160 B ain Resea ch, 525 (1990) 160-164 Else ie
BRES 24225
Di e en ial s imulus coupling o dopamine and no epineph ine s o es in
abbi ca o id body ype I cells
A. Gomez-Ni io, B. Dinge , C. Gonzalez and S.J. Fidone
Depa men o Physiology, Uni e si y o U ah School o Medicine, Sal Lake Ci y, UT 84108 (U.S.A.)
(Accep ed 1 May 1990)
Key wo ds: A e ial chemo ecep o ; Hypoxia; Nico inic ecep o ; Chemo ansmission; T ansmi e elease; Ca echolamine
Recen s udies sugges ha p eneu al ype I (glomus) cells in he a e ial chemo ecep o issue o he ca o id body ac as p ima y ansduce
elemen s which espond o na u al s imuli (low 02, pH o inc eased CO2) by eleasing chemical ansmi e agen s capable o exci ing he closely
apposed a e en ne e e minals. These ype I cells con ain mul iple pu a i e ansmi e s, bu he iden i y o he na u al exci a o y agen s
emains
an un esol ed p oblem in ca o id body physiology. Cha ac e iza ion o pu a i e ansmi e in ol emen in he esponse o na u al
and pha macological s imuli has he e o e become undamen al o u he unde s anding o chemo ansmission in his o gan. The p esen s udy
demons a es ha a na u al s imulus (hypoxia) e okes he elease o dopamine (DA) and no epineph ine (NE) in app oxima e p opo ion o
hei unequal s o es in abbi ca o id body (DA elease/NE elease = 8.2). In con as , nico ine (100/~M), a cholino nime ic agen hough
o ac on he nico inic ecep o s p esen on he ype I cells, e okes he p e e en ial elease o NE (DA elease/NE elease = 0.17). These
indings sugges ha dis inc mechanisms a e in ol ed in a di e en ial mobiliza ion o hese wo ca eeholamines om he abbi ca o id body.
The chemosenso y issue o he mammalian ca o id
body consis s o mo phologically dis inc ype I (glomus)
cells which lie in synap ic associa ion wi h a e en ne e
e minals o he ca o id sinus ne e (CSN), a b anch o
he glossopha yngeal (IX h) c anial ne e. A undamen-
al issue in ca o id body physiology conce ns he ole
played by ype I cells in chemo ansduc ion and chemo-
ansmission o na u al and pha macological s imuli (low
pO2, pH o ele a ed pCO2; and choline gic, pep ide gic
and ca echolamine gic agen s) 1~. Wi h espec o chemo-
ansduc ion, p e ious s udies ha e demons a ed ha
ype I cells espond o na u al s imuli in i o and in i o
in he absence o inne a ion 1°, hus implying ha hese
cells may be good candida es o he ole o chemosen-
so y ansduce in he ca o id body. Mo eo e , ecen
epo s ha e shown ha ype I cells possess a unique
O2-sensi i e po assium conduc ance, which is dec eased
by hypoxic s imuli wi hin he physiological ange 2~. Wi h
espec o chemo ansmission be ween ype I cells and
senso y ne e e minals, a majo p oblem emains how
he mul iple pu a i e neu o ansmi e s ound in ype I
cells (including biogenic amines and neu oac i e pep-
ides) a e able o in e ac in he ini ia ion and modula ion
o he chemosenso y discha ge o he CSN.
The pu a i e ansmi e s p esen in highes concen-
a ions in he ca o id body a e he ca echolamines
dopamine (DA) and no epineph ine (NE). While he
p ecise ole o DA emains unce ain, i is clea om
p e ious s udies wi h he abbi ca o id body ha he
syn hesis and elease o DA by ype I cells is inc eased
by na u al s imuli 1°'11, and ha dopamine gic (Dz)
ecep o s a e p esen on CSN a e en s 5'24. In con as ,
i ually no hing is known ega ding he egula ion o NE
me abolism in he o gan, and al hough i s syn he ic
enzyme (dopamine l-hyd oxylase; DBH) is known o be
p esen in ype I cells 2'27, a emp s o demons a e
NE/DBH sensi i i y o chemo ecep o s imuli ha e un il
e y ecen ly me wi h li le
success 14'15'26.
Likewise,
while he esul s o pha macological expe imen s sugges
ha ce ain chemo ecep o esponses by he ca o id body
may be media ed by l-ad ene gic ecep o s a2, a mecha-
nism coupling speci ic s imuli o NE u no e and
u iliza ion has ye o be demons a ed.
In he p esen s udy, we ha e examined he elease o
[3H]DA and [3H]NE (syn hesized om [3H] y osine)
e oked by wo classical chemoexci a o y agen s H (low 0 2
and nico ine) om abbi ca o id bodies supe used in
i o. While he da a indica e ha he elease o bo h
ca echolamines is inc eased by hese s imuli, i is clea
ha hypoxia e okes he elease o [3H]DA in p opo ion
o i s la ge con en in he issue, whe eas nico ine
p oduces a nea ly selec i e elease o [3H]NE. The esul s
he e o e sugges ha unc ionally dis inc mechanisms
egula e he u no e o endogenous DA and NE in he
Co espondence: S.J. Fidone, Depa men o Physiology, Uni e si y o U ah School o Medicine, 410 Chipe a Way, Resea ch Pa k, Sal Lake
Ci y, UT 84108, U.S.A.
0006-8993/90/$03.50 © 1990 Else ie Science Publishe s B.V. (Biomedical Di ision)
ca o id body. P elimina y epo s o hese indings ha e
appea ed elsewhe e 14'15.
Rabbi ca o id bodies we e i s ch onically sympa-
hec omized o elimina e he sympa he ic (NE-con-
aining) ne e e minals om he ca o id body. Unde
pen oba bi al anes hesia (35 mg/kg), supe io ce ical
sympa he ic ganglia we e bila e ally excised om adul
New Zealand whi e abbi s 10-14 days p io o expe i-
men a ion, a which ime he animals we e e-anes he-
ized and hei ca o id bodies su gically emo ed and
cleaned o adjoining connec i e issue in a ba h o
ice-cold modi ied Ty ode's solu ion (in mM: NaCI 112,
KCI 4.7, CaCI 2 2.2, MgCI 2 1.1, sodium glu ama e 42,
HEPES bu e 5, glucose 5.6, pH = 7.42) equilib a ed
wi h 100% 0 2 . The issues we e pooled and incuba ed o
2 h, as p e iously desc ibed 9, in media con aining
[3H] y osine (20-40 Ci/mmol; 20-25 / M; Ame sham)
plus asco bic acid (100/~M) and y osine hyd oxylase
co ac o (6-MPH4; 50/~M). Following incuba ion, ca o id
bodies we e sepa a ed in o g oups o 2-4 and washed o
90 min ( esh media e e y 30 min) in s anda d scin illa-
ion ials con aining modi ied Ty ode's solu ion equili-
b a ed wi h 100% 0 2. Ca echolamine (CA) elease was
de e mined u ilizing adiolabeling echniques in conjunc-
ion wi h HPLC sepa a ion o DA om NE, and was
assessed du ing s imulus cycles which each consis ed o
sequen ial con ol (100% O2-media ), s imulus (low 0 2-
o nico ine-con aining media) and pos -s imulus (100%
O2-media ) pe iods. Simila esul s o hose epo ed he e
we e ob ained when a bica bona e-CO 2 (95% 02/5%
CO2, pH = 7.42) bu e was used in place o he
HEPES-O 2 (100%
0 2 o
10%
02/90% N2)
bu e ; i.e.,
elease p o iles we e quali a i ely he same, and quan i-
a i ely wi hin 10% o each o he . Supe usa es we e
collec ed in ials con aining asco bic acid (10 mM), plus
ace ic acid (4 M), and s o ed o e nigh (4 °C). [3H]DA,
[3H]DOPAC and [3H]NE we e elu ed om alumina
columns (see e . 10) wi h 1 N pe chlo ic acid, and he
labeled p oduc s combined wi h unlabeled NE, DA and
DOPAC p io o HPLC sepa a ion on a C-18 e e se
phase column (Rainin) in phospha e-bu e ed mobile
phase. Sample aliquo s spiked wi h 3,4-dihyd oxyman-
delic acid (DOMA) and 3-me hoxy-4-hyd oxy-phenylgly-
col (MHPG) we e ch oma og aphed sepa a ely o quan-
i y hese NE me aboli es. CA was de ec ed elec ochem-
ically wi h an ESA Coulochem (Model 5100A; 5021
condi ioning cell; 5011 analy ical cell) in he educ i e
mode. Peaks o in e es we e collec ed au oma ically wi h
a Gilson Model 202 ac ion collec o o subsequen
coun ing in a Packa d Model 1500 scin illa ion spec om-
e e .
The da a p esen ed in Fig. 1 ( op) show o al [3H]CA
elease om an expe imen in which ca o id bodies we e
161
exposed o wo s imulus cycles; he i s cycle con ained
media equilib a ed wi h 10% 02, he second cycle
con ained 100% 02 equilib a ed media along wi h 100
/ M nico ine, which in p elimina y dose- esponse expe i-
men s had p o en o e oke an in e media e amoun o
[3H]CA elease. Be ween s imulus cycles he issue was
washed o 30 min wi h wo changes o 100% 02-
equilib ium media. We consis en ly obse ed a di e en
ime cou se o CA elease o low 0 2 s nico ine
s imula ion. CA elease e oked by low 0 2 pe sis ed in o
he i s pos -s imulus pe iod, whe eas nico ine-e oked
elease ended ab up ly a e he 5 min s imulus pe iod.
Re e sal o he s imulus o de esul ed in simila ela i e
pa e ns o CA elease by low 0 2 and nico ine. The
A
e*
0
a.
_e
9
20-
10-
0
////
~
Q
Hypoxia
I~
Nico ine
Time~
'0
0
m
m
0
m
9
I--
Hypoxia Nico ine
Collec ion Pe iods
(10 min. each )
I
Time
Fig. 1. Basal and s imulus-e oked [3H]ca echolamine ([3H]CA)
elease om 4 sympa hec omized abbi ca o id bodies supe used
in i o. The supe usion media we e eplaced a 10 min in e als,
excep du ing s imula ion (low 02 o nico ine) which las ed 5 min;
o compa ison pu poses, elease du ing hese pe iods was mul i-
plied by 2. Basal elease was e alua ed immedia ely p io o
s imula ion in media equilib a ed wi h 100% O 2. The ca o id bodies
we e s imula ed wi h media equilib a ed wi h 10% 02 o wi h media
equilib a ed wi h 100% 02 and con aining 100/~M nico ine, and
elease was e alua ed h ough 3 pos -s imulus pe iods. Be ween
s imulus cycles he issue was washed o 2 x 15 min in 100% 02
media. Uppe panel: o al
[3H]CA
eleased; lowe panel: p o ile o
3H-NE (open ba s), 3H-DOPAC
(c oss-ha ched ba s) and [3H]DA
( illed ba s) elease de e mined by HPLC and scin illa ion analysis.
162
easons o his di e ence in ime cou se o elease is no
known, bu ecep o desensi iza ion by nico ine 2°'22 mus
be conside ed a possible explana ion o u u e expe i-
men s add essing his issue. The ecep o speci ici y o
he nico ine e ec was es ablished in con ol expe imen s
which showed ha mecamylamide (100 ~M), hexame-
honium (100 k M) and (+)- ubocu a ine (50 ~M) blocked
mo e han 95% o he nico ine-e oked elease o
[3HICA.
Fig. 1 (bo om) shows he ela i e p opo ions o DA
and NE eleased du ing he wo s imulus cycles desc ibed
abo e. The con en o [3H]NE, [aH]DA and [SH]-
DOPAC a e exp essed as a pe cen o he o al [3H]CA
([3H]NE + [3H]DA + [3H]DOPAC) eleased in each
sample. In mos ins ances he NE me aboli es DOMA
and MHPG amoun ed o only 4-5% o he eleased
[3H]CA, and hey ne e exceeded 11% o he o al
[3H]CA elease ei he unde es ing condi ions o in
esponse o hypoxia o nico ine. I is appa en om he
da a ha he ela i e p opo ions o [3H]DA and [3H]NE
elease a e di e en o he low 0 2 s he nico ine
s imulus. Exposu e o low OE-media p ima ily e oked
elease o [3H]DA, while [3H]NE domina ed he p o ile
o nico ine-e oked elease. These di e ing pa e ns o
elease a e unlikely due o non-speci ic e ec s o he
s imuli, because exposu e o ca o id bodies o high K +
(75 aM) p oduced a elease p o ile which closely e lec s
he ela i e [3H]DA/[3H]NE con en in he o gan (no
shown).
Da a om mul iple elease expe imen s u ilizing low
0 2 and nico ine as sec e ogogues a e p esen ed in Table
I. [3H]CA elease in con ol (100% OE) supe usion
media du ing he 10 min pe iod immedia ely p io o
s imula ion consis ed o 16.9% [SH]NE and 83.1%
[3H]DA + [3H]DOPAC. Release du ing supe usion
wi h 10% OE-media was comp ised o 98.1% [aH]DA +
[3H]DOPAC. Al hough only a small po ion o he
e oked elease was due o [3H]NE, i s concen a ion in
he supe usion media was none heless app oxima ely
doubled by he hypoxic s imulus. Howe e , i mus be
conside ed ha he scin illa ion da a alone may no
accu a ely e lec he ela i e amoun s o NE and DA
eleased in hese expe imen s, because he speci ic
ac i i y o hese wo CA (and hei me aboli es) in he
issue may be di e en . Indeed, he speci ic ac i i y o
DA in he issue a e he expe imen was usually 2-5
imes g ea e han ha o NE, due o he slowe
u no e and syn hesis o NE by he ca o id body 9.
Con e sion o he ac ional adiolabelled con en e-
leased o he physiologically ele an pa ame e o
absolu e amoun eleased, equi es an es ima e o he
speci ic ac i i ies o he eleased [3H]NE and [3H]DA.
Expe imen s in ou labo a o y add essed his poin o
he elease o DA/[3H]DA e oked by hypoxia and
ele a ed K + (60 aM; e . 3). The esul s showed ha he
speci ic ac i i y o eleased [3H]DA (plus [3H]DOPAC)
was e y simila o ha o he [3H]DA emaining in he
issue. Thus, i appea s ha du ing he 90 min wash
pe iod be o e collec ion o samples, he newly syn he-
sized [3H]DA equilib a es wi h he endogenous unlabeled
DA pool in ou expe imen s. These esul s a e in
ag eemen wi h o he s udies desc ibing he inco po a-
ion o newly syn hesized NE in o he endogenous CA
pool in sympa he ic ne e e minals in he spleen 13'18.
Consequen ly, we used he speci ic ac i i y da a o
DA/[3H]DA and NE/[3H]NE con en om s imula ed
ca o id bodies in o de o calcula e he o al s imulus-
e oked elease o NE and DA, and hese esul s a e
p esen ed in Table II. The da a show ha con e sion
om dpm eleased/mg issue, o absolu e amoun e-
leased (pmoi/mg issue) con i ms he p edominance o
DA elease by hypoxia and ac ually exagge a es he
p edominance o NE elease by nico ine. The absolu e
amoun s o NE and DA eleased in esponse o hypoxia
we e app oxima ely in p opo ion o he ela i e con en
o hese wo CA in he issue, whe eas in esponse o
nico ine he nea ly 5- old p e e ence o NE elease
e lec s a ma kedly disp opo iona e mobiliza ion o NE
s DA s o es in hese sympa hec omized ca o id bodies.
The da a addi ionally show ha basal elease consis ed o
TABLE I
Release o adiolabeled CA om sympa hec omized abbi ca o id bodies measu ed in media equilib a ed wi h 100% 02 (con ol), 10% 02 o 100%
02-media con aining lO01~m nico ine
Values a e means + S.E.M. wi h numbe s o samples in b acke s.
dpm/mg issue
[3H]NE
% o o al CA
[3 I]DOPA C + [3H]DA [3HINE [3H]DOPAC + [3H]DA
Con ol(basal) 242 + 37 (16) 1193 _+ 191" (16)
10% 0 2 538 +- 77* (11) 28138 -+ 7946* (11)
100/~M nico ine 4223 + 78* (6) 2747 _+ 410" (6)
*P < 0.001 s basal elease.
16.9% - 2.6% 83.1% + 13.3%
1.9% -+- 0.3% 98.1% --- 27.7%
60.1% + 1.1% 39.9% -+ 5.9%
163
TABLE II
Absolu e amoun s o CA eleased (pmol/mg issue) calcula ed om measu emen s o he speci ic ac i i y o DA/[3H]DA and NE/[3H]NE in
s imula ed ca o id bodies
Values a e means + S.E.M. wi h numbe s o samples in b acke s.
pmol/mg issue % o o al CA
NE DOPAC + [3H]DA NE DOPAC + DA
Con ol (basal) 0.227 + 0.03 (16) 0.224 + 0.04 (16) 50.3% + 6.7% 49.7% + 8.9%
10% 02 0.833 + 0.16" (11) 6.851 + 1.936" (11) 10.8% + 2.1% 89.2% + 25.2%
100/~M 3.143 + 0.49* (6) 0.544 + 0.09* (6) 85.2% + 13.3% 14.8% + 2.4%
*P ~< 0.001 s basal elease.
app oxima ely equal po ions o DA and NE.
Ou indings demons a e ha nico ine and hypoxia
di e en ially mobilize NE s DA om ca o id body CA
s o es. Howe e , he e is no comple e selec i i y by
hese s imuli, because hypoxia consis en ly e oked he
elease o small amoun s o [3H]NE, while [3H]DA was
eleased a ela i ely low le els in esponse o nico ine
(see Table I). In his ega d, i may be impo an o
conside ha elease-p omo ing e en s migh be occu -
ing seconda y o he ini ial s imulus-induced elease; o
example, he ac i a ion o l-ad ene gic ecep o s in he
ca o id body has been epo ed o e oke DA ou low 25,
and consequen ly a possible sequence o e en s migh
in ol e i s a selec i e nico ine-induced elease o NE,
ollowed by l- ecep o ac i a ion and he subsequen
elease o DA. In addi ion, p elimina y expe imen s
which examined he e ec s o combined s imula ion wi h
nico ine and hypoxia showed ha he o al [3H]CA
elease was la ge han he sum o he elease e oked by
each condi ion, sugges ing in e es ing in e ac i e e ec s
o hese s imuli.
The obse a ion ha hypoxia and nico ine e oke he
elease o DA and NE om he ca o id body in dis inc ly
di e en p opo ions sugges s ha hese s imuli ac i a e
di e se mechanisms o mobilizing hese wo CA om
he ype I cells o his chemosenso y o gan. Al hough i
has been conjec u ed ha sepa a e dopamine gic and
no ad ene gic cells may exis in he ca o id body 1,
2,4,16,17.23, ecen immunocy ochemical s udies ha e
shown ha i ually all ype I cells con ain bo h y osine
hyd oxylase (TH), he a e limi ing enzyme o CA
syn hesis, and dopamine- l-hyd oxylase (D lH), he syn-
he ic enzyme o NE p oduc ion 2'27. While hese s udies
sugges a ubiqui ous dis ibu ion o DA and NE amongs
ype I cells, he le els o immunocy ochemical eac ion
p oduc o D lH epo ed in hese s udies indica e ha
some cells may con ain much mo e NE han o he s. This
possibili y, coupled wi h he obse a ion by Chen and
Ya es I ha speci ic a-bunga o oxin binding si es in he
ca o id body a e es ic ed o a subg oup o ype I cells
(dis inguished on he basis o dense-co e esicle size;
e s. 16, 23), sugges s he possibili y ha he obse ed
p e e en ial elease o NE o e DA migh a ise om he
selec i e dis ibu ion o nico inic ecep o s on cells which
con ain ela i ely high le els o NE. Al e na i ely, ype
I cells in he ca o id body may ep esen a homogeneous
popula ion wi h espec o hei con en o DA and NE
and hei sensi i i y o nico ine. Di e en p opo ions o
CA elease would hen be achie ed h ough he selec i e
mobiliza ion o dense-co ed esicles con aining ei he
mos ly DA o NE. The a ailable da a a e equi ocal wi h
espec o he cellula mechanisms in ol ed in he
obse ed di e en ial elease o CA, and al hough ecen
immunocy ochemical s udies o TH and D lH ha e
p o ided use ul in o ma ion in his ega d, i mus also be
ecognized ha he demons a ed p esence o a ans-
mi e 's syn he ic enzymes do no necessa ily signal he
p esence o he ansmi e 19.
Finally, he in ol emen o nico inic ecep o s in he
esponse o ype I cells o chemo ecep o s imuli (na u al
and pha macological) sugges s a ole o ACh in chemo-
sensa ion. Mo e han 20 yea s ago, Eyzagui e and
Zapa a s demons a ed ha anoxia o elec ical s imula-
ion o he ca o id body e oked he elease o an
ACh-like subs ance om he o gan. Ea ly neu ochemical
and au o adiog aphic s udies placed ACh in he ype I
cells 1~, and his p ospec was i mly es ablished by ecen
immunocy ochemical s udies localizing o hese cells he
syn he ic enzyme o ACh, choline ace yl ans e ase
(CHAT) 28. Ligand binding s udies using a-bunga o oxin
and quinuclidinylbenzyla e (QNB) ha e u he demon-
s a ed ha choline gic ecep o s a e loca ed on ype I
cells 6'7. The cu en demons a ion ha nico inic ecep-
o s e oke he p e e en ial elease o NE om he ca o id
body emphasizes he need o u he expe imen a ion
ega ding he physiological oles played by ACh and NE
in he ca o id body.
Suppo ed by USPHS G an s NS12636 and NS07938, and
DGICYT PB86-0325 (Spain).
164
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