Reflex Cardiovascular and Respiratory Effects of Serotonin in Conscious and Anesthetized Dogs

Transcription

1 59 Reflex Cardivascular and Respiratry Effects f Sertnin in Cnscius and Anesthetized Dgs IRVING H. ZUCKER AND KURTIS G. CORNISH SUMMARY Cardivascular and respiratry effects f intra-left atrial r intra-left ventricular injectin f sertnin were studied in cnscius dgs (n = 8), anesthetized clsed-chest dgs (n = 13) and anesthetized pen-chest dgs (n = 9). Sertnin (5-2 /ig), injected as a blus, resulted in an initial bradycardia and hyptensin fllwed by a delayed tachycardia and hypertensin in the cnscius dgs. The hypertensin was seen as an increase f 21.5 ± 2.7 (mean ± SE) nun Hg frm a cntrl pressure f 12.5 ± 1.9 mm Hg, whereas the initial decrease in pressure was 22.6 ± 1.9 mm Hg. The tachycardia was 23.3 ± 3.9 beats/min abve a cntrl heart rate f 14.9 ± 3.9 beats/min whereas the bradycardia was 58.5 ± 3.7 beats/min belw cntrl. There was a significant attenuatin f the hyptensin in bth grups f anesthetized dgs. In fact, n hyptensin was elicited in the pen-chest anesthetized dgs. Open-chest anesthetized dgs shwed nly a hypertensive respnse (mean increase 67.2 ± 5.5 mm Hg). Stimulatin f respiratin was seen in all grups f dgs. In cnscius dgs there was a ± 15.4% increase in respiratry depth and a 2.8 ± 3.1 breaths/min increase in respiratry rate. Atrpine significantly reduced the bradycardia and ablished the hyptensin in cnscius dgs. Bilateral cervical vagtmy did nt ablish the respnse in pen-chest anesthetized dgs. We cnclude that the s-called "hypertensive crnary chemreflex" is altered dramatically by the state f the preparatin and by anesthesia. Circ Res 47: , 198 A HYPERTENSIVE crnary chemreflex has been described (James et al., 1975; James et al., 1976), which is characterized by an intense vascnstrictin, resulting in sme cases in elevatins f arterial pressure f ver 1 mm Hg within a few secnds. In additin, a transient bradycardia (James et al., 1975), hyperpnea (Eckstein et al., 1971), and depressin f atrial cntractility (Urthaler et al., 1978) have been described. The stimulus fr activatin f this reflex is sertnin, which must be injected clse t the left crnary stia t be effective. If sertnin is given int the descending thracic arta r cartid circulatin, it is ineffective in eliciting this reflex (James et al., 1975). If it is given int the distal tw-thirds f the left crnary system apprximately cm distal t the rigin f the main left crnary, it results in a slight Bezld-Jarisch respnse (i.e., bradycardia and hyptensin) (James et al., 1975). The sertnin-sensitive receptr is a small area f chemreceptr-like tissue which is supplied by a small crnary artery arising frm either the left circumflex r the left anterir descending crnary artery near the rigin (Eckstein et al., 1971). This tissue has been bserved in dgs, cats, and humans (James et al., 1975). The afferent limb f this hypertensive reflex Frm the Department f Physilgy and Biphysics, University f Nebraska Cllege f Medicine, Omaha, Nebraska. Supprted by Natinal Institutes f Health Grant HL I.H. Zucker is an Established Investigatr f the American Heart Assciatin. Address fr reprints: Irving H. Zucker, Ph.D., Department f Physilgy and Biphysics, University f Nebraska Cllege f Medicine, 42nd Street and Dewey Avenue, Omaha, Nebraska Received Nvember 19,1979; accepted fr publicatin May 22, 198. is reprted t be in the vagi and the efferent limbs are in bth the vagi and cardiac sympathetics as well as the peripheral sympathetic nerves (James et al., 1975; Urthaler et al., 1978; Hageman et al., 1978). It has been prpsed that this reflex may be beneficial t humans when a thrmbus accumulates in the left main crnary artery (James et al., 1976). The platelets, which are rich in sertnin, wuld prvide the stimulus t this chemreceptr-like tissue causing a rapid elevatin in arterial pressure, thereby disldging the clt. With the exceptin f three cnscius dgs (James et al., 1975), all f the wrk cncerning this reflex was dne in the pen-chest anesthetized dg. Little attentin has been given t the rle f the respiratry respnse in mediating the vascular cmpnents f this reflex. The present study was undertaken t investigate the varius cmpnents f this reflex in the cnscius dg, in the clsed-chest anesthetized dg, and in the pen-chest anesthetized dg. Methds Thirty mngrel dgs weighing 22.7 ±.9 (mean ± SE) kg were divided int three grups as fllws: 8 cnscius dgs, 13 anesthetized clsed-chest dgs, and 9 anesthetized pen-chest dgs. Cnscius Dgs A left thractmy was dne at least 2 weeks prir t the experiment t implant Silastic catheters in the thracic arta and in either the left ventricle r left atrium. Fur dgs als had a Silastic catheter

2 51 CIRCULATION RESEARCH VOL. 47, N. 4, OCTOBER 198 implanted in the left circumflex crnary artery apprximately cm distal t its rigin frm the main left crnary artery. During the recvery phase, the dgs were trained t stand quietly in a Pavlv sling. Atrpine sulfate (.2 mg/kg) was given t six f the dgs. Effectiveness f the blckade was assessed by inhibitin f the bradycardia and hyptensin elicited by a 5-jug iv blus f acetylchline. Ventilatin was measured with a pneumgraph placed arund the chest and attached t a Millar cathetertipped micrmanmeter. Anesthetized Dgs Dgs were anesthetized with either pentbarbital sdium (Diabutal, Diamnd Labs, 3 mg/kg) r a- chlralse (Fischer, 1 mg/kg). In clsed-chest anesthetized dgs, a catheter was placed in the left ventricle via a femral artery. In pen-chest anesthetized dgs, a catheter was placed in the left atrium via a small pulmnary vein. Arterial pressure was measured in the arch f the arta with a Millar catheter-tipped micrmanmeter inserted thrugh a femral artery. A femral venus catherter was placed fr administratin f supplemental anesthesia. Temperature was cntrlled at 37 C, with a heating pad, with the aid f a Yellw Springs Temperature Cntrller. Arterial bld gases were similar t thse bserved in the cnscius dgs described abve and were maintained within thse limits. In several anesthetized dgs, the cervical vagi were islated and lse ligatures placed arund them fr later retrieval and sectining. Renal nerve efferent activity was recrded in six pen-chest anesthetized dgs by means f biplar platinumiridium electrdes. The signal was differentially amplified with a Grass P15 preamplifier and displayed n a chart recrder alng with integrated nerve activity. The nerve traffic als was displayed n a strage scillscpe. Renal nerve activity was quantified with a "RC" integratr with a time cnstant f 3.84 secnds. Zer renal nerve activity was btained at the end f the experiment by crushing the central end f the nerve. In three f the six dgs, renal nerve activity was recrded after bilateral cervical vagtmy. Integrated renal nerve activity was quantifier! by pen deflectin and expressed as percent change frm cntrl. Ventilatin was mnitred with a pneumgraph placed arund the chest in clsed-chest anesthetized dgs and at the level f the diaphragm in pen-chest anesthetized dgs. Respiratry depth was quantified by pen deflectin and expressed as the percent change frm cntrl. Heart rate was measured in all dgs with a Hneywell carditachmeter, which was triggered by the arterial pulse. The maximum bradycardia and tachycardia fllwing the injectin f sertnin was used t quantify the changes in heart rate. Mean arterial pressure was measured by electrnic damping f the arterial pulse. All parameters were recrded premanently n magnetic tape (Vetter; mdel D) and n a Hewlett-Packard eight-channel recrder (mdel 7758A). Experimental Prtcl After cntrl measurements f bld pressure, heart rate, respiratin, and (in sme dgs) renal nerve activity had been made, a blus f sertnin (creatinine sulfate cmplex; Sigma) was injected int the left ventricle r the left atrium. The sertnin was disslved in istnic saline and given in dses ranging frm 5 t 2 fig. The cncentratin was 1 fig/ml; therefre the vlume f injectate varied frm.5 t 2. ml. Injectin was dne ver a 1- t 2-secnd perid. Mre than ne injectin usually was given each dg. Each injectin was separated by an interval f 2-5 minutes. N tachyphylaxis was bserved during this prtcl. There was n difference in respnses elicited by the intraventricular r by the intra-atrial rute. Similar injectins f the sertnin vehicle (istnic saline) were als dne in each grup f dgs. The peak respnse f each parameter fllwing the injectin f sertnin was recrded (initial and delayed). The data amng grups were analyzed fr statistical significance using a ne-way analysis f variance and Duncan's multiple range test. The data within a grup were analyzed by the paired -test. Results Figure 1 shws representative recrdings frm ne dg in each grup. Sertnin (2 jug) was injected at the arrw in each panel. The characteristic respnse in the cnscius dg, as well as in the clsed-chest anesthetized dg (panels A and B), is an abrupt bradycardia fllwed by a slight tachycardia. There is an initial hyptensin which cincides with the bradycardia. Althugh nt seen in Figure IB, in mst dgs we saw a secndary hypertensin which cincided in time with a secndary tachycardia. Simultaneusly with the vascular effects, r in sme dgs slightly befre, there is a stimulatin f respiratin. The respnse that was bserved in the pen-chest anesthetized dg (panel C) was different frm that seen in the previus tw grups. Althugh the dg culd nt alter its ventilatin, it made strng respiratry mvements, as can be seen in Figure 1C. There was an immediate pressr respnse in the pen-chest anesthetized dg (latency 3.4 ±.3 sec) in which bld pressure rse t a maximum f 185 ± 6 ; 1 mm Hg frm a cntrl pressure f 117 ± 3.6 mm Hg in 12. ±.7 secnds. The initial hyptensin seen in cnscius and clsed-chest anesthetized dgs was absent. The bradycardia was present (and, in sme dgs, prlnged), prbably due t the marked hypertensin. There was n significant change in bld pressure, heart rate, r respiratin when the vehicle (istnic saline) was given by either the intra-atrial r intraventricular rute t seven cnscius and nine anesthetized dgs. Figure 2 shws the mean change frm cntrl f

3 REFLEX EFFECTS OF SEROTONIN/Zucker and Crnish 511 BLOOD (mm Hg) MEAN (mmhg) HEART RATE (bpm) RESPIRATION """H^^^ JULlJlLJJU 1 SEC t t FIGURE 1 The respnse t sertnin injected int the left atrium r left ventricle in A, a cnscius dg; B, a clsedchest anesthetized dg; and C, an pen-chest anesthetized dg. Sertnin (2 jig) was injected as a blus at the arrws. The respiratry tracing shws inspiratin as a dwnward deflectin in A and as an upward deflectin in B. The respiratry tracing in C depicts an inspiratry effrt; * symbls indicate statistical significance. bld pressure and heart rate in the three grups f dgs after the injectin f sertnin. When cmpared t the cnscius dgs, the initial hyptensin was significantly decreased in the anesthetized clsed-chest dgs and was ablished in the anesthetized pen-chest dgs. Only a hypertensive respnse was seen in the pen-chest anesthetized dgs. This Q O 2 I O *e ±1.9 ±3.5 tie Wai MTtl* uji is depicted as an increase in pressure in the lefthand panel f Figure 2. Likewise, the initial bradycardia was reduced in the clsed-chest and pen-chest anesthetized dgs relative t the respnse in the cnscius dgs. The hypertensive respnses were greater in the tw grups f anesthetized dgs, cmpared t thse in the cnscius animals. The UJ < Z < X ^CONSCIOUS " 9-5 ' 3 t 5 5 : (n = 8) ANESTH CLOSED CHEST (n=l3) r.flanesth OPENCHEST ±±! (n=9) FIGURE 2 The mean changes in bld pressure and heart rate in the three grups f dgs studied fllwing sertnin injectin. The bars n the left f each panel shw the mean (± SE) hyptensive and bradycardiac respnse. (These bars refer t the initial r immediate respnses; see text.) The bars n the right shw the hypertensive, tachycardiac respnse fr each grup. (These bars shw the delayed respnses; see text.) Cntrl mean arterial pressures and cntrl heart rates fr bth hyp- and hypertensive respnses are shwn belw each bar n the left f each panel. The numbers in parentheses in each bar represent the number f injectins made in that grup.

4 512 CIRCULATION RESEARCH VOL. 47, N. 4, OCTOBER 198 [-] CONSCIOUS (n=9) FIGURE 3 The mean percent changes in respiratry depth and the mean change in respiratry rate fr cnscius and anesthetized clsed-chest dgs fllwing injectin f sertnin. Since respiratry depth was measured in units f pen deflectin, n cntrl values have been prvided in the figure. The cntrl rates are shwn fr respiratry rate belw the bars. Numbers in parentheses dente the number f injectins upn which the data are based. latency fr nset f the hypertensin in the penchest anesthetized dgs was the same as the latency f the hyptensive respnse in the cnscius and clsed-chest anesthetized dgs (3.2 ±.2 and 3.4 ±.5 secnds, respectively). The secndary tachycardia was significantly greater in the pen-chest anesthetized dgs, cmpared t that f either the cnscius r clsed-chest anesthetized dgs. This secndary tachycardia was nt seen in Figure 1C because f the large hypertensive respnse which evked a bradycardia. As can be seen frm Figure 2, the cntrl heart rates and bld pressures were significantly higher in bth grups f anesthetized dgs than in the cnscius dgs. Figure 3 shws the mean data fr the respiratry respnse in eight cnscius and nine clsed-chest anesthetized dgs. Fllwing the injectin f ser- :SSUR i. a _j^ «E z UJ z< X tnin there was a ± 15.4% increase in respiratry depth in the cnscius dgs, whereas there was a ± 19.6% increase in respiratry depth in the clsed-chest anesthetized dgs, a significantly lwer value. Respiratry rate increased by 2.8 ± 3.1 breaths/min in the cnscius dgs. A similar increase f 25. ± 3.1 breaths/min was bserved in the anesthetized clsed-chest dgs. These changes in rate were nt significantly different frm each ther. The abslute respiratry rate in the anesthetized clsed-chest dgs was significantly lwer than in the cnsius dgs (P <.1), prbably because f the depressant effects f the anesthesia. In additin, the smewhat elevated respiratry rate in the cnscius dgs may have been due t panting in sme animals. We cncur with previus wrkers that the receptr that initiates the reflex effects f intra-left atrial r left ventricular sertnin must be lcated near the prximal left crnary system (Eckstein et al., 1971; Eckstein, 1977; James et al., 1975). In fur cnscius dgs with chrnic left circumflex crnary artery catheters, we injected 2jug f sertnin int the crnary apprximately cm frm the main left crnary artery. Arterial bld pressure decreased by 12.8 ± 5.7 mm Hg (P <.5), and heart rate increased by 1.7 ± 6.2 beats/min. There was n stimulatin f respiratin fllwing intracrnary injectin. Intracartid injectins (dne nly in anesthetized dgs) and intra-artic injectins (given apprximately 5 cm frm the artic valve in cnscius dgs) did nt result in any significant cardivascular r respiratry respnses. The efferent cmpnent f the bradycardia and hyptensin was investigated in six f the cnscius dgs. Figure 4 shws that, after the administratin f atrpine the bradycardia was significantly reduced and the initial hyptensin was ablished cmpletely. Althugh the secndary hypertensin was nt altered by atrpine, the tachycardia was reduced significantly. The effect f vagal sectin n the cardivascular respnse t sertnin in five pen-chest anesthe p^.i H i 1 1 (2) HlSB I7r (1) i ij.7 UJ 5 r I IN HEAF P<5 1 1 (2) H^H F J 1" * T 12) A- 1 1 P< 1 FIGURE 4 The mean changes in bld pressure and heart rate in cnscius dgs t sertnin befre and after administratin f atrpine. Bars n the left f each panel dente hyptensive and bradycardiac respnses (initial). Bars n the right f each panel dente hypertensive and tachycardiac respnses (delayed). c BEFORE ATROPINE AFTER ATROPINE (n=6)

5 REFLEX EFFECTS OF SEROTONIN/Zucker and Crnish 513 Z(E Zen J ui E OQ P <O I_) m Z FIGURE 5 The bld pressure and heart rate respnses t sertnin in pen-chest anesthetized dgs befre and after right vagtmy alne and after right plus left vagtmy. * Indicates statistical significance.! [PREVAGOTOMY RT VAGOTOMY VAGOTOMY n = 5) tized dgs can be seen in Figure 5. Right vagtmy did nt significantly alter the hypertensin r the tachycardia. Hwever, a cmbinatin f right and left vagtmy, significantly reduced the magnitude f the hypertensive respnse but did nt alter the tachycardia. We culd nt ablish cmpletely the hypertensive respnse t sertnin (by bilateral vagtmy) in any pen-chest anesthetized dg. In pen-chest anesthetized dgs, the efferent cmpnent f the hypertensin was investigated by recrding renal efferent nerve activity. Figure 6 shws a recrd frm ne such dg. After the left atrial injectin f 2 fig f sertnin (at arrw), there is an almst immediate increase in renal nerve activity fllwed by respiratry mvements and the hypertensive respnse. Renal nerve activity then returns t cntrl after abut 15 secnds. Table 1 shws the percent increase in renal nerve activity in this grup f dgs befre and after sectin f the right and left vagus. There was a ± 7.% increase in renal nerve activity fllwing the adminstratin f sertnin in the intact pen-chest anesthetized dg (P <.1). Right vagtmy did nt alter the respnse. Bilateral vagtmy reduced the increase in renal nerve activity belw that f the intact and right-vagtmized dgs; hwever, this TABLE 1 The Percent Change in Renal Nerve Activity after Left Atrial Injectin f Sertnin in Open-Chest Anesthetized Dgs Cnditin Percent increase frm cntrl Intact ± 7.*t (7/3) Right vagtmy 296. ± 7.4 (3/3) Bilateral vagtmy ± 7.4 (4/3) * Standard errr f the mean. t P <.1, paired t-test. % Numbers in parentheses dente the number f injectins/ numbers f dgs. value was nt statistically significant frm the intact dgs, prbably due t the small number f dgs and the high standard errr, but clearly the increase in renal nerve activity culd nt be ablished cmpletely by bilateral vagtmy. Discussin A reflex alteratin in bld pressure and heart rate has been demnstrated fllwing the intraatrial r intraventricular injectin f sertnin. The characteristics f this respnse are dramatically altered by the experimental preparatin. In the pen-chest, pentbarbital- r chlralse-anesthetized dg, this reflex was characterized by a rapidly develping hypertensin and an initial bradycardia. These respnses were similar t thse described by James and c-wrkers (James et al., 1975; James et al., 1976; Hageman et al., 1977; Urthaler et al., 1978). In the present experiments, the cardivascular respnse was dramatically altered when sertnin was injected int the left atrium r left ventricle f cnscius dgs and f clsed-chest anesthetized dgs. In these tw grups, it was characterized primarily by a bradycardia and hyptensin. James et al. (1975) have injected sertnin int the left atrium f three cnscius dgs and bserved a transient hyptensin, fllwed by a hypertensin (which ranged frm 48 t 73 mm Hg abve cntrl), as well as a transient bradycardia. This hypertensive respnse wuld appear t be lwer than the mean fr their 32 pen-chest anesthetized dgs, which was 96 ± 18 mm Hg abve cntrl. In all f the dgs in the present study, the administratin f sertnin by the intra-atrial r intraventricular rute resulted in an immediate and prfund stimulatin f bth the depth and rate f respiratin. Indeed, even in ur pen-chest anesthetized dgs, we bserved pwerful respiratry mvements fllwing the sertnin injectin. The nly reference in the literature t the respiratry cmpnents in this reflex is the wrk f Eckstein et al.

6 514 CIRCULATION RESEARCH VOL. 47, N. 4, OCTOBER 198 (1971) wh bserved inspiratry effrts in 18 f 2 animals when sertnin was injected at r clse t the crnary vessels supplying the receptr tissue. Prir t the present study, the respiratry respnse has been largely ignred in describing this reflex. The efferent cmpnent f the reflex bradycardia and hyptensin in cnscius dgs appears t be lcated primarily in the vagus, since the administratin f atrpine cmpletely ablished the hyptensin and significantly reduced the bradycardia. Alternately, it is pssible that there is a peripheral sympathetic chlinergic cmpnent mediating the hyptensin in the cnscius dg which wuld be blcked by atrpine. The secndary tachycardia als was reduced after atrpine, mst likely because n hyptensin was elicited. This wuld be cnsistent with the view that the delayed tachycardia is mediated by barreceptr unlading. Since sme bradycardia still was elicited by sertnin after administratin f atrpine, sme sympathetic withdrawal may als be a cmpnent f the bradycardia in the intact dg. Althugh we bserved a ptent activatin f the afferent renal sympathetic nerves in the pen-chest anesthetized dgs after administratin f sertnin (Fig. 6), it is unclear whether this ccurs in the cnscius dg. This sympathetic stimulatin undubtedly results in the systemic hypertensin seen in the pen-chest anesthetized BLOOD (mmhg) MEAN (mm Hg) HEART RATE (bpm) RESPIRATION RENAL NERVE TRAFFIC I R N A FIGURE 6 The effect fintra left atrial injectin f 2 Hg f sertnin (at arrw) n bld pressure, heart rate, respiratry effrt, and renal efferent nerve activity in an pen-chest anesthetized dg. - * * dg (James et al., 198). If this sympathetic stimulatin were a generalized phenmenn and tk place in the cnscius dg fllwing sertnin administratin, ne wuld expect the hypertensin t be present, at least in part, when sertnin was given fllwing atrpine. In ur experiments, this was nt the case. Therefre, it can be inferred that there was either n r a greatly reduced activatin f the peripheral sympathetic nervus system in the cnscius dg cmpared t the pen-chest anesthetized dg. In the pen-chest anesthetized dg, atrpine ablishes the negative intrpic effect n the atria that is elicited by sertnin, as well as the bradycardia, but des nt ablish the hypertensin (Urthaler et al., 1978). This further pints t a real difference in this reflex when elicited in a cnscius intact preparatin r an anesthetized pen-chest preparatin. The present study indicates that the afferent arm f this reflex is nt exclusively in the vagus, since we culd nt ablish the hypertensin r the respiratry respnse by bilateral cervical vagtmy in the pen-chest anesthetized dgs. It wuld appear, hwever, that at least part f the afferent pathway is in the left vagus since, after left vagtmy, we culd reduce the hypertensin significantly. Urthaler et al. (1978) came t the cnclusin that the afferent pathway was exclusively in the vagus since bilateral stellectmy did nt ablish the reflex whereas vagtmy did (James et al., 1975). Hwever, Hageman et al. (1978) culd nt eliminate the reflex in 16 f 39 dgs fllwing varius cmbinatins f vagal and cardiac nerve cling. Althugh James et al. (1975) bserved a depressed hypertensive respnse after bilateral vagtmy in 12 dgs, they culd nt ablish the hypertensin. There was still an increase f 17 ± 6 mm Hg after bilateral vagtmy cmpared t 88 ± 15 mm Hg befre vagtmy. Mre recent evidence indicates that the residual effect may be mediated by the actin f sertnin n the adrenal medulla, althugh latenc data wuld have been helpful t elucidate this. Urthaler et al. (1978), in a mre recent paper, state "... severing the vagi in the neck (with r withut bilateral stellectmy) cmpletely ablished the vascnstrictin." We cannt find any evidence fr this statement in their paper. Furthermre, there are sympathetic afferent pathways which d nt g thrugh the stellate (Mizeres, 1955). Based n ur findings, we cnclude that part f the afferent pathways fr this reflex traverse the sympathetic nerves and d nt travel via the vagi. Sympathetic afferents have been shwn t cnvey mechanical and chemical stimuli int the central nervus system (CNS) (Ueda et al., 1969; Uchida and Mura, 1975; Uchida and Mura, 1973). Indeed, there are several pieces f evidence that indicate that cardiac sympathetic afferents cnvey cardiac pain t the CNS (Brwn, 1968; White et al., 1933). It is nt clear why we fund such a dramatic

7 REFLEX EFFECTS OF SEROTONIN/Zucker and Crnish 515 alteratin in the respnse t sertnin when we cmpared cnscius dgs with pen-chest anesthetized dgs. Anesthesia itself has been shwn t alter the respnse t a variety f drugs as well as the reflex cntrl f bld pressure, mycardial cntractility, and peripheral flw (Vatner and Braunwald, 1975). Surgical trauma, especially in the penchest dg, may alter cardivascular reflex mechanisms by decreasing heart size and cardiac utput and by altering resting vagal tne. This, in turn, culd lead t a variety f stimuli frm bth mechanreceptrs, chemreceptrs, and nciceptrs which, when prcessed by the CNS, can alter the respnse f a given reflex such as the ne described here. In summary, we have cmpared the respnse t intra-atrial r intra-ventricular sertnin in three grups f dgs: cnscius, anesthetized clsedchest, and anesthetized pen-chest. It is clear that the experimental preparatin can alter the respnse elicited dramatically. Because f the prfund brdadycardia and hyptensin that we bserved in the cnscius dg, we wuld nt term this respnse a hypertensive chemreflex. In additin, ne shuld take great care in extraplating the clinical significance f this reflex t the intact awake human. The hypertensive respnse may be elicited, hwever, in humans underging thracic surgery under the influence f general anesthesia. Acknwledgments We wish t express ur gratitude fr the excellent technical assistance f Mrris Ellingtn. References Brwn AM (1968) Excitatin f afferent cardiac sympathetic nerve fibers curing mycardial ischemia. J Physil (Lnd) 19: Eckstein RW, Shintani F, Rwen HE Jr., Shimmura K, Ohya N (1971) Identificatin f left crnary bld supply f artic bdies in anesthetized dgs. J Appl Physil 39: Eckstein RW (1977) The artic bdies supplied by crnary arteries in the dg. Circ Res 41: 46-5 Hageman GR, Urthaler F, James TN (1977) Cyprheptadine blckade f a cardigenic hypertensive chemreflex. Prc Sc Exp Bil Med 154: Hageman, GR, Urthaler F, James TN (1978) Neural pathways f a cardigenic hypertensive chemreflex. Am J Physil 235: H345-H349 Hageman GR, Urthaler F, Swatzell RH Jr, James TN (198) Analysis f sympathetic discharges during cardigenic hypertensive chemreflex. Am J Physil 238: H61-H65 James TN, Isbe JH, Urthaler F (1975) Analysis f cmpnents in a cardigenic hypertensive chemreflex. Circulatin 52: James TN, Urthaler F, Hageman GR (1976) Chemreceptrs f the heart. Trans Am Clin Climatl Assc 88: Mizeres NJ (1955) The anatmy f the autnmic nervus system in the dg. Am J Anat 96: Uchida Y, Mura S (1973) Bradykinin induced excitatin f afferent cardiac sympathetic nerve fibers. Jap Heart J 15: Uchida Y, Mura S (1975) Acid induced excitatin f afferent cardiac sympathetic nerve fibers. Am J Physil 228: Ueda H, Uchida Y, Kamisake K (1969) Distributin and respnse f cardiac sympathetic receptrs t mechanically induced circulatry changes. Jap Heart J 1: 7-8 Urthaler F, Hageman GR, James TN (1978) Hemdynamic cmpnents f a cardigenic hypertensive chemreflex in dgs. Circ Res 42: Vatner SF, Braunwald E (1975) Cardivascular cntrl mechanisms in the cnscius state. N Engl J Med 293: White JC, Garry R, Atkins JA (1933) Cardiac innervatin: Experimental and clinical studies. Arch Surg 26: