Becker, K.

Brodde, O.-E.

Jakubetz, J.

Konschak, U.

Poller, U.

Radke, J.

Zerkowski, H.-R.

Elsevier - Publisher Connector 

Age-dependent decrease in human cardiac β-adrenergic and muscarinic receptor function: in vitro and in vivo study 

JACC Februar), 1908 ABSTRA("I,'S - ()rat 177A 
9:00 
~l-Ad~neqll¢ ~tlmulltlon Induc~s C~l~-y~ 
~ptol~Whlch I .  Not Mediated by an Increase In 
Y, Shlxukuda, E,H, ~ lne f~:k ,  D,L G~ln ,  A,C, Bor~uk, R,N, Kitst~, 
IXOg~ heart fail~= To e~ ! ~  ~.ha~,  we~kedwhefher 
~me ~ w~m a~lated  ~ emoptotlc myo~t  ~,  ;o~, 
MMho¢l~ FOU~ 9f~p~ of mls 1f~I~1 fo~ 34 hm were ¢om~m¢l; 
(C); I~m~mol (11o) of eitt~ 40 H~kgav or 400 .tVk0,1v ia ~et  
I1dnipufflp; fflechank~a! p~-mg (500 blpfll). Fogowing ~f~a~t .  h~fl~ weld 
~v4lv4t~ usm9 TUNEL ~ on 5 ,m se¢IX~s f~m the n,Xl.v~nlfi¢!e 
wall. 
C Ito 4OO !~ 4O pacm~ 
HR (~(~n) 424 t t6 ~t? ~ :~!' 497 t 6" 509 • 6" 
Apo (per area) O3 t 0-3 ?O ¢25' 0.I~ = 05 1.7 * 0.? 
Apo (pe~r cel~) 004 t 0.04 t~z039 '  0.13 ~ 006 023±008 
ot ,at~ 5 4 6 5 
(Data mmean ±5EM. SBP,, s~1o~ b~oo~pm~.=re. I~ra~e~ i~, cm~ pe~ ce~; per 
HR w~ increased by Iso 400. fso 40, and pacing. SOP was sm~lar 
amongst ~ four gro~os. Apo was incmese~ by ~o 400, bat not amy the omer 
treatments. 
~ - ~ .  Thus, 24 hams of continuous p~adreme~  m- 
d~ces sig~fica~ caRf~,~e apol~m aml ~ elfect ~s not medlat~ so~ty 
by an increase in HR 
9:15  
- ~  Aitecations Myocard ia l /$ -A~or  Subtypes in 
and Signal Transduetlon PaUnvay In Nerve Grewth 
Factor O~mmpressleg ~qra,mgenic Mk:e 
E. Do~g, A. Brood, HJ. Federoff, C.-S. LJang. Umvers~ at RocP~ster 
Medk::al Center, ~ P.~, USA 
Backgmur~" We have established a trensgen~c mouse model in which selec- 
tive overexpnsssa~n of nenm growth factor (NGF) results in cardiose!eclzve 
sympamet¢ t~pemmervatmn and cardiac hypertrophy. 
Methods: To detemne whether the cardmse~ sympathetic hyper- 
innen~ation alters the norepmeph~e (NE) uptake function and myocardial 
6-adrenecePfor (~AR)-cou~ adenylyl cyctase sagnat ransduction system. 
we measured ca~:kac NE uptake site densdy (fmo~mg) by 3H-nmoxebns bind- 
ing, total pAR and Fh/'~ subtype denny (fred;ring) by ' :m I-iodocyanopimkdol 
radio]igand assay, dissociatio~ constant (Kz, nM) of Ihe pAR for i so~,  
and maximum increase in cyclic AMP (cAMP, pmoMm~min) produced by Lso- 
protomnot in 4 week-old control and ~n ic  mice. 
Resu/ts: 
NE-uptake fAR P2 K~ cAMP 
Control 186 ~. 55 35 t 5 12 ~: 2 0 17 ± 005 4.6 ~: 0.8 
NGF 1~06 ± 221" 55±5" 28z3" 039±0.07" 16±0.2" 
Values are means ± SE "p < 0.05. vs. Control. N = 11. 
Conclusion: Carchoseleclive sympathetic hyperinr~n~alion in the trans. 
gsnic meuse causes an increase in NE-uptake sites, an increase in/'~zAR 
density, and no change in t~AR density. The adenylyl cyclase response 
to isoproterenol, however, is reduced, probably because of the marked un- 
coupling of pAR to G-protein. The findings show that increased cardiac NE 
causes ,~AR subsensitivity without receptor downregulation. 
9:30 
~ Age-dependent in Human Cardiac Decrease 
/3-Adrenergic and Muscadnic Receptor Function: In 
Vitro and in Vivo Study 
O.-E. Brodde, K. Becker, J. Jakubetz, U. Konschak, U. Poller, J. Radke, 
H.-R. Zerkowski. University of Halle-Wittenberg, Halle, Germany 
In ageing cardiac p-adrenergic receptor (AR) function declines while little is 
known on muscadnic M~-R changes. To study possible mechanisms of p-AR 
and M2-R changes with age we assessed a) in vitro in nght atria (RA) from 
91 patients of different age (5 d-83 yrs) without apparept head failure/~-AR 
and M~-R densities. 10 I~M GTP. 100 ;~M isopren~tine (ISO). 10 mM NaF 
and 10 mM Mn "° -activated and c.adoacho; (CAR 10 nM--t00 .M).~l~tule¢l 
adenylyt ¢yctase (AC) activity and b) in ~vo in 6 your, g (.30 y~) ~ 6 
elder (60 yrs) ~mlunt~m I$O-mfu~on (3,5-35 n g / k ~ ~  mc~se 
and I~r~zel~n~ (PIR 032 and 0,64 .g  i v bokm),cause~ decrease m henri 
ra~ (HR). 
FAeWu~: I) p.AR: In vtffo/f-AR ¢kmiHy ~d .eu l~ ~ (:N not 
¢h~gQ WI~!o GTP, ISO, NaF #n¢l Mno-.ectlwd~l AC doOM,rod wW~ ~i~ In 
v~o I~D.mttmto~ (~ok~ IqR,tecmaMs we~ e~t ¢Mkm~ tx~-emtm y~!  
HR4n¢~I  wt~f~ rMfklc~f (mhencld m yo~g but not ie eld~ vt~uetel~, 
PIR4educed decfeale in ISO,e~oked HR.~¢fease m ! ~  
The P.AR ~ Is due to ~ ~ a¢ttvtly ~_f A ~  u~1; tho I~.R 
decma~ i~ ¢ltm Io a reduced R-demaly, The t le¢~ m Ma,R dee~ ~ e¢, 
cornpanled t~y a blunled neg~We ~ re~x~e to k~ ,R ~Im~lat~n 
m v~o. wfule the de~ea~e in/~-AR lunct~m ~an be demonatm~ m v~o o~ly 
when the countem~u~to~/ac~o~ f p a ~  ~ m mmove~. 
9:45  
~ Eehocardlographic end Xistol~ho!ogic=t 
Ctuv~-tevl=,~m of Young a~l Old TnmsSmsk: U~e 
JO. Po~ HD. ~ ,  J,O, ~ ,  O.A. KnucBioe. TJ. Be~k~er, 
A Pende,~R.Bns~ow. UrmmmyotCo~m~ Oemer" CO. USA 
~ "  The ~qt -ad~ mCetl~r (pl-AR) tS cenlml to mgulallon of 
m ~  confxacl~My, fo1he fang  heafl. #~e tI1.AR ts chmnca~ over-stlm. 
,~ed e~e to h~jh ~ of nore~neph,ne. Themfum. we w~d 
to exantit~ the effect of ~-~iifutnm/~I-AR o~er-u~q~r~ in m ~  
Mefhods: The human tl I-AR ras ovemR~med in Iransgenic (TG) race, 
in a cardiac-specific comext, u=;,=,g an .-myosm It~W ctmin promOtor Re- 
caper exprnsso~ ,a,-,,;,~ betwee~ I and ~.5 pmoUmg membrano proem. 
Car~t~c ~ ( ~ )  and h=fapa~o~ (l"r~'vome and 
H&E) were examined at 4-5 mo~t~s (young (yng~), an~ 6-20 moff~s of 
age (o~). 
Resu~: Old TG n.ca had s~n~can~y ~ ~ vehicular cham~r 
s~zes in both systo~ (LVlDS) and diastole (LVIDD) and a s~gn~canlty reduced 
f rac t~ shode~ng (FS) compared to young and o;d con~l and m youn9 
TG race. 
CON-~ TG-~] CON~old TG.,oIO 
FS|%) 58 : 1 59~ 1 60±2 30¢4" 
LVtOS tram) I $ ¢ dO2 I 3 ~ 0 1 I 3 : 003 32 t 04" 
LVIDD tram) 3.5 ~ 0.03 32 • 0.1 3.4 ± 0.2 45 ¢ 0.3' 
('p < 005 I~y ANOVA) 
Hiato~oathoingic~ly, both young and old TG race had sut~anttat my- 
ocardial remodeling with myoojte hypertrophy end large areas of interstitial 
replacement fibrosis. 
C ~  Consltlutwe cardiac-~recfad over -e~=~t  of t~e/¢I-AR 
in TG mice appears to produce a bme-depcmdent remodeling fesuttmg in 
venfdcufar dilatation and eventual cardiac failure. The pl-AR tTa,-,=~3~-,-~ 
mouse should be a highly useful model of adrenergicatly mediated dilated 
Coronary Blood Flow and Endothelial 
Dysfunction 
Tuesday, March 31, 1998, 8:30 a.m.-10:00 a.m. 
Georgia World Congress Center, Room 254W 
8:30 
~ Effect of the Menstrual Cycle on 
Endothelium-dependent Vasod|lation ol tt le Brachlal 
Artery 
J. English, G. Green, LO. Jacobs, T.C, Andrews, W/fiord Haft Medical 
Center, Lack/and AFB. TX: The Universi~ of Texas Souff'm,'esfem Med~t 
Center. Dallas. TX, USA 
Background: Estrogen alone or in co~:ert with progesterone therapy has 
beneficial effects on enduthelium-dependent vasodgatton i postmenopausat 
women and such improvement inendothelial function may explain the reduc- 
tion in cardiovascular events associated with hormone replacement th~r'~Loy. 


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Age-dependent decrease in human cardiac β-adrenergic and muscarinic receptor function: in vitro and in vivo study

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