ether pressor or depressor cardovascular responses accordng to the types of nerve fbers actvated (1,9, 10). The afferent fbers of nerves from muscle of the cat have been classfed accordng to ther sze (11, 12). The myelnated fbers nclude groups I, II, and III. The unmyelnated fbers are called ether group IV or C fbers. Group I afferent fbers have dameters of 12 to 20 fl and arse from prmary endngs of muscle spndles and from Golg tendon organs (13). Group II fbers range n sze from 4 to 12 f and many orgnate at secondary endngs of muscle spndles. Group III afferents are OrcnUton Rtsurcb, Vol. XX!1, Aprl

2 508 MITCHELL, MIERZWIAK, WILDENTHAL, WILLIS, SMITH myelnated fbers smaller than 4 f. They nnervate several knds of receptors wthn and about muscle, ncludng pressure-pan endngs (14, 15). The C fbers are presumed to arse from pan receptors. The afferent fbers whch have been shown to have cardovascular effects nclude groups II and III and the C fbers. In the present study cardovascular responses elcted by stmulaton of the afferent fbers of the quadrceps nerve were nvestgated n an open-chest dog preparaton. Ths approach also allowed the determnaton of the reflex acton of muscle afferent fbers upon ventrcular functon when heart rate, cardac output, and blood pressure were held constant. Prevous studes have emphaszed the effects of such stmulaton upon the perpheral vascular bed (1,10). Methods Mongrel dogs were anesthetzed wth alphachloralose ( mg/kg) n polyethylene glycol. Respraton was mantaned by a Harvard pump, and end-expratory Pco 2 was montored. The expermental preparaton s dagrammed n Fgure 1, and the basc detals have been descrbed n a prevous publcaton (16). In essence, the left ventrcle ejected blood through a Starlng resstance nto a reservor from whch the blood was returned by a rotor pump nto the FIGURE 1 Schematc dagram of the preparaton. Tr.C. = tracheal cannula; CCA. = common carotd artery; R.A. = rght atrum; R.V. = rght ventrcle; L.V. = left ventrcle; E.M.P. = electromagnetc flowmeter transducer; S.R. = Starlng resstance; Hg M. = mercury manometer; Res. = blood reservor; Pump = rotor pump; H.E. = heat exchanger; P.E1. = pacng electrode; Tr. = pressure transducer; St. = Grass stmulator; Q.N. = quadrceps nerve. Arrows ndcate drecton of blood flow. Pump Crculaton Research, Vol. XXII, Aprl 1968

3 MUSCLE AFFERENTS AND VENTRICULAR PERFORMANCE 509 thoracc aorta and common carotd arteres. The upper fve pars of ntercostal arteres, brachocephalc artery, and subclavan artery were all lgated, thus drectng the cardac output (except the coronary flow) nto the extracorporeal crcut. A pacng electrode connected to a Grass stmulator (model S4) was sutured to the rght atrum. In some of the studes heart rate, aortc pressure, and aortc flow were not controlled. Ths was accomplshed by dsconnectng the Grass stmulator and excludng the Starlng resstance, blood reservor, and rotor pump from the extracorporeal crcut. In the controlled studes the heart was paced at a rate well above the spontaneous rate, whle the aortc pressure and aortc flow were mantaned constant by settng the Starlng resstance and rotor pump, respectvely. Aortc pressure was measured by a Statham pressure transducer connected to a metal cannula, whch was nserted through the rght common carotd artery nto the arch of the aorta. Left ventrcular pressure was measured by a Statham pressure transducer connected to a metal cannula nserted drectly nto the left ventrcle at or near the apex. To determne the maxmal rate of left ventrcular pressure rse, a Dallons-Telco ntracardac mcromanometer, whch has an almost unform response to frequences as hgh as 200 cycles/sec (17), was also nserted nto the left ventrcle. The frst dervatve, dp/dt, of ths pressure recordng was contnuously computed by an R-C dfferentatng crcut that had a lnear response to 70 cycles/sec. Aortc flow was measured by a Statham electromagnetc flowmeter (M-4001) utlzng an extracorporeal transducer (A-2012) placed n the crcut proxmal to the Starlng resstance. Zero flow could be determned at any tme durng the experment bv drectng aortc flow through a parallel shunt. The system was calbrated after the experment was completed by pumpng measured flows through the transducer. Heart rate was measured by a cardotachometer. All values were contnuously recorded on a Sanborn drect-wrtng recorder; ntermttent hgh speed recordngs durng bref perods of mposed apnea were made on an Electroncs for Medcne photographc recorder. Snce the dogs were supne for convenent access to the thoracc cavty, the most approprate nerve for stmulaton was the one to the quadrceps muscle. In each experment, the quadrceps nerve was dssected free for several centmeters from ts cut perpheral end and mounted on a par of platnum electrodes n a pool of mneral ol held between skn flaps. Sometmes both quadrceps nerves were prepared n ths fashon. A Grass S4 stmulator wth an solaton unt Orcvbttnt Rts.rch, Vol. XXII, Aprl 1968 provded rectangular pulses for stmulaton. The stmulus duraton was ether 0.1 msec or 1.0 msec. The strength of stmulaton was judged n terms of multples of the mnmal level (at a gven stmulus duraton) requred to elct a vsble flexon reflex contracton (18). It was not feasble to relate the strength to the threshold for the most exctable afferent fbers because of the poston of the dog. We employed dfferent stmulus strengths to actvate afferent fbers of two sze ranges. Intermedate-szed afferent fbers were presumably excted by stmul two to four tmes the threshold strength for the flexon reflex. These fbers produced a depressor effect that was greatest when low frequences of stmulaton were used (about 1/sec). When stmulated n solaton, lower threshold afferents seemed to have no cardovascular effect. Impulses n small-szed, hgh-threshold afferent fbers were presumably also actvated by stmul 5 to 25 tmes the threshold for the flexon reflex. The pressor response produced by these fbers was largest when the frequency of stmulaton was hgh (generally 100/sec). After the threshold strength for the flexon reflex was determned, t was often convenent to nject gallamne trethodde (2 mg/kg, ntravenously) to abolsh reflex movements and spontaneous respratory efforts. The subsequent paralyss dd not appear to nfluence the expermental results and served to prevent secondary actvaton of afferent fbers from receptors n other parts of the lmb. Followng stablzaton, control recordngs were taken. Stmulaton of the nerve was begun, and then further recordngs were obtaned. In four of the dogs studed, propranolol ( m g/kg) was admnstered ntravenously, new control recordngs were taken, and stmulaton of the nerve was repeated. In two other dogs the studes were performed after blateral adrenalectomy. Measurements were made of aortc pressure, aortc flow, left ventrcular pressure, left ventrcular end-dastolc pressure, and the maxmal rate of rse of the left ventrcular pressure (max dp/dt). Stroke work, stroke power, and mean rate of ejecton were calculated (19). The performance of the left ventrcle was evaluated by a method whch has been descrbed prevously (16). The data were analyzed statstcally by Student's t-test for pared observatons (20). Results Cardovascular Responses to Afferent Stmulaton of the Quadrceps Nerve In sx dogs, ether a depressor or a pressor cardovascular response could be elcted by

4 510 MITCHELL, MIERZWIAK, WILDENTHAL, WILLIS, SMITH t_l 200 II I 1 ' I 1 1 ' -T 200 0L 40 r 0L 3330 r dp/dt mm Hg/sec; r 3330 L hmnh HmrH FIGURE 2 Cardovascular responses to stmulaton of afferent fbers of the quadrceps ferce. AP = aortc pressure; LVP = left ventrcular pressure; LVDP=fe/t ventrcular dastolc pressure; and dp/dt = rate of left ventrcular pressure change. Left panel, stmulaton of central end of cut quadrceps nerve at twce threshold for the flexon response s ndcated by the black bars. Rght panel, stmulaton of the quadrceps nerue at 20 tmes threshold for the flexon response s ndcated by the black bars. afferent stmulaton of the quadrceps nerve, dependng upon the strength of the stmulus used. Examples of these responses are shown n Fgure 2. A depressor response s shown n the left panel. Heart rate was held constant by a pacng electrode. The quadrceps nerve was stmulated at a frequency of 1/sec by pulses havng a strength two tmes threshold for the flexon reflex. The perod of stmulaton s ndcated by the black bar n the lower part of the tracng. Durng stmulaton, aortc pressure, left ventrcular pressure, and maxmal rate of rse of left ventrcular pressure all decreased, and left ventrcular dastolc pressure remaned unchanged. Such a response was almost nvarably obtaned when the quadrceps nerve was stmulated at two to four tmes threshold for the flexon reflex. A pressor response s shown n the rght panel. The quadrceps nerve was stmulated at a frequency of 100/ sec by pulses havng a strength 20 tmes threshold for the flexon reflex. A small ntal depressor response occurred; t may be attrbuted to actvaton of the ntermedate-szed muscle afferent fbers whch would have a more rapd conducton velocty than the fbers responsble for the pressor response. After the ntal, bref depresson, aortc pressure, left ventrcular pressure, and maxmal rate of rse of left ventrcular pressure all ncreased, and left ventrcular dastolc pressure remaned relatvely constant. Cardac output also consstently ncreased at these stmulaton levels. Both the depressor and pressor cardovascular responses were stll present after blateral vagotomy. Snce the purpose of ths study was to deorcuuton RSfrcb, Vol. XXII, Aprl 1968

5 MUSCLE AFFERENTS AND VENTRICULAR PERFORMANCE 200 AP mmhg LVP mmhg 200 r 40 r ) / r d t mmh'sec 511 example of ths response when heart rate was not controlled s shown n Fgure 3. The small ntal depressor response was agan seen. Then there was an ncrease n aortc pressure, left ventrcular pressure, maxmal rate of left ventrcular pressure rse, and heart rate. These changes were accompaned by a fall n left ventrcular dastolc pressure. Heart rate ncreased by 50 beats/mn. Cardac output, not shown n ths fgure, also ncreased. In ths study, a response was not seen untl 15 seconds after the onset of nerve stmulaton. The delay from onset of stmulaton to response vared from 2 to 15 seconds n the seres of experments, a perod of latency compatble wth recrutment of neurons from repettve stmulaton. The depressor response that followed the pressor response n ths study was abolshed by blateral transecton of both carotd snus and vagus nerves. Despte these procedures, however, arteral pressure and heart rate tended -to return toward control values durng contnued stmulaton. Effect of Afferent Stmulaton of the Quadrceps Nerve on Left Ventrcular Performance HR beats/mn 280 r 80L; -1 mn FIGURE 3 Pressor response to stmulaton of afferent fbers of the quadrceps nerve. HR = heart rate; other abbrevatons same as n Fgure 2. Stmulaton of the quadrceps nerve at 25 tmes threshold for the flexon response s ndcated by the black bar. termne whether stmulaton of afferent nerve fbers from muscle can produce cardovascular responses smlar to those seen durng muscular exercse, further observatons were concerned only wth the pressor response. An CrcmUton Rturcb, Vol. XXII, Aprl 1968 The effect of stmulaton of the central end of the quadrceps nerve on left ventrcular performance was studed n 32 experments on eght dogs; an example s shown n Fgure 4. In ths experment, wth aortc pressure, aortc flow, and heart rate held constant, the quadrceps nerve was stmulated at a frequency of 100/sec by pulses havng a strength 25 tmes threshold for the flexon reflex. Durng stmulaton left ventrcular end-dastolc pressure remaned constant, and the maxmal rate of left ventrcular pressure rse ncreased by 1670 mm Hg/sec (41*) above the control level. Stroke power ncreased by 8.2 g-m/ sec (12 ), and mean rate of ejecton ncreased by 6.0 ml/sec (9%). A summary of the effects of afferent stmulaton of the quadrceps nerve s gven n Table 1. The quadrceps nerve was stmulated at a frequency of 100/sec and at ntenstes of 5 to 25 tmes threshold for the flexon reflex. The latency before a response was seen was smlar to that observed wth the aortc

6 512 MITCHELL, MIERZWIAK, WILDENTHAL, WILLIS, SMITH AP mm Hg LVP mm Hg LVDP cmh 2 O dp/dt "30 mm Hg/sec L 3000 r AF 2O0030 ml /mn 1000\ 0 0 p-1 mrn p-1 LVDP cm H2O LVP mm Hg dp/dt mm Hg/sec 6660 LVDP LVP -I second - FIGURE 4 Effect of afferent stmulaton of the quadrceps neroe on left ventrcular performance. AF = aortc flow; other abbrevatons as n prevous fgures. A and B n upper slow-speed tracng (0.5 mm/sec) ndcate tmes at whch hgh-speed tracngs (100 mm/sec) were obtaned. Stmulaton of the quadrceps nerve at 25 tmes threshold for the flexon reflex s ndcated by the black bar n the upper tracng. CrcuUutm R«MMA, Vol. XXII, Aprl 1968

7 MUSCLE AFFERENT* AND VENTRICULAR PERFORMANCE 513 I V q* t H q CO O O O O V O5 CO t-; CO cd d S oq co cd d c o c a pressure and heart rate changes. In each experment the left ventrcular end-dastolc pressure remaned constant or decreased slghtly. The mean value for maxmal rate of pressure rse ncreased by 408 mm Hg/sec (1235), stroke power ncreased by 4.3 g-m/sec (5%), mean rate of ejecton ncreased by 2.7 ml/sec (43!), and stroke work ncreased by only 0.2 g-m (2%). The ncrease n maxmal rate of pressure rse, stroke power, and mean rate of ejecton wthout an ncrease n left ventrcular end-dastolc pressure demonstrates an ncrease n contractlty or a postve notropc effect of the left ventrcle. Although these mean changes are small, some ndvdual experments showed greater changes, as demonstrated n Fgure 4. To nvestgate the role of the cardac betaadrenergc receptors n the ncrease n left ventrcular contractlty, afferent stmulaton of the quadrceps nerve was performed before and after the admnstraton of propranolol n four dogs. In the control studes stmulaton of the afferent fbers of the quadrceps nerve caused an ncrease n the maxmal rate of pressure rse, stroke power, and mean rate of ejecton wth ether no change or a decrease n left ventrcular end-dastolc pressure. After admnstraton of 0.8 mg/kg propranolol, these effects of stmulaton of the quadrceps nerve were abolshed. When the stmulaton was agan repeated 30 mnutes later, the responses had returned toward those found durng the control studes. The ncrease n contractlty of the left ventrcle durng afferent stmulaton of the quadrceps nerve was not affected by blateral vagotomy. Also, n two addtonal dogs the ncrease n contractlty was present after blateral adrenalectomy. Dscusson The results of ths study n dogs are n general agreement wth prevous studes on cats (1, 9, 10). Electrcal stmulaton of muscle afferent fbers may produce depressor or pressor responses, dependng on the types of fbers excted and the frequency of stmulaton. Antdromc frng of motor fbers can be ruled CkcnUtcn Retmcb, Vol. XXII, Aprl 1968

8 514 MITCHELL, MIERZWIAK, WILDENTHAL, WILLIS, SMITH out as a cause of cardovascular responses, snce ventral root stmulaton produces no such effect (9). The present experments have demonstrated that stmulaton of muscle afferent fbers not only causes alteratons n aortc pressure and heart rate, but also an ncrease n left ventrcular contractlty when aortc pressure, aortc flow, and heart rate are held constant durng stmulaton at ntenstes and frequences whch otherwse would have caused an ncrease n aortc pressure, aortc flow, and heart rate. It s not possble at present to relate wth certanty the stmulus strengths whch produced cardovascular responses n the present study to the specfc types of muscle afferent fbers excted. Ths s due not only to the condtons of the experments but also to the lack of data on the fber composton of perpheral nerves and responses of the varous fber groups to electrcal stmulaton n the dog. However, there do seem to be parallels between the responses observed n ths nvestgaton and those seen n the cat. Frst, no cardovascular effects were seen n dogs untl the stmulus strength exceeded twce threshold for the flexon reflex. In the cat, group 1 fbers produce no detectable cardovascular responses (1, 9, 10). Second, stmulaton of what we presume to be ntermedate-szed afferent fbers by low frequences produces a depressor response n the dog (Fg. 2) as has been demonstrated n the cat (1, 9,10). Thrd, hgh-frequency stmulaton of what we beleve are small-szed, hgh-threshold afferent fbers produces a pressor response n the dog (Fgs. 2 and 3) as has also been demonstrated n the cat (1,9). The depressor response n cats s carred n group III fbers (1, 9, 10). In the present study n dogs, t s probable that the same group of fbers s nvolved; however, t s possble that a contrbuton was made by group II fbers. Both group II and group III fbers are partcpants n the flexon reflex mechansm and are known to actvate ascendng tracts whch project onto retcular formaton neurons (21, 22). The falure of blateral mdcervcal vagotomy to abolsh the decrease n arteral pressure and heart rate mples that cardac sympathetc wthdrawal s a factor n the efferent pathway of the depressor response n dogs. Ths s n agreement wth Johansson's fndngs n cats (1). A pressor response n cats has been reported wth hgh frequency stmulaton of group II fbers when the anmals were decerebrate (9). However, wth chloralose anesthesa, actvaton ether of group III fbers at hgh frequences (2) or of C fbers (1, 9) s requred. The effects of actvaton of smallszed muscle afferents on cardovascular functon are probably medated at least n part through the bran stem (1), although proprospnal connectons to sympathetc pregangl onc neurons may also be mportant, partcularly for the pressor response (1). Furthermore, Sato and Schmdt (23) recorded reflex dscharges from the cervcal sympathetc trunk prmarly n response to stmulaton of group III fbers n muscle nerves of the hnd lmb of the cat. The actvaton of the sympathetc efferent system manfested by an ncrease n heart rate and arteral pressure n the uncontrolled preparaton was demonstrated n the controlled experments by sgnfcant ncreases n mean maxmal dp/dt, mean stroke power, and mean rate of ejecton wthout an ncrease n left ventrcular end-dastolc pressure (Table 1). Thus, actvaton of these fbers caused an ncreased contractlty of the left ventrcle. The fact that actvaton of the cardac beta-adrenergc receptors was responsble for the ncrease n left ventrcular contractlty was demonstrated by the abolton of the response after the admnstraton of propranolol. Ths response could be due to ncreased cardac sympathetc efferent nerve actvty, to catecholamne release from the adrenal medulla, or to both of these mechansms. The persstence of the ncrease n contractlty after blateral adrenalectomy suggests that the cardac sympathetc efferent fbers play a role n the response but does not rule out the partcpaton of the adrenal medulla n the response as t s usually seen. Ths confrms the observaton of Johansson (1) that a CtrcmUton Rsurcb, Vol. XXII, Aprl 1968

9 MUSCLE AFFERENTS AND VENTRICULAR PERFORMANCE 515 pressor response can occur n the absence of adrenal medullary functon. It should also be noted that blateral vagotomy dd not affect the response. The possblty that small-szed, hgh-threshold muscle afferent fbers play a role n the responses of the cardovascular system to muscular exercse s of nterest. The changes produced n the present study are small compared wth those seen n normal dogs durng exercse; however, these responses were elcted by contnuous stmulaton of a nerve from a sngle muscle n an anesthetzed anmal. In an awake, exercsng anmal, more muscles would be nvolved and, snce muscle contracts rhythmcally, a contnuous volley of mpulses would not be present. Further, the physologcal stmul and the receptors concerned reman undefned. Group III afferents n the cat arse from varous receptors located wthn and around muscle (14, 15). Although some of the receptors requre hgh-ntensty stmulaton whch mght be consdered panful, others are known to be actvated by muscular contracton (14). It would be of consderable nterest to know whch types of receptors gvng rse to group III fbers are nvolved n the producton of pressor responses and whch n producton of depressor responses. Further studes are requred to nvestgate the mode of actvaton of the C fbers found n muscle. Also, the proposal of Alam and Smrk (6, 7) that afferent fbers medatng the ncrease n cardac actvty may arse from receptors responsve to hgh local concentratons of metaboltes of muscular exercse deserves consderaton. The present study makes no attempt to dentfy the receptors or the central nervous system nterconnectons requred for the reflexes that have been demonstrated. However, the study does suggest that smallszed, hgh-threshold muscle afferent fbers, when stmulated approprately, may play some role n elctng the ncrease n left ventrcular contractlty that occurs durng muscular exercse. Acknowledgment The authors gratefully acknowledge the valuable techncal assstance of Mr. Eugene Berry and Mr. Cratttof R*$frcb, Vol. XXII, Aprl 1968 James Jones, and the valuable assstance of Mrs. Joan Resch n the statstcal analyses. References 1. JOHANSSON, B.: Crculatory responses to stmulaton of somatc afferents. Acta Physol. Scand. 57: suppl. 198, KAO, F. F., AND RAY, L. H.: Respratory and crculatory responses of anesthetzed dogs to nduced muscular work. Am. J. Physol. 179: 249, KAO, F. F., LAHIRI, S., WANG, C, AND MET, S. S.: Ventlaton and cardac output n exercse; nteracton of chemcal and work stmul. Crculaton Res. 20 (suppl. I): 1-179, KROGH, A., AND LINDHARD, J.: Comparson between voluntary and electrcally nduced muscular work n man. J. Physol. (London) 51: 182, ASMUSSEN, E., AND NIELSEN, M.: Experments on nervous factors controllng respraton and crculaton durng exercse employng blockng of the blood flow. Acta Physol. Scand. 60: 103, ALAM, M., AND SMIBK, F. H.: Observatons n man upon a blood pressure rasng reflex arsng from the voluntary muscles. J. Physol. (London) 89: 372, ALAM, M., AND SMIRK, F. H.: Observatons n man of a pulse-acceleratng reflex from the voluntary muscles of the legs. J. Physol. (London) 92: 167, WIGGERS, C. J.: Physology n Health and Dsease (5th ed.). Phladelpha, Lea & Febger, 1949, p LAPORTE, Y., BESSOU, P., AND BOUISSET, S.: Acton r flexe des dff^rents types de fbres affeentes d'orgn musculare sur la presson sangune. Arch. Ital. Bol. 98: 206, SKOGLUND, C. R.: Vasomotor reflexes from muscle. Acta Physol. Scand. 50: 311, " LLOYD, D. P. C, AND CHANG, H. T.: Afferent fbers n muscle nerves. J. Neurophysol. 11: 199, REXED, B., AND THEHMAN, P. 0.: Calbre spectra of motor and sensory nerve fbres to flexor and extensor muscles. J. Neurophysol. 11: 133, HUNT, C. C: Relaton of functon to dameter n afferent fbres of muscle nerves. J. Gen. Physol. 38: 117, PATNTAL, A. S.: Functonal analyss of group IH afferent fbers of mammalan muscles. J. Physol. (London) 152: 250, BESSOU, P., AND LAPORTE, Y.: Etude des recepteurs musculares nnerves par les fbres affeventes du groupe III (fbres myelnsees fnes), chez le chat. Arch. Ital. Bol. 99: 293, 1961.

10 516 MITCHELL, MIERZWIAK, WILDENTHAL, WILLIS, SMITH 16. MITCHELL, J. H., GUPTA, D. N., AND BARNETT, S. E.: Reflex cardovascular responses elcted by stmulaton of receptor stes wth phanna- 20. cologc agents. Crculaton Res. 20 (suppl. I): 1-192, GLEASON, W. L., AND BRAUNWALD, E.: Studes on the frst dervatve of the ventrcular pressure pulse n man. J. Cln. Invest 41: 80, ECCLES, R. M., AND LUNDBERC, A.: Synaptc ac- 22. tons n motoneurtmes by affetents whch may evoke the flexon reflex. Arch. ItaL Bol. 97: 199, MITCHELL, J. H., WALLACE, A. G., AND SKINNER, N. S., JR.: Intrnsc effects of heart rate on left ventrcular performance. Am. J. Physol. 205: 41, OSTLE, B.: Statstcs n Research. Ames, Iowa, Iowa Unversty Press, POMPEIANO, O., AND SwETT, J. E.: Actons of graded cutaneous and muscular afferent volleys on bran stem unts n the decerebrate, cerebellectomzed cat Arch. Ital. Bol. 101: 552, MACNL, F., AND WILLIS, W. D.: Subcortcal and perpheral control of bran stem retcular neurons. Arch. Ital. BoL 102: 434, SATO, A., AND SCHMIDT, R. F.: Muscle and cutaneous afferents evokng sympathetc reflexes. Bran Res. 2: 399, CtraOoon Rvurcb. Vol. XXII, Aprl 1968