Gen Phvsiol B i o p l n s (1096) 1 5 , Vu 369 3 5 7

Changes in Cardiac Contractility in I D D M and N I D D M Diabetic Rats

J B A W \ S ľ I K A I A P O S * S/ Kl LLMEN and 1 K O \ \( S

Depaifment of Physiology Thin tisity Medical School of Debrecen Debiect n Ihinqnii)

A b s t r a c t . Differences m nr\ocíudial contiae tihť\ weie studied in ťspe I (msuhn-depeudent IDDM) and ť<, p e II (non insulin dependent NIDDM) diabetic íats Us­ing the stiepto/otocin-mduced diabetes as an expenmeutal model the contiae tile piopeities of leit \e i i t iuuhu nnoe aidnim of IDDM and MIDDM animals weie com-pai(d to smulai paiameteis of then age-matched (Oiitiols Coutiaction f OK e was a n a h / e d as a function of the pai nig fiequen<\ Paned-puls(> stimulation and cate-< holamiiK t ieatment weie applied to (onipaie the motiopu íesponses obtained in tlu two h pes of diabetes Diabetic and (ontiol piepaiat ions developed cepial peak tension at (a( h d m i u g hecpienc\ upon the application ol paned-pulse stimulation with fixed n i tdpul se m t e n a l T1K> mteipulse mtei\al dependence of paned pulse induced motiop\ was alteied and the \<lociť\ of c ontiac tion and K laxation de-cicased m IDDM but not in M D D M muscles Scnsiti\it\ to lsopioteie nol and noiepmephiim was de < u ase d m both ľ\ pc s oí diabete s howe\ei the isopiote lenol lcsistancc of old diabetic animals was a t t u b u t a b l e to age lathei than to the dia­betic state The íesults indie ate that alteiations m the e ontiactile pa iamete is and e ate (holamine sensiti\it\ in IDDM diffei horn those o b s e n c d m \ I D D M foim ol diabe tes melhtus

K e y w o r d s : Diabetes Stimulated imoc a idmm Rat — Contiactiht\ Ca­techolamine

I n t r o d u c t i o n

Mechanic al d\ shine tion of diabetic m^oeaidmni has been studied e x t e n s n e h din­ing the last decade While the alteieel e aiehae function m IDDM has been chai-

Conesponde nee to T a m a s B a m a s / M D P h D D e p a i t m e n t of Ph\ siolot^ I n n e i -hit\ Medical School ol Debiecen H 1012 Dc bit ren P O Box 22 FIuni2,ai\ Phone (?f>)-52 l i b b i l l a x 0 6 ) r>2-132-289 Ľ-mail T O M <>P1I\ S D O II III

*Pie sent addicss D e p a i t m e n t of 1st I n t e m a l Medicine Um\eis i t\ Medic d School ol D<l)i«ein Debiere n IIun^ai\

358 Banvas/ e t al

acteii/ed m detail oui knowledge is í e l a t n e h pooi íegaidmg these alteiations m NTDDM Decieaseel \tkxiťs of both coutiaction and íclaxation weic o b s e n e d m IDDM b\ sc\eial imestigatois (Rubinstein et al 1981 Mkms c t al 1983 HeUmger et al 1986 Rosen et al 1986 Sehaffei ( t al 1989 Tanaka et al 1992 Downing et al 1993) wheieas otheis íepoited similai changes m NIDDM as well (Srhaffei et al 1985 Sakai et al 1992) Lnalteied \elocit\ of coutiaction with oi without decieased veloc it\ of íelaxation was íepoited in IDDM but not m M D D M (Fem et al 1980 Penpaigkul et al 1980 \ eima and IM c Neil 1991) In IDDM de\eloped \eimiculai piessme was decieased with oi without noinial e aiehac output (Pen paigkul et al 1980 Rubinstein et al 1934 He\lmgci et al 1986 R o s e n e t a l 1986 Schaffei at al 1989 Tanaka et al 1992 \ e i m a and McNeil 1994) wheic as NIDDM pioduced no change m the \entnculai s\stolíc piessme (Fein et al 1980) m spite of the deciease m caichac woik obsened (Sakai et al 1992 Sehaftei and Y\ llson 1993) The heteiogeneous obser\ations might in pait be a lesulr horn the pc lhiseel heait model used in these experiments since diffeient expcimiental conditions (i e filling piessme ionic milieu se\eiiťy of diabetes etc ) might altei caichac function too

In addition, conticneisial íesults ha\e been obtained with lcgaiel to the mag mtude of the de\cloped tension of diabetic lmocaidium m IDDM Piact icalh all potential alterations of ímocaidial foiee pioduetion ha\c be c n íepoited I sing -um tiiculai muscle stiips papillaiv oi t iabeculai muscles of the íat decieased (Fein et al 1981) oi mc leased (Xiang and McNeil 1991a) as well as unaltered (Fem e t al 1980) contiactile foiee has been íepoited Catecholamine induced motiop\ has been studied b\ se\cial authois howe\cr no attempt has been made to c onipaie the absolute \alues of tension m diabetic and health's animals (\n and McNeil 1990 W u n e i et al 1991 V a n g and McNeil 1991b) Similaih no data on absolute \a lms of tension aie a\ailable m NIDDM. íats With lespect to othei eontiactilc paiameteis like time to peak tension oi half íelaxation time icseaicheis again a i m e at unanimous conclusions It is geneialh accepted that the diuation of the coutiaction cui\e is piolonged m diabetic animals compaied to contiols

The piesent studs was peiloimed to chaiac tenze the tension d c u l o p m i nt and its time couise cluiing the contiactile cycle m health's ^nd diabetic animals at \ ai ions states of the disease We desned to obtain infoimation on the foiee fiecmenc*, lelationship and the motiopic íesponse of diabetic iiľsocaidnun To aclnc\e this fne chaiactenstie paiameteis (peak tension time to peak tension maximum \e loei^ of coutiaction half leluxation time and aiea under the c ontiae tion c iu\e) of the contiaeting m\ocaidmiii weie compaied m noinial and diabetic (both IDDM and NIDDM) caidiac piepaiations paced at diffeient chiving íates Inotiopic íe spouses were e\aluated bv applying isopioteienol (ISO) and noiepmephime (NE) Since the effects of both ISO and NE aie known to be complex on woikmg cai­chac tissue we induced motiopu using paned pulse stimulation as well The benefit

Oaidiac C ontiartiht\ m Diabetic Rats 3 5 9

of application of paned-pulse piotocol is that saicolemmal íeeeptoi functions and subsaicoleminal signah/ation aie not involved m the mechanism of this kind of inotiopy Compaiing these phaimaeologically induced (catecholamine) and d n e e t h induced (paned-pulses) inotiopie íesponses the mechanisms i n \ o h e d in diabetic alteiations of caichac foiee generation may be better elucidated

Mater ia l s and M e t h o d s

Induction of ti/jn I (IDDM) duibitcs

Adult, landomly selected Wistai iats of eithei sex weighing 120 150 g, weie in­jected into tail \em with G5 mg/kg Stieptozotocm (STZ), dissolved m c í t ia te buffei Age matched contiol animals weie injected with the vehicle onl\ Hypeig lv emia was confiimed bv blood glucose test using en/smatic teclmicjues F u s t blood glu­cose test was j)eifoimed 48 houis aftei the STZ t ieatment them the tests weie lepeated we akh In animals t ieated with STZ blood glucose lewels mcieased abo\e 10 mmol/1 Exi)eiiments were peifoimed following 4 weeks (28 da-\ s ± 2 days) of the STZ tieatment

Indu<tw7i of typ( II (NIDDM) diabtta

Neonatal animals of hcaltln \\ istai paients we íe siibch\ided into two gioups ían-domh at age \omign than 48 horns \ccoidmg to the method of Schaffei and his colleague's (Schaffei et al 1989 Schaffei and Wilson 1993) one gioup of animals was t ieated with 90 mg/kg STZ i p (e oiitiols iecei\ed the \elurle onh, ) then the [Mips were gľsen back to then mothers Minimis weie used foi expeiiinent at the age of 12 months 1 he diabetic state of the STZ tieated animals was followed b\ blood glucose monitoiing and glucose tolciancc tests Glue ose load (m dose of 1 g/kg boch weight) was peifoimed at the beginning and at the end of the hist houi of the glucose tolerance test (double load test) Blood samples were taken at 0 0 5 1 2 3 and 4 houis aftei the fust glucose load then glucose concentiation was deteimined en/ymatic alh horn the samj^les

The animals were lend on standaid laboiatoiv diet lecciving water and food ad libitum and weie maintained on natuial light and claik cs cle m a constant t e m p e i a t m e envuoument at 24°C

Mrasit7f7ncnt of i oniiartihti/

Tiabee ulai muscles weie e aiefulh, exe íse el fiom the left \entnc k and mounted m a the lmoiegulatc d (32 °C) exjxrimental chamber c ontmuoush peifused with ox\ ge n satuiated T u o d e solution containing (m mmol/1) NaCl 150 KC1 5 MgCli , 1 5 CaCl 2 2 5 H E P E S 5 at pH 7 24 The chamber \olume was leheshed 9 11 times l>ei minute P a n s of paiallel platinum electiodes weie used foi held stimulation

3 6 0 Bam is/ c t <il

(40 m A / i n r ) pacing the muscle eontinuoush at a constant fiecjuencs with 2 ms wide lec tangulai pulses Resting length of the muscle was adjusted so as to develop maximal active tension undei isometiic conditions The e apac iti\e tianscluc ei used m om experiments pioMcled lmeai soltage i espouse m the lange of 0 5 15 niN The analogous electneal signal was digitizer! and a n a h / e d on IBM compatible PC using Sigmaplot and Sigmastat scientific softwaies ( lanele 1 Cnipoial ion San Rafael ( A LSA) The contiactile1 j)aiamcters ^de\eloped peak tension (P) time to peak tension (UP) using \eloeit\ of developed tension (dP/df) half íelaxation t line (HR ľ) and aiea nuclei the c ontiae tion c ui\ e (Int< <JI a I)) we íe c ale ulat c d and stoied ten fuithei anahsis Rising late of the coutiaction cui\e was estimated b\ lmeai fitting to the 25 75'/ lange ol the using phase then it was noimali/ed to the peak tension \ p a i t fiom the (onij)Utei use el foi data anahs i s all equipments weie dc\eloj)ed and manufactuied at oui depaitinent

A t\j)ieal experiment Wris peifoimed as follows \fter mouiiTing the jnepaia-tion m the experimental chambei a 60 nun penod of ccjuilibiation at a constant p<u nig fiecpieuie\ ol 0 5 11/ was allowed to stabilize the contiactile pa iamete i s of the muse h Then the stimulation iiecpie nc \ was set to the desiied\aluc and kept constant foi fuithei 10 mm when the hist ineasiueiiic nt was made Depending on the pacing hequones 10 to 25 conseeutne contiae tions weie lecoidecl and the d a t a w e n stoied M he n ]>ane cl-j)iilse stimulation was a])j)hed 25 to 50 c ontiae tions weie e \oked beioieic e oiding Dining this tunc the motiopic íesjxmse iea< he el its mrixiiiium lc \e 1 and the e ontiae tile paiamc teis stabih/e el In the < xpeiimeuts using c .itec holamine s the dings we le applie d loi 10 mm m nic ic asmg e one c nt iat ions

Ml c he line als weie j)inc haseel horn SIGMA Chemicals (St Louis I S V) Gioups of piepaiat ions weie compaied using AN()\ \ anahs i s Student-New man-Is. e tils test w.is used to determine st at is tie al signihe ane c of the1 e hangc s (Zai 198 1) Changes were1 considered significant when p was less than 0 05 Data aie expiessed as means i S E M \. s u m m a n of the e xpeinneutal gioups and then niteipicta-tions is piosideel in Table 1 Abbie\ lations of gioup name's will be e onsistc n t h used thiougliout the text The entne msestigation confoimed to the guidelines loi

Table 1. Gioups of expe nine ntal animals

(houp name

\oung chabc tie 'loung c ontiol Old diabetic Old contiol

\l,l )i< \ l a t

\ D \Ĺ

OD OC

ion lnteipie tation

4 months old ía t s with S I Z - m d u c e d IDDM Ago-mat (hod contiol gioujj of YD 12 months old ía t s with SPZ-mchuod \ I D D \ 1 \ge-mate lif el contiol gionj) of Ol)

It sliould 1)0 note d that all animals wen adults ulien use d h mis \oung and old it loi to the diflc- ic nt age ol these annuals ( 1 end 12 niont lis m 1 lie c ase ol \oung and old giou]>s lespeef i seh) Foi fuithei details sec the text

C aidiae Contiacti l i ts m Diabetic Rats 3 6 1

the c aie and use of l abo ia ton animals published b\ the US National Institutes of Health as well as to the pimeiples outlined m the Helsinki Declaiation

R e s u l t s

Caichnal ssmptoms of IDDM such as nicicased blood glucose lesel pohphag ia pohchpsia polviuia and loss of weight weie obseivcd m íats of the AD gioup Blood glucose conccntiation was signihcantly elevated in the AD gioup (21 3 ± 1 47 mmol/1 compaimg to the contiol value of 5 2 ± 0 35 miuol/1 in A C p < 0 001) In coiitiast to the A'D animals the modeiate elesation of blood glucose lesel was not significant m the OD gioup Hossesei decieased glucose toleiance following the double1 glucose load ic sealed the piesence of NIDDM m the OD gioup (Fig 1) Fasting blood glucose c oncentiations \sere identical in the OC and OD gioups but follosvmg the glucose loads the elesated blood glucose les'el was piolonged in the OD animals

Also paiameteis of contiaction changed maikedh m IDDM Since the shape of the coutiaction e u i \ e was altered b\ pane d pulse stimulation itself only twitches c soke el In single jMilses \sere examine el this was Coutiaction of the left sentiieulai nrsoi aieliuin was piolonged in the AD gioup compaied to AC The piolongation deseloped as eaily as 2 sseeks aftei the STZ t ieatment and leached its maximum aftc i week 4 (Fig 2) Time to p< ak tension (UP) and half n laxation time (HRT)

\ 12

<D in 6 O o 3 4 o> T, 2 o ° 0 m

0 1 2 3 4 Time [ h o u r ]

F i g u r e 1. Glucose toleiance test in 12 months old \ \ istai ía ts T Old contiol (OC) A old diabetic (OD) The a n o u s maik the tune of the glucose loads (0 and 60 m m ) The me an glucose lesels m the M D D M gioup weie s ignihranth highti rastciisks denote p < 0 05) than the time matching conliol \ allies mias iucd following the second glucose load I ach da ta point ie picscnts mean ± S I M obtained liom 27 animals

(jo'

A ~ II

Normal ized d P / d t [ 1 / m s ]

oo «o O -» M

-< o

a

CT

u

Z3- * -

- -

o

Integral [ m N * m s ]

t tP [ m s ]

c c

-< o o u o

u o

3 o O o

< •

CJ1 O

>

HRT [ m s ]

íllll x ~~ - ~ — •- 0 — ~ i

«- X - CT" — ^ C- • . ^ ~ ~ — ~ t „ ^ "L - ~

lí C- 3 "

,._, , . _̂

o CJi o o *

3ĽB-si 4-o LLJ

SB-

O O

*

cn O

O

o

-< o -< o

o o o o

oo o o o

• -

• -

—

--

N) O

DO

«

j (t — to

to (55 to

Time [ m s ]

OTOooroAcnooo O O O O O O O O

c

p ? '—-~̂ A

• — •

-_; zl

r

m y

, -H-j

- i

-> „

^

t~

• ^

, , ~ _̂ , , i ŕ

" •

Ľ. ^

~

~ -> tv_

_•*

^ zr „

í-

,— "

—

"— =

~ Z-t

•—' , n ; ~ ~

< O "

-< O

-< O --ŕ-

-< o • Ol

-< o oo

:*) -o

- r ^

O a i d i a e ( ' o u t iac tifit v ill D i a b o l i c R a t s 3 6 3

— 6

c O

"(ň c (U

TJ « Q. O

V > «

IDDM

í PAIRED

SINGLE

0.0 0.2 0.4 0.6 0.8 1.0 1.2

Pocing frequency [ H z ]

r-, 8 z E T 6 o <n c v 4

J3 w Q.

> « o o

NIDDM

PAIRED

SINGLE

0.0 0.2 0.4 0.6 0.8 1.0

Pocing frequency [Hz] 1.2

F i g u r e 4 . I o u e-In qui ne s n kit l o n s h i p ol t i i l x i u l a i m u s í le s o k l a m e d len l l ) l ) \ l t Íl a n d \ I D D \ 1 [U] p u p n a t i o n s ( oni iae t u r n s wile i \okee l li\ single (eipen s \ m b o l s ) a n d p a i u il-pulsi s t i m u l , u ion (Id led s \ i n b o l s ) S\ m b o l s a m i b a u . l e p u ^ s e n t nie a n i S k \J \ ilue s o b t a i m e l b o m ') ld pi e p a l al ions L n o i b a i s smal l t i t h a n tlie s\ in l )o l M/e not s h o w n S i p i a u s \ o u n g e out lol ( ^ ( ' ) d i a i i ľ m d s \ o u n g d i a b o l le (S D ) i i p w a u l t n a u g l e s o l d c o n t i o l ( ( ) ( ' ) ( l o u n w a u l t u a n g l e s old d i a l x lie ( O D )

sscre> piolonged in all IDDM annuals (Fig i A, B) Changes m these paiamete is were ahsass paiallol the1 lat io of UP and IIRT was not filtered In AD annuals the selocits of tension development decieased (Fig ](') sshereas the aiea nuclei the euis'e mcicvised siginhcanth (p < 0 0") compaied to the A'C OC oi OD gioups(Fig 3D) In e ontiast to IDDAI. XIDDM caused no significant changes in the contiactile paiameteis All the contiae tile paiametei studied ssTere identical in

364 Bansas/ e t al

^ 2 5 r Q. O

~ 2.0 c

s 1 - 5

1.0

0.5

t ̂ítfcte!

•-•-•-•'

100 200 300 I n t e r p u l s e i n t e r v a l [ m s ]

4 0 0

F i g u i e 5. Inte i\al-de pe nik nre ol t he pal K d-pulse mcluc e d mot i opíc n spouse m i at t la­be ( ulai musrle s nie asuií d at a c onstant pai mg In qui ne s oi 0 "> 11/ ľe ak ti nsion \alues obtained with paned-pulse s weu noímall/od to lliose í K o u l e d with single pulse s pnoi to tlie i p p l u a t i o n ol tlie ]iaiu d-pulsc |>iotocol Saníc s\ nibols as m big ! Lae h point u pu se nts nie an ± S L \I obtaim d fioni 0 16 pi e p,nations

tlie OC and OD gioups (Fíg 3 4 - D) All the paiameteis selected to elesc libe the c ontiae lion pioc ess we le ide ntie al m the A C OC and OD gioups Clc.uls the duiation of the1 contiactile piocess was identical m AC OC and OD but it ssas me leased in the1 AD gioup

The c ontiae tile foiee of lat tiabec ulai muscle dec n aseel w itli the me ic asmg of the stimulation fiecpiencs between 0 1 and 1 H/ m all gioups examined (ncgatise foie c-hequeiie s lolationslnp Fig 4) Continucms stimulation ssith paned-pulses u suited in positise niotiopie lesponses in each gioup nidepe ndeiith of the pacing hequenes oi diabetic state Sinnldih} the magnitude of the des eloped foi c e ssas not signihcantls diffeient in the contiol and diabetic animals Nesertheless the slope of the foice-hequencs lelationship was gieatcr in old animals (OC and O D ) t h a n m the voung ones (AC and AD)

Fig 5 shosss the1 lesults obtained at a e onstant pacing hequeiits of 0 J 11/ using paned-pulsc piotocol with inter pulse inters als langing betsveen 100 and 330 ms Since the lengths and the diameters of the tiabeculai muscles sailed withm a wide lange the contiactile foiee esoked bs paned-pulses was dnieled bs the contiactile foiee obtained ssith single stimuli m older to dec uvise nidisidual flue tuations In the A'D gioup both the1 mtei sal-dependence and the degiee of motiopv weie diffeient fiom the íe speetne paiameters nieasuie d in the othei gioups The application of paned-pulses with a 100 ms niteiptilse mtersal induced significant motiops m the A'C , but not m the A D gioup In soung diabetic animals (A D), a minimum interval of 200 ms ssas íecpined to mciease c ontiae tihts bossesei the degiee1 of this motiops,

( auliae C onliae tilits in Diabetic Ra t s 3 6 5

1 1

z E

o V-

O C

0 6

0 4

0 2

0 0

- 0 2

- 0 4

- 0 6

0 1 1 Isoprotereno l [ n m o l / l ]

10

1 5

1 0 •

>> 0 5 Q. O

0 0

- 0 5 L

B

t h =

0 0 1 0 1 1 10 Norepinephr ine [ / umo l / l ]

1 0 0

F i g u r e 6. < unmlatne dose -íesponse euises o b t a m t d with isopiotc íenol ( 1) and noie piutplnini (B) m d i abd i c ía ts I he magni tude of the motiopie lesponse is gisen at the oidinate as the difleionce between the pie-diug and post-chug sallies Ssmbols has t smi-dai meanings as m Fig I

lernained beross the lespcctise contiol level (AC) While the motiopie lespouse in

A C msoc aichuni íeae hed its nia\iiimin between 200 and 300 ms, motiops' in the A D

annuals c ontinuousls, mc leased up to 100 ms Animals of the old gioups (OC and

OD) chsplased consideiable1 sninlaiits m then motiopu lesponses obtained with

pane d pulse piotocol Then were no diffeienc c s m the1 magnitude of the motiopie

lesponse and the mtcrsal depe nelcnce between the msoc aidium of old contiol (OC)

and old diabetic (OD) animals

Sumniaii /mg these íesults one might c oncluch that age and NIDDM has e little

366 Ransasz (t al

efh c t on c ontiac tilils m íat t iabceulai muscle ssheieas the coutiaction pioeess is altered maikedh m IDDM Using paned-pulses to indue e1 motiops the niters al-dependenee was altered onh m IDDM but not m NIDDM In contiol animals the age had no effect on the contiae tile1 piopeities including the motiopie lesponse

Cone inflat ion dependent effects of isopiote íenol (ISO) and non pine plume (NE) on the e ontiart i le foiee sseie also examined to studs the motiopie K spouses obtained bs, stimulation of alpha and beta achcrieigie leceptois in contiol and diabetic animals (Fig GAB) ISO indue ed positise motiopie lesponse m soung (AC and AD) but negatise motiops m old annuals (OC and OD) independent of then diabetic state1 In coiitiast to ISO NE me leased the contiae tihts m contiol (AC and OC ) but not in diabetic animals (OC and OD) This positise motiopie lesponse hemes c i was sigmfic antls smallei (p < 0 05) in the OC than m the AC gioup Again old contiol animals sseie less sensitise to catecholamine's than the soung one-s since the di>giee of the c atec holamme-indiic c d positise motiops ssas smaller in the OC gioup

D i s c u s s i o n

Oui einii ssas to obtain mfoimation on the contiactile piopeities of msoc aidiuin

m healths and diabetic íats It ssas found that mechanical alterations of íaf nrso-

eaiclmm in fDDM and NIDDM aie ehaiae teristie alls different

When expiessed m absolute sallies the aseiage dcweloped fences (induced ei­

ther bs single oi paned-pulse stimulation) were identical in the healths and diabetic

animals as ssell as the1 negatise foie e-fieciuencs lelationslnp chaiac teristie to íat

sentiic ulai msoc<udnim Thus oui data aie m aeeoidance ssith the1 data íepoited

bs Fern et al (1980) and also with those of Lopasehuk and Russel (1991) authois

l ipoi t ing no alterations m caidiac c ontiac tihts m IDDM and MDDAI diabetes

K spec t is e Is Howes oi oui data appeal to conflict ssith the ic suits of Schaffei and

Wilson (199 3) who íepoited decieased caichac peifoiinaiic e m NIDDM d ins e on-

tiaehction might be lesolsed with the nitiochie tion of altered msocaichal < omph­

alic c into the model of the ssoikmg heait NIDDM heait is knossn to has e de e ic ased

ioiii])liance (Schaffei et al 1985) lesulting m dee leased diastolu filling soluine at

,i paitieulai pieload Reduced e nd-ehastolii soluine ssith unaltered ss stolíc p u s

sine w ill ncccssaiils lead to de c leased caichac ssoik associated with a shift m the

pic ssuie-e aichac ssoik lelationslnp

While the niagnitude of the des eloped tension ssas sninlai m IDDAI and

NIDDM piepaiat ions the1 t.nne ionise of coutiaction ssas altered exclusisels in

IDDM piepaiat ions sninlai to íesults i(>poited fiom other laboiatoue s (Rubinstern

et al 1964 Atkmse ta l 1985 He s huge i et al 19SG Rosen c t al 19SG Schaf t e i i t a l

1989 Tanaka et al 1992 Downing et al 1993) This dee ie ase el se loc its of c ontiae -

tion and íelaxation mas affect the inters al-dependence of the paned-pulse induced

Oaidiac Contiaetihts m Diabetic Rats 367

motiops These lesults also indicate that the cellulai nice hainsms ins oh eel in the deselopment of changes aie basicalls different in IDDM and NIDDM Schaffei et al (1985) íepoited i educed msocaidial contiaetihts and íelaxation in NIDDM ob-seisations cpute diffeient horn oui lesults Although this disciepancs might be due to the use of different biological piepaiations. it has to be emphasized that oui íe-sults obtained in IDDM tiabeculai muscles, aie in aecoidance svith the piesioush published data obtained m isolated ssoikmg heait (Fern et al 1980, Rubinstein et al 1984 Atkins et al 1985 Heslinger et al 198G, Rosen et al 1986 Schaffei at al 1989. Tanaka et al 1992)

In the piesent íepoit , catecholamines sseie shown to act iinecpiallv on IDDM and NIDDM iirs'ocaidiuin Although the motiopie i espouse ss-as i educed m both ts pes of diabetes old contiol animals (OC) also displased i educed sensitisits to ISO oi NE compaied ssith soung c oiitiols (A'C) Decieased ISO sensitisits svas íepoited eaihei in IDDAI (Atkms et al 1985), however, no sninlai data aie1 avail­able foi NIDDM piepaiations The deceased catecholamine inotiopv mav be due to crthei defectise subsaie oleinnial signali7ation oi mipaned fence pioduction of the myofilament al ss stern Diabetes-induced biochcrnic.il changes m the1 contiactile pioterns sseie1 íepoited m eaihei studies Inc leased haction of \ ' { ms'osin lsoen-zs me is knossn to be piesent m both foims of diabetes as ssell as in non diabetic aged msoc aidnini(Schaible et al 1983 Rubinstein et al 1984 Schaffei et al 19S5 Lev/aid et al 198G Tahiliani and Ale Neil 198G) Howescr oui data obtained ssith paned-pulse piotocol suggest that diabetic msoc aichuni is able to des clop con tieie tile foie e equal to the e ontiae tion of he afths muse le (see Fig i\,B) Thus it appeals that the de c leased e atec holamiiie sensitis its obscrsed m diabetes mas be due to ehangecl íeceptoi function oi signali/ation lathe i than to alterations of the contiae tile pioterns

The inter pietation ol the e one entiation-depeiiderit effects of ISO and NE is epntc1 difficult since the lesults mas be distoited bs sescral tinie-depeiidc nt esenls sue h as leeeptoi deseiisiti/ation oi exhaustion of the1 muse les Sninlai difficulties anse1 sshen Using to explain the dee lease d catecholamine sensitisits obseised in both foi ms of diabetes The ISO íesistaiue found in IDDAI is consistent ssith the lesults of Sundaiosan et al (1984) ssho íepoited decieased beta leeeptoi binding capaeits in IDDM íats No smnlai findings hase1 been published foi NIDDM Oui data suggest that i educed beta leeeptoi de nsits mas be anticipated m lion msulni-dependerit diabetes mellitus as ssell The ISO lesistance found m the OD gioup ssas also piesent m the age matched e oiitiols (gioup OC) Tins sninlaiits betsseen OC and OD annuals eleaih shows that decieased ISO sensitisits found m N1DDAÍ is mol e likels a lesult of aging than fioni the stiepto/otoc m t ieatment itself This hspothesis is suppoited bs the lesults of Guaiinoii at al (1980) ssho found that the c ontiae tile1 lesponse to catecholamines m the1 msoc aidiiim of senescent íats is diminished sshen eonipaiocl to soung adults ()m lesults also niche ate lhal changes

368 Bans as/ c t al

in beta leeeptoi function aie different in the insulin-dependent and non liisulin-(lependent foi m s of diabetes niellitus bosses cr this diffe u nee mas at least m pait be a t t u b u t e d to aging

Age- 01 diabetes-dependent i eduction m the densits of alpha ice eptois has e not been obscrsed pies lousls There sseie onh modeiate diffe lcmces obscrsed bets-seen the NE sensitisits of soung and old c oiitiols (A'C and OC) ssheieas both diabetic gioups (AD and OD) displased excessise NE lesistancc Iheiefoie the decieased lesponsiseness to NE m both ts pes of diabetes must be a t t u b u t e d to tin effect of diabetes niellitus induced bs S I Z t ieatment

Sunmiaii/ing oui conclusions it can be suggested that both age1 and diabetes mas eontnbute to the alpha and beta leeeptoi disfunction obscrsed in NÍDDAÍ Hossesei dec leased be ta ic ceptoi ac tis its is a lesult of piedoniinantls aging ssheie­as alpha leeeptoi disfunction is a lesult of e lneffs the diabetic strite

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He s huge i O h R o d i i g u e s B M c N e i l I H (lOeSG) 1 He e t ol c h o l i n e a n d m e t h i o n i n e t u a t n i f i i t o n c a u l i a e d s s l u n r t i o n oi d i a b e t i c í a t s D i a b e t e s 3 5 . 1152 1157

I o p a s i h u k (e I) R u s s e l I ( (1001) M s o e a i d i a l d i l u t i o n a n d ( l n i g s s u b s t i i t e n u -t a b o l i s m m the i n s u l i n u s i s t a n t K R L \ c o i p u l e n t l a t I W ' ľ ' P l i s s i o l 7 1 , I M)> 1 «kS

P o n p a i g k u l S Schaib lc i \ i p i i i t s o i I S i h e u e i 1 (1080) 1 he e f h e t of d i a b e t e s o n p c i f o i m a n c e a n d m i t a b o l i s n i ol l a t l u a i t s C u t Re s 4 7 , '111 021

R o s e n P W i n e h c k P Z m i n i i i II (, I u n / c l II B m i i g Is I Re m a i n i II (10<S(>) M s o c a i d i a l p e i l o i n i a n c e a n d me l a b o h s n i m non-kc tot le d i a b e t i c l a t lie a i t s m s o ­e a i d i a l f u n c t i o n i n d m e t a b o l i s m in two a n d m the i s o l a t e d p e i l u s e d IK n t nucle i the l i i l luenee ol i n s u l i n a n d o e l a n o a t e Basic R e s C a u l i o l 8 1 . d 2 0 bi"i

Caicliai Cont iae t iht s m Diabetic R a t s 3 6 9

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Sakai \1 D a n / m g t i R S Xiao R P Spmgeon H A L a k a t t a E G (1092) ( ontiacti le lesponse ol mdis uliial c aichac msoc vte s to noiepmephi ine dechnes with senescence \mei 7 Phssiol 262,11184-11189

Schaible T F Malhot ia A B a u m a n W A Scheuer I (1983) Left s e n t n c u l a i function aftei < hi oui c insulin t i e a t m e n t m diabetic and noimal rats I Mol Cell Cardiol 1 5 , 111 158

Sehallei S \\ Wilson O L (1993) Insulin losistance and mechanical disfunction m hea i t s ol W istai íats wit 11 s tu ptozotocin-induced non-msulm-depe ndent diabetes niellitus Diabetológia 3 6 , 105 100

Schaffei S Vs Boen H 1 Wilson G L (1985) Development of card iomsopaths m a model of uonmsulm-dependent diabetes Vmei I Phssiol 2 4 8 , H I 7 9 HI 85

Schaffei S W Mo/afFan M S \ i t m a n \I W ílson G L (1080) Basis foi msoeaidia l me­chanic al defects associated ssith non-insulm dependent diabetes Vmer I Phssiol 2 5 6 , L25 I 30

S u n d i i c s m P R S i m u l a ' s Is G m g o l e l S I B a n e i i e e S P (19S4) Decieased i adíciu i 0 ic ie (_< plois in íat he lit m s t iepto/otoom induced diabe tes lole of ths loid hoiinoiics Tiidoi nnologs 1 1 4 , 1358 1363

l a h i l i a n i A G M c N e i l l H (198b) Diabetc s-induced aunounal i t ios m t h e msoc u d i u m life Sci V 3 8 050 971

Ianaka 5 Isashnsagi V Sacki Y Shigeta \ (1002) \bnoimal i t ies m (aichac Oi idle nore ptoi and its signal 1i insduction m stiepto7otoem-induc( d diabetic í a t s Vine i J Phssiol 2 6 3 , 1425 I 129

M i m a S McNeil J 11 (1901) M( ttoi nun impioscs c nebac function m isol ited s t iep lo /otoi in diabetic ia1 heai t s S u m I Phssiol 2 6 6 , H711 - I I 7 1 0

W a i n t i I J G dasso I I h o m p s o n ( I Bclloni F I (1001) \ a s o d i l a t i s e and anti-aclu in lgic (f[o( 1s of adenosm m diabe tu l a t h i a i t s Can I Phssiol 70, H 19

Xian r t II McNeil I II (JOOli) o ( Velienex e ptoi ine dialed pliosphomosit ide bie ikdoss n núl motiopie lesponse s m di the lie he u t s Vine i 1 Phssiol 2 6 0 , 11557 H562

Xi tug II Me Neil I II (1001b) Inline nee of aiaclndonie acid metabolite s on cauha i in adienoe eptoi lesponses m dialx tie ía t s ( a n 1 Phssiol P h a i m a c o l 7 0 , 6 8 0 686

Au Z Mc Wil 1 II (1000) Vlte ic d motiopie re spouses m diabetic ca id iomsopalhs and hspe i tens i se ih ibet ic eaul ionisopaths I P h a i m a c o l F x p I h e i 2 5 7 , 6 4 71

Zai I II (1081) Biostat ist iral Vnalvsis Pient ice Hall Ine Englessood Cliffs Ness d i s c s

Tmal seision accept eel O d o b e i 5 1906