Indian Journal of Experimental Biology
Vol. 38, September 2000, pp. 881-886
Phenyldiguanide activates cardiac receptors to produce responses by involving
three different efferent pathways in anaesthetized rats
Sovan Bagchi & Shripad B Deshpande*
Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Indi a
Received 7 September 1999; revised 24 May 2000
The present study was undertaken to determine the afferent and efferent pathways involved in the phcnyldiguanide
(PDG)-induced retlex response in rats. Intravenou s (iv) inj ection of PDG (10 Jlg/kg), produced hypotension , bradycardia
and ap nea over a period of time. Bil ateral vagotomy aboli shed the PDG-induced reflex changes. Atropine (2 mg/kg; iv)
blocked only the bradycardiac response produced by PDG, while prazosin (0.5 mg/kg; iv) blocked the hypotensive response,
and bilateral vagotomy in these animals abolished the ap neic response. In separate series of experiments, intraperi cardial
injecti on of li gnocaine aboli shed the hypotensive and bradycardiac responses evoked by PDG in artifi ciall y ventil ated rats.
The results reveal that the PDG-induced refl ex is mediated through vagal afferents originating from the heart and efferents
involve three different pathways. The bradycardiac response was through the muscarinic receptors, the hypotension is
mediated th rough a 1 adrenoceptors and the ap nea presumably through the spinal motoneurones suppl ying the respiratory
mu scles.
Cardiopulmonary refl exes in man and experimental
animals can be eli cited by intravenous inj ections of
variety of agents such as phenyldiguanide (PDG),
phenylbiguanide (PBG), serotonin , lobeline etc, 1- 10 •
As repeated admini stration of PDG does not produce
tachyphylaxi s 11 , it is used by many investigators·'-6·12- 16 . PDG as we II as ot her agents are known to
activate high thres hold vagal C fibres originating
from heart and lungs 3-6 . Presence of PDG in the intravascular compartment as happens after intravenous
administration, can be able to activate both the
receptors situated in heart and lungs . In the lung, the
receptors at juxtapulmonary capillary site (]receptors) are ac ti vated to produce bradycardia,
hypotension and apnea-tachypnea res ponse, known as
J-reflex 3-5 . While the activation of receptors at the
cardiac sites (distributed around coronary vessels in
the ventricles) also produce refl ex hypotension,
bradycardia and apnea/tachypnea and known as
Bezold-Jarisch refl ex 7·8 • The only difference in these
reflex responses is th e latency of onset. But in smaller
animals like rats, the difference in latencies of these
reflexes is shorter and separation is not as di stinct as
in cats 3_5 _ Therefore in rats, the PDG res ponse pattern
alone will not reveal the location of receptors. Further
*Correspondent author: Phone: 91 -542-317629;
Fax: 91-542-367568/317074; E-mail: [email protected]
bilateral vagotomy abo li shed the reflex in rats 12
whereas bilateral vagotomy in cats 1t or cooling of
both vagi in rabbits 17 did not block the PDG-induced
reflex changes. Thus, the rol e of vagal efferents in
mediating the PDG reflex in rats requires to be
identified _ In studies elsewhere, reduction in ren al
sympathetic nerve activity is shown after the injection
. . the contn'b utton
.
o f PBG t 8·19 but wtt- hout ment10n111g
18 19
of cholinergic nerves ' • Thus, the efferent pathways
involved in PDG reflex remain less defined. This
study has therefore been undertaken to identify the
location of the receptors for producing PDG-induced
reflex responses 111 rats. Further, the rol e of
parasympatheti c and sympat hetic systems tn
mediating the reflex responses has also been
ascertained_
Materials and Methods
Animals, anaesthesia and reco rding proceduresAdult rats ( 150-250 g) of either sex belonging to
Charles Foster strain were anaesthetized with an ip
injection of ureth ane ( 1.5 g/kg). Tracheal cannulati on
was done to keep the res piratory tract patent,
followed by right jugular venous cannu lation to
deliver drugs. Femoral artery cannulation was
performed to record the arterial pressure by a Stathum
transducer. The electrocardiographic (ECG) potential s were obtained usin g needle electrodes in
882
INDI AN J EX P BIOL, SEPTEMBER 2000
standard limb lead II co nfiguration . The sk in over the
xiphisternum was secured with a thread to a force
displacement transdu cer to record the respi ratory
movements. All the recordings were made on a
polygraph . The heart rate (HR) and respiratory rate
(RR) were calculated manually by countin g the waves
in I 5 s and co nvertin g them to a minute. The mean
arterial pressure (MAP) was calculated from the
calibration made after each ex periments as mentioned
.
I y 14·16 . Recta I temperature was mom.to red
prev iOus
throughout the ex periment and maintained around
37°C. The animals were allowed to stabilize for at
least 30 min after the surgi cal procedures.
Procedure of intrapericardial injection-In
separate series of experiments, animals we re anaesthetized with urethane, then tuboc urarine (I 5 11g/kg;
iv; Sigma Chemical Co. USA) was injected to
paralyse respiratory musc les before conn ecting to th e
respiratory pump . The minute ventilati on was kept at
400 ml/kg body weight (50 strokes/min ; 8
mllkg/stroke) and was maintained throughout th e
experi mentati on as described elsewhere 20 . Thorax
was opened between the second and third left
costochondral junctions. The pericardia( sac was
identified, and a fine pol yethylene catheter was
introduced in it after making a sma ll openin g. Sa li ne
or lignocaine (As tra IDL Ltd . Indi a) was applied
through thi s catheter (vol=O . I ml ).
Experimenta l protocol-The animals were di vided
into 3 groups accordin g to drug application and
experimental cond iti ons. In all th e groups, PDG ( 10
!Jglkg; Koch Light Lab. UK, a gift from Prof. A.S.
Paintal, V.P. Chest Institute, Delhi University, Delhi )
was inj ected into jugular vein to e licit the reflex
respo nse . The vo lume of injec ti ons of PDG or
antagon ists was kept at 0.1 mi.
In group I, afte r obtai nin g the in itia l PDG
response, bilateral vagoto my was perfo rmed and I0
min later PDG response was obtained again .
In group II animals, PDG response was obtained
initially, 30 min after the admini strati on of atropine
(2 mg/kg; iv ; Sigma, USA), I0 min after the injecti on
of prazosin (0.5 mg/kg; iv; Sigma, USA) and finally
I0 min after bi latera l vagotomy in th e same animal
sequ enti all y.
In gro up IIl, th e PDG respo nse was obtained
initi ally, 10 min after injection of tubocurarine (15
f.lg/kg), after ope nin g the thorax, and I0 min after
intrapericardial injecti on of 2% lignocaine or saline.
Analysis of data and statistics--The values of
MAP, HR and RR at every 5 sec upto 60 sec after
injecting PDG were normali sed to the initial values
seen before injecting PDG as described earli er 14• 16 •
The values at every 5 sec were pooled to obtain mean
±SE. Student's t test (paired and unpaired observations) was used for comparing two groups and P
value< 0.05 was considered significa nt.
Results
Bilateral vagotomy abolish ed th e PDC-induced
reflex response-Jugular venous injection of PDG
( I0 f.lg/kg) produced hypotens ion, bradycardia and
apnea upto 30-60 sec (Fig. I). The responses began
after a latency of 2-2.5 sec and reached maximum
after I0-15 sec. The recovery time of res piratory rate
(RR) was shorter than BP or HR (F ig. I) . Injection of
Resp
m~w.~~~~~rrtmmrrmm
1'
~
,-..
.-
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·~
.s
<-H
100
0
6'(
'--'
(])
C/}
q
0
50
~
0
MAP
(])
0
HR
RR
C/}
~
d
Q
~
6
0
L.
0
20
40
60
Ti1ne (seconds)
Fi g. 1-Phenyldiguanide
(PDG )
produced
hypoten sio n,
bradycardia and apnea for a period of time. [Ori ginal tracin gs or
bl ood pressure (BP). electrocardiogram (ECG) and respiration
(Resp) afte r the jugu lar ve no us (i v) injection o f PDG ( I 0 p g/kg)
from a si ngle experiment are presented in the lo p panel. The arrow
indicates the point o f iv injection of PDG. The mean± SE values
(n=7) o f mean arte ri al pressure (BP). heart rate (HR ) and
res piratory rate (RR ) arc presenled in lower box].
BAGCHI & DESHPANDE: PDG-INDUCED REFLEXES ORIGINATE FROM HEART IN RATS
equal volume (0.1 ml) of saline produced no
perceptible effect on MAP, HR or RR.
After bilateral vagotomy (group I animals), FOGinduced reflex changes on HR, MAP and RR were
not elicited. On the contrary, a significant increase in
MAP at 10 sec after POG (120 ± 8.5; P < 0.05) and a
brief tachypnea immediately after POG were
observed (Fig. 2) . In these animals before exposure to
POG, there was slight increase in resting HR (from
276±7.3 to 298±3.12 beats/min), the MAP was not
altered and the respiration became slow (75±2.5/min
became 42±1.4/min after vagotomy) and deep as
expected (Fig. 2).
Efferent pathways of reflex responses-In group II
animals, injection of atropine (2 mg/kg; iv; Figs 3 and
4) blocked the bradycardiac response induced by
POG. Prazosin, an a 1 adrenoceptor antagonist (0.5
mg/kg; iv), abolished the hypotensive component of
the reflex respon se produced by POG (Figs 3 and 4) .
Bilateral vagotomy, in these animal s abolished apnea
totally (Figs 3 and 4).
After atropinization heart rate increased slightly,
but no change was observed in MAP and RR (Table
I) . After prazosin there was significant fall in BP and
increase in RR (P < 0.05) but reduction in HR was
not significantly different (Table 1).
lntrapericardial injection of Lignocaine abolished
the hypotensive and bradycardiac response elicited
by PDG- In thi s seri es, as the animals (group III)
were kept on respiratory pump, respiratory activity
was not recorded . After tubocurarine injection, the
RESP
!3P
ECG
ffi'I'/'I'I'IY'fm~jflf('ff{'f('f('ffi'(f
883
POG-induced changes in BP and HR were not altered
from the initial reflex response (Figs 5 and 6).
However, after opening the chest the POG-induced
BP response was lesser in magnitude than the earlier
responses. Intrapericardial injection of lignocaine
blocked the hypotension and bradycardia produced by
POG (Figs 5 and 6). After injection of tubocurarine
the MAP decreased significantly with no changes in
HR (P < 0.05, Table 2). But, after intrapericardial
administration of lignocaine, HR also decreased
significantly (P < 0.05, Table 2).
Discussion
The results of this study, indicate that the FOGinduced reflex responses are mediated through vagal
afferents originating from the cardiac site. Three
different efferent pathways can be demonstrated viz.,
cholinergic system for HR, adrenergic system for BP
and the somatic motor system for respiration .
125 [
BP
75.
EcG
Before
~~~\-\\\~\1\\%\\\\\\\\~\\\\\l\\\\\~\\~~\\\\lt\~\\~\\\~\\\al\\\\\~\\'M\iilt~-III
&namttl\iml«««ffil«ll«Milll~!llllll\Wu~~~~ml!mtllllllliiiii~RBJ
Aller atropine+ prazosin
BP IOO[•
..'dlllll~--·l&lWllll1111iiiUililiUI .......t&!QHQe$Ww MtH;•Wjjlll l
50
~~~(----~~-Jm01~M W1HfHrHttiiiiiHIHIIfttllltllltUI11HII1iiUIIII!Ii!CIIIM:~
t
REsP
rvv-()v-vn ~-vmvvvrnrvrmr
l
Ud"orc
Aller vagotomy
RESP
100[
BP 50 ~~..... """-"V'~"~
DP
ECG
~ ~~(------
.ECG, Gl!lill!ll~l'tllii®tl111:::11Q~It\Jit;tt;~nJtl<iPWJIIt.t«MJ ,A..I;j,t,
r.iimiEm~!11lMirnRII;~®Iifi~\l!I~~~~M~J~rulr~~~~m~~~r~
t
After Vagotomy
,___....,
5s
RES!'
>-----<
5s
Fig. 2-Bil ateral vagotomy abolished th e hypotensive.
bradycardiac and apneic responses elicited by phenyldiguanide
(PDG ; I 0 ~J g/kg). [The original trac in gs from a sin gle experiment
before and after bilateral vagotomy are presented. The arrows
indicate the point of injecti on of PDG. Note the blockade of the
refl ex respon ses after vagotomy. Similar observations were made
in 4 more experiments. ]
Fig. 3-The effect of different an tagonists and bilateral vagotomy
on the phenyldiguanide (PDG)-induced retlex response are
presented. [The original tracin gs of blood pressure (BP in mm
Hg) , electrocardiogram (ECG) and respiration (RESP) from a
single experiment are presented. Arrows indicate th e point of
injection of PDG.]
INDIAN J EXP BIOL, SEPTEMBER 2000
884
The mean maximal changes in HR was taken as a
10
parameter in earlier studies 5' . Probably that is the
reason for the weaker response pattern described for
10
bradycardia5· • Since, the reflex changes were
temporally dispersed, time response area provides the
accurate
representation
of reflex
responses.
Accordingly, the reflex changes were represented in
relation to time either in thi s study or in previous
HR
.
reports 11-16
- . s uc h representatiOn
o f the HR changes
can be comparable with that of hypotensive or
respiratory response (Figs I and 4). Bilateral
vagotomy abolished the hypotens ive, bradycardiac
and apneic responses either in this study or simi lar
10 12
studies elsewhere ' , suggesting the existence of
afferent or efferent pathway in the vagus. The burst of
afferent vagal discharges seen after PDG, supports for
DP too[
Before
50
~
.........
60
.......
..~
...
20
ro
.......
ECG
~
~
'-'
(!)
IUO(
Arter tubocurarine
50. ~---------..
MAP
4-;
0
BP
ECG
100
75
U')
~
0
50
~
RESP
U')
(!)
~
100
c.J
Q
•
50
n
~
"'
0
20
0
Atropine
Prazosin
Vagotom y
40
60
Time (seconds)
Fig. 4-Atropine - blocked bradycardiac respo nse, prazos in
blocked the hypoten sive response and bilateral vagotomy
abolished apnea. [The mean± SE values of mean arterial pressure
(BP), heart rate (HR) and respiration (Resp) as % of initi al
respon se (n=5) at every 5 sec up to 60 sec are presented in th e
boxes].
Afler inlrapericardialli gnocaine
131 '
I
00
50
[.'H
''
· HIHIJillf/1/lillifltIIilln·l/l.f~IUII!i!IIIHIIW!i~lrlilti·~KfhHI/IIHH~I.
!HI~If1<·1HIKifllit~I~IIXKKIK~IHI
ECG m\\\\\\\\\\~\l\ l\l\ l\ \ \~\ l\~\ \ l \ \l \ l\ \ \ \ \ \ \ \\\\\\\m\~\\\\~\\\\\\\\\\\I\\\I\~.\~~~\ \ \~~\I\~II\~III\~1\~\I,IJ~I~~~
i
Fi g. 5-Intrapericardial 111Jection of lignocaine blocked the
by
hypotensive
and
bradycardiac
responses
eli cited
phenyldiguanide (PDG). [Original tracin gs of blood pressure (B P
in mm Hg) and electrocardi ogram (ECG) from a single
experiment are presented . Arrows indicate the point of injection
of PDG (I 0 J.l g/kg) . A minimum of I 0 min was allowed after
tubocurarine (15 iJ.gl kg) or after opening thorax or aft er
lignocaine (0.1 ml f 2%) or saline (0. 1 ml )].
Tab le !-Effect of atropine, prazosin and vagotomy on mean arterial press ure (MAP), heart rate (HR )
and respiratory rate (RR).
[V alues are mean± SE from 5-7 different experiments]
Co ndition
Restin g HR
(beats/min)
Resting MAP
(mm Hg)
Resting RR
(beats/min)
Before
332 ± 4.2
95 ± 7.3
68 ± 8.8
After atropine
356 ± 20.4
92 ± 6 .4
72 ± 6.6
After prazos in
336 ± 13.5
71 ± 6.1 *@
88 ± 4 .4*@
Afte r vagotomy
368 ± I 1.1
71 ± 6.1 *
46 ± 4.2*
The conditions are presented in the o rder of sequence of the injecti ons. A minimum of 30 min elapsed
after the injection of atropine (2 mg/kg; iv) and I 0 min after the injection of prazosin (0.5 mg/kg, iv).
*P < 0.05 as compared to before values (St dent's 1 test for paired observations).
@P < 0.05 as co mpared to after atropine values (Student's 1 test for paired observations).
885
BAGCHI & DESHPANDE: PDG-INDUCED REFLEX ES ORIGINATE FROM HEART IN RATS
Table 2-Effect intrapericardial injection of li gnocaine on
resting heart rate (HR ) and mea n arterial pressure (MAP).
J-IR
[Values are mean± SE from 5 different experiments]
Cond ition
o
•
•
Con tro l
T ub o~.: urarinc
Lignocaine
Before
After tubocurarine (iv)
After salinet
After lignocainet
Resting HR
(beats/min)
27 3 ± 18.00
265 ± 17.25
268 ± 12. 15
214± 11 .73*@
Resti ng MAP
(mm Hg)
9 1 ± 6.29
70± 10.14*
70± 10. 14*
70± 10. 14*
The co nditi ons are presented in th e order sequ ence of injection
an d I 0 min was allowed after th e injectio n of tuboc urari ne
( 15 J..lg/kg) or li gnocai ne (0. 1 ml of 2%) or saline (0. 1 ml).
*P < 0 .05 as compared to before va lues (S tudent's 1 test for
paired observations).
@ P < 0.05 as co mpared to values after tubocurari ne (Student's
1 test for paired observations).
tindicates intrapericardial injec ti on.
9
50
0
40
20
GO
Ti111e (seconds)
Fig. G-Data showing the blockade of hypotensive and
bradycardiac responses produced by PDG are presented. [The
mean± SE va lues of mean arterial pressure (MAP) and hea rt rate
(HR ) were ob tained from 5 different experiments. A minimum of
I 0 min was allowed after tuboc urarine (IS mg/kg) or after
opening thorax or after lignocaine (0. 1 ml of 2%) or saline
(0. 1 ml)).
1 15
the afferents in the vagus' ' but do not exc lude the
efferents in it. Origin of the afferents can be from the
heart or from the pulmonary s ites. Inj ection of PDG
in rats at different s ites like aortic arch and carotid
artery elicited refl ex a lteration s of similar magnitude
in either of the routes of administration making it
12
difficult to locate receptor site conclu sively . Hence,
a better technique is necessary to identify the recepto r
locati ons.
In thi s stud y, an attempt was mad e to isolate th e
location of receptors using cardiac denervation
technique by intrapericardial inj ect ion of local
9 1
anaestheti c as described elsewhere ·' • Intrapericardi al
lignoca ine blocked hypoten sive and bradycardiac
responses e licited by PDG, in artificially ventilated
animals of the present study (Figs 5 and 6) . However,
in cats after intrapericardi a l injection of loca l
anaesthetic did not alter the PDG-induced vaga l
di sc harges suggestin g th e non-in vo lvement of cardiac
11
receptors in cats whil e in rabbits the intraperi cardi al
injection of local anaestheti c aboli shed the
phenylbigu anide (PBG)-induced refl ex response .
These observations indicate that the acti vati on of
cardiac/pulmonary receptors by PDG or PBG varies
with the species of the animals under study.
The afferent vaga l fibres from the cardiopulmonary
receptors terminate in the nuc leus tractu s solitarius
21
(NTS) '22 . These afferent inputs reaching the NTS
have been shown to produce hypotension,
23
bradycardi a and apnea . Second order neurones
project from NTS to the caudal ventro latera l part of
24
the medulla '25 . Efferents fro ll'r these termin ate
around the parasympathetic, sy mpatheti c and
respiratory centres .
The blockade of the bradycardi ac respo nse after
atropine indicates the in vo lvement of efferent
cholinergic (mu scarinic) system in mediating the
bradycardiac component of PDG reflex. It is also to
be noted that after atropine the hypotensive and
ap neic responses still persist (Figs 3 and 4).
Prazosin, when injected in atropi ne treated animals
blocked the hypotensive response of PDG reflex. Thi s
result indicate the in vo lvement of sympatheti cs at a 1
receptors for med iat ing the response. The observed
dec rease in BP after prazosi n (Tab le I ) correspond s
to the blockade of sympathetic rone elsew here 9 .
Earlier studies have show n that stimul at ion of
pulmonary J-receptor produced inhibiti on of spi nal
26
monosy naptic
reflex .
Fu rther,
glyci nergic
interneurons have been impli cated in the inhibition of
27
sp inal monosynapti c reflex pathway . Thus it can be
speculated that the inhibiti on of respirati on e li cited by
PDG may be medi ated by the inhibition of resp iratory
886
INDIAN J EXP BIOL, SEPTEMBER 2000
motoneuron poo l but the tachypn ea needs furth er
exploration.
To conclude, the results of the prese nt study in
rats, show that PDG mediates its action throu gh the
increased afferent vagal activity mostly generated
from heart, as intrapericardial injection of loca l
anaesth es ia blocked the response. Th e efferent
pathways comprise three different neural mechanisms
involving parasy mpathetic, sympathetic and somatic
nervou s system.
Acknowledgement
S . Bagchi is a rec ipient of research fell owship from
UGC , New Delhi , Indi a.
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