effects of persantin (ra8), a new coronary vasodilator, on...

Effects of Persantin (RA8), A New CoronaryVasodilator, on Coronary Blood Flow and

Cardiac Dynamics in the Dog

By James W. West, Ph.D., Samuel Belief, M.D., Ugo C. Manzoli, M.D.,and Otto F. Miiller, M.D.

• In 1951, Fischer and Roch1 made avail-able an entirely new class of compounds whichwere basically a double-ring structure con-sisting of two condensed pyrimidine rings.Immediately following the introduction ofthis group of compounds, numerous deriva-tives from this pyrimido-(5, 4-d)-pyrimidineseries were synthesized, and certain ones weredemonstrated to possess interesting proper-ties worthy of clinical evaluation. One ofthese compounds, Persantin (RA8) (fig. 1),was shown by Kadatz2 to have significanteffects on coronary blood flow. Since thistime, much interest has been stimulated byvarious investigators in evaluating the abilityof this compound to improve coronary bloodflow.

In experiments performed on normal dogs,Persantin increased the coronary blood flowas much as 123 per cent as determined by thebubble flowmeter,2 90 per cent with the Ther-mostromuhr of Rein,3 and 35 per cent withthe nitrous-oxide method of Kety andSchmidt.4 Bretschneider et al.,5 using theStromuhr catheter of Kanzow, reported flowincreases up to 400 per cent with a 200 percent increase persisting for 10 minutes and100 per cent increases for several hours. Inthese experiments, papaverine was only halfas effective and its duration of action onlyone-fifth that of Persantin. Theophylline wasfound to be the least effective agent; the

From the Division of Cardiology, PhiladelphiaGeneral Hospital, and the Department of Pharma-cology, University of Pennsylvania Medical School,Philadelphia, Pennsylvania.

This work was supported by a grant from the To-bacco Industry Research Fund, the Eli Lilly Com-pany, Indianapolis, Indiana, the Life Insurance Medi-cal Research Fund, and the American Heart Associa-tion.

Eeceived for publication July 17, 1961.

Circulation Research, Volume X, January 196S

coronary blood flow increased by only 25 percent within one minute. The oxygen satura-tion in the coronary sinus blood increased onan average of 65 per cent during the effectsof Persantin. A fall in mean arterial bloodpressure was not observed when coronary op-timal doses of Persantin (0.2 mg./Kg., in-travenously) were administered. Higherdoses5 were required to affect the peripheralcirculation and produce a fall in blood pres-sure.

Various studies have also shown that Per-santin does not change right atrial pressuresand that myocardial oxygen consumption re-mains constant.5

Persantin apparently has a specific meta-bolic action on the heart; it increases the ATPconcentration of the myocardium which isespecially pronounced in the presence of hy-poxia. Lactic acid oxidation is slightly in-creased.3

The above findings seemed importantenough to justify further experimental in-vestigations with this drug. Our investiga-tion consisted of a study of the effects ofPersantin on the coronary blood flow in nor-mal dogs and in a smaller group of dogs withcoronary insufficiency produced by variousmethods described below. The latter seriescomprises dogs with chronic insufficiencycaused by narrowed main branches of the leftcoronary artery (three dogs) and myocardialinfarction produced bj' ligation of the an-terior descending branch of the left coronaryartery (four dogs).

MethodsAdult mongrel dogs, weighing' 20 to 30 Kg.,

were lightly anesthetized by intramuscular injec-tion of morphine (3 mg./Kg.), followed by intra-venous injection of a combination of equal parts

,of pentobarbitnl-sodium veterinary solution (60mg./ml.) and Dinl-urethane solution (100 and

35

by guest on May 19, 2018

http://circres.ahajournals.org/D

ownloaded from

http://circres.ahajournals.org/

36 WEST, BELLET, MANZOLI, MILLER

HO -H,CHiC

HO-HiC-H,C N

CH.CH.OH

CH.-CH.-OH

FIGURE 1

Structural formula of Persantin (BAS) 2, 6-Bis-(diuethanolamino)-4, 8 dipiperidhw-pyrimide (5,!-d) pyrimidine.

400 mg./ml., respectively), the dosage being 0.25ml. of the mixture per kilogram.0

The dogs with myocardial impairment werestudied during various stages of the developmentof their altered physiological state. These con-sisted of two groups of dogs: (1) those at vari-ous periods following ligation of the anteriordescending branch of the left coronary arterywhich corresponded with the acute, subacute, andhealed stages of myocardial infarction; (2) thosewith varying degrees of coronary arteiy narrow-ing produced by placing' casein rings around thecircumflex and/or anterior descending branch ofthe left coronary artery. The casein swells andwithin a period of two to three weeks the lumenis considerably narrowed and in some instancesalmost entirely obliterated."

Systemic blood pressure was recorded fromthe femoral artery, using a Statham transducermanometer and a. direct-writing Stillborn polyvisorecorder. The electrocardiogram was continu-ously monitored on the same recorder, using apreeordial lead (V3) and limb lead (III). Coro-nary blood flow was determined as outflow fromthe coronary sinus and quantitative measurementswere obtained by timing a measured blood volume.This was also recorded on the Sanborn polyvisorecorder by the use of a Shipley-Wilson rotameter.A femoral vein was utilized for returning theblood to the circulation by means of a Dale-Schuster or Sigmamotor pump. Catheterizationof the coronary sinus was accomplished in theintact animal with a special coronary sinus cathe-ter (modified Morawitz cannula) inserted via theexternal jugular vein under fluoroscopic guidance.The catheter was provided with multiple open-ings at the tip and an inflatable balloon for secur-ing it in the coronary sinus.s Catheterization ofthe main left branches of the coronary arteries(anterior descending and left circumflex) was alsoaccomplished under fluoroscopic guidance.9 Themain pulmonary artery was catheterized to ob-tain mixed venous blood for the estimation of

cardiac output by the direct Fick method. Arte-rial blood samples were collected through afemoral artery catheter. Coronary sinus venousblood samples were collected by means of a smallpolyethylene catheter inserted in the main coro-nary sinus catheter. Mannronate (10 mg./Kg)was used as an anticoagulant. The trachea wasintubated for collection of the expired air by aTissot spirometer. Expired air samples werecollected from the Tissot spirometer into a to-nometer for analysis of oxygen mid carbon di-oxide by the technique of Scholander. Oxygenuptake was calculated for periods of 5 minutesby multiplying the pulmonary ventilation (fromthe spirometer feeding, reduced to standard con-ditions) by the difference between the oxygen con-tents of inspired and expired air. Analyses ofthe blood samples for oxygen and carbon di-oxide were made by the manometric .method ofVan Slyke and Neill.10

The standard experimental procedure beganwith control measurements of coronary blood flowuntil blood flow was stabilized; this was followedby a three-minute period for the estimation of thecardiac output. Persantin was then administeredintravenously or intra-arterially (coronary artery),and measurements were again obtained.

In other preparations, myocardial contractilitywas measured by means of a, Walton strain gaugesutured directly to the exposed surface of theventricle (left) in the area supplied by the coro-nary artery (left anterior descending) into whichinjections of Persantin were made. The ampli-tude of the strain-gauge record is proportionalto the force of contraction.11'12 The myocardio-gra.ni was recorded on a multichannel, Sanbornpolyviso recorder.

The chest was intact in all experiments, exceptthose involving the Walton myocardiograph. Inthe latter experiments, the trachea was cannu-lated and the lungs were inflated by the use of aStarling Ideal Pump.CALCULATIONS

The following were calculated from the ob-tained data.: coronary blood flow; cardiac oxygenconsumption (coronary flow and coronary arterio-venous oxygen difference); cardiac output (ml./min.); cardiac work (Kg./min.) from mean bloodpressure and cardiac output; total peripheralresistance (T.P.R.) (absolute units) accordingto Poisseuille's law by the formula T.P.R. = meanarterial pressure (mm. Hg) X 1332 -r- cardiacoutput/second; coronary vascular resistance ex-pressed as mean arterial blood pressure -H coro-nary flow; coronary oxygen content (volumes percent); and myocardial efficiency estimated fromthe energy equivalent of the observed cardiacoxygen consumption, the actual cardiac work, andthe approximate mean weight of the left ventricle.

Circulation Research, Volume X, January 1962



ownloaded from


NEW CORONARY VASODILATOR 37

Following each experiment, the animal was sac-rificed, the entire heart was weighed, and the leftventricle was then excised and weighed sepa-rately.13

ResultsNORMAL DOGS

Since Persantin is not a water-soluble coin-pound but; is supplied for injection in a spe-cial vehicle, we embarked upon the investi-gation of this drug by first determining theeffect of the solvent alone on the various cir-culatory parameters. The solvent consists of4.0 rag. of tartaric acid (NPX), 100 nig. ofpolyethylene glycol 600 (highest purity), and2 ml. of distilled water. Following this, wdetermined the maximal effective dose rangeof the drug (drug + solvent preparation).Each dog received at different times Per-santin in solvent preparation, drug, solvent,and saline. In this way a comparison wasmade of the drug preparation (in solvent)with the drug solvent alone and with salinealone. The intravenous dosage range of thedrug preparation was evaluated from 1.0Hg./Kg. to 1.0 mg./Kg. Equivalent volumesof the drug solvent and saline were com-pared in each case. It was found that theoptimal dose range of the drug prepara-tion was between 200 and 500 /xg./Kg. Ingeneral, the optimal dose was approximately200 jug./Kg. (intravenously). However, atthis dose of the drug the equivalent solventalone produced essentially no effect. There-fore, one can attribute the effects producedon the coronary blood flow primarily to thedrug itself. In general, doses of the dingunder 50.0 /ig./Kg. were ineffective.

Intracoronary doses of the drug (1.0 to200 /xg./Kg.) were also evaluated. It wasfound that 1.0 to 2.0 /j.g./Kg. were effective inproducing a definite increase in coronaryblood flow and coronary venous oxygen satu-ration without producing changes in the sys-temic circulation, while equivalent volumesof solvent produced essentially no effect onthese determinants. However, higher dosesabove 100 /xg./Kg. at times produced cardiacarrhythmias which made it difficult to evalu-ate the change in coronary blood flow.

In the following data, the optimal intra-

Circulation Research, Volume X. January 196S

Control

FIGURE 2

Effects of intravenous injection of Persantin.These consisted of a marked sustained increase incoronary blood flo-w (C.B.F.), a slight decreasein mean arterial blood pressure (M.A.B.P.), anda slight increase in heart rate (Jl.li.). This graphrepresents the effects obtained in a single experi-ment. The variation of effects in 14 normal dogsis noted in table 2.

venous dose employed was 200 /xg./Kg., al-though intracorouary injections of 2.0, 25,and 100 /^g./Kg. were given. At this intra-venous dose range, Persantin produced amarked sustained effect on the coronary cir-culation lasting at least 20 to 30 minutes, withthe peak effect being reached within 3 min-utes. By intraeoronary injection, the effectof the drug was only momentary, lasting lessthan 5 minutes unless the infused dose wassimilar to that which was effective by the in-travenous route.Coronary Blood Flow

Table 1, (column .1) shows the averagevalues of coronary blood flow obtained beforeand after Persantiu in the series of 14 normaldogs. Following intravenous injection ofPersantin (200 /xg./Kg.), coronary blood flowincreased on an average of 159 per cent overthe control value. A graphic representationof the typical responses of this drug on coro-nary blood flow is illustrated in figures 2and 3.



ownloaded from


TAB

LE

1

Effe

ct

of

Per

sant

in

in N

orm

als

and

Dog

s w

ith

Cor

onar

y In

suffi

cien

cy

(Mea

n V

alue

s)oo

Cor

onar

y in

suff

icie

ncy

Con

trol

80 9.

574.

2624

89 12

0

15

4

4251

1.60

12.1

278

.419

.9

Nor

ms

Per-

sant

in

20

7 9.21

3.61

2587 10

2

14

3

3199 or

.\r5.

2335

.719

.3

ll do

gs Cha

nge

Incr

ease

159 4

in p

er c

ent

Dec

reas

e

4

15 15 7

25

04 57

55 7

A.

Dog

s w

ith r

ings

B.

Dog

s w

ith H

gatio

n

Con

trol

Per

-sa

ntin

Cha

nge

in p

er c

ent

Incr

ease

D

ecre

ase

Con

trol 4 626.

514.

0925

09 12

5

16

0

4232

2.02

10.5

775

.725

.6

Per

-sa

ntin

16

4 7.17

4.20

2931 11

0

15

3

3144

0.69

4.55

33.2

23.9

Cha

nge

inIn

crea

se

16

5 10 4 17

per

cent

Dec

reas

e

12 4 26 66 57 567*

To

tal

num

ber

of d

ogs

14C

oron

ary

bloo

d

flow

(m

l./m

in.)

Car

diac

O» c

onsu

mpt

ion

(m

l./m

in.)

Car

dia

c w

ork

(Kg

.-M

./m

in.)

Car

dia

c o

utp

ut

(ml.

/mii

i.)

M.A

.B.P

. (m

m.

Hg

)C

ardi

ac

rate

(b

eats

/min

.)T

.P.R

. (A

.U.)

Cor

onar

y

resi

stan

ce

(P-F

)C

oron

ary

(A-V

) 0=

(vol.

%

)C

oron

ary

O2 u

tili

zati

on

(%

)C

ardi

ac e

ffic

ienc

y

(%)

3 51 6.27

3.07

2036 112

157

44422.24

12.43

72.9

24.2

75 8.85

2.92

2237 96 168

3447 1.

2410.34

60.5

21.1

51 41 1014 21 45 17 17 12

*

*Xot

de

term

ined

in

a

.suf

fici

ent

num

ber

to

lie c

onsi

dere

d si

gnif

ican

t.

jS-

ra o § ̂ S3

racr

-2.

ra'•<

—

P

Cr

a^

ra

ratr

p ra

tf

C

°o

...

a

B §

tr

H.

V.

H8 s

-2

>-i

5 P

3 C

fi

93

ra

^

g ra

<•«

—

'

P

ra

Xra

ra

«

-i—

F—

ra

ra

ra

39

0 9

5

c-

t-

CO

CO

ra

ra

,+i

OJ

O

02

93 w 9=

i B

£.

ra

6 g

„.K

B

r! 2.

e

5?

ra

a •

no

B

a

T

O

QJ

"

s s-

C

— o

a 2 £L

en

rt-

J.̂

o

o

— r

arr

t »-

; ra

—

X<

o

§ 3o

r

o

o?

9-

~ •

*

sr

ora

s

l^

CO

ra -.

o

O x «< <o o

15

»

5

^ n

™ •

°

• ra

- |

^ §

§

I- J

a. "

-

g »

^ B

-o

cr

=

i-

i p

jO

J —

M

- o

Sra

£

• ^t

, «J

ra

rv

ora

^

" -i

Cij

~.

ra

ra'

ra

i-!

c-

s:

™ 2

' %

I'

X-'

a?

&,S

rara

J^

33

.^

Ij

ra

33"

o

^ X

; ra

.

ra

«

„.

=r

••

Ms

15

x

7

„.

ram s

»B

ra

_

•

"̂:

r̂ "̂

ra

f ^ i ̂

jij.

""

^

93'

? !l

? .?

2

ora

ra

o

2ra ra ra

0?

o

i en

O

cr r

ora

P

J

O

.O

ra

O g

ra

93

93 to ra

<i

o

tr.

a?

5

©o

2^

a co

S'

^

5^

si

»" =

~:

o

'f i

*§*

s, a

s^

o

o

^

?i ~" 1

=•

'•&

~.

=

-.

">

-a

5-

& 5

-a

S

foh-

I

s s.

r u

fi

CO

[

<?

3 W CO H M W t M > N O f (H I

by guest on May 19, 2018http://circres.ahajournals.org/Downloaded from


NEW CORONARY VASODILATOR 39

2 0 0 -

150 —

100 —

50 —

PER Sfl NT IN100 irMe,. ICB

* . - . « W.AB.fiC»M.HS)_ . . ._ H.R.(BEBTS/MIN.)

3 flRT.OZCONT.• COR. SINUS OZ

KVMW/SWMi vW-V«.i

-I—I—I—T-ConVrol. 10

FIGURE 4

Effects of Persantin injected into the anteriordescending branch of the left coronary artery.Note the instantaneous increase in coronary bloodflow in the presence of a full in blood pressureand a rise in heart rate. A simultaneous rise incoronary sinus venous oxygen content was alsoobserved.

Myocardial ContractilityIntravenous administration of Persantin in

three dogs, employing four to six injectionsof the drug and a comparable number ofsolvent administrations in each dog, producedno effect on myocardial contractility (figs. 5and 6). , To evaluate better the local actionof the drug on the heart's force of contrac-tion, intracoronary arterial injections werealso employed in these same three dogs. Ap-proximately 10 to 15 injections (drug and sol-vent alone) were made in each of the dogs,following which there was either a slight de-crease or no change in contractility. Todemonstrate that the site of injection and theWalton strain gauge were not at fault, acomparison was made with local injectionsinto the same site with a known cardiac stimu-lant (epinephrine) and a depressant (sodiumpentobarbital). The characteristic responsesof the drug are illustrated in figures 7 and 8.Related Circulatory Dynamics

Intravenous injection of Persantin pro-duced minimal increases in myocardial oxy-gen consumption and the cardiac output,while at the same time they slightly decreased

- ~7.

FIGURE 5

Effects of intravenous injection of Persantin onmyocardial contractility. The records (from top tobottom) show electrocardiographic leads V^ and II,myogram (strain gauge attached to the anteriorsurface of the left ventricle), and femoral arterialblood pressure. There was essentially no changein the height of contraction and only a slight de-crease in the mean arterial blood pressure.

FIGURE 6

Effects of intravenous injection of Persantin(greater than the maximal effective dose) on myo-cardial contractility. The records (from top tobottom) shoio electrocardiographic lead II, myo-gram (strain gauge attached to anterior surfaceof left ventricle), and, femoral arterial blood pres-sure. Height of contraction was essentially un-changed while blood pressure showed a mild sus-tained decrease.

the cardiac work, mean arterial blood pres-sure, heart rate, and cardiac efficiency (table1). Total peripheral resistance was moder-ately decreased, while coronary oxygen utili-zation was decreased markedly. Of all ofthese parameters, the heart rate was the mostvariable; however, the overall average re-sponse was a slight decrease in rate.

To test the significance of these results, thet-test was utilized. In table 2, the signifi-cant changes were an increase in coronaryblood flow and decreases in mean arterial

Circulation Research, Volume X, January 1962



ownloaded from


40 WEST, BELLET, MANZOLI, MttLLER

•um [1*1A/VW

t I

FIGURE 7

Comparative effects of intracoronary arterial injections of epinephrine and Persantinon myocardial contractility. The tracings from top to bottom show electrocardiographsleads Fj and II, myogram (strain gauge attached to anterior surface of left ventriclewithin the distribution of the left anterior descending coronary artery), and femoralarterial blood pressure. Note the marked increase in the height of contraction accom-panied by a rise essentially in systolic, blood pressure and a transient asi/stole followingepinephrine injection, while Persantin produced essentially no effect.

0*6 "H MftMT MIT n v n O W CM <

4t M X E M O I N CCM A

FIGURE 8

Compwrative effects of intracoronary arterial injections of sodium pentobarbilal andI'ersantin (greater than the equivalent maximal effective intravenous dose) on myo-cardial contractility. Records from top to bottom shoiv electrocardiographic lead II, myo-!/rum (strain gauge attached to anterior surface of left ventricle within the distributionof the left anterior descending coronary artery), and, femoral arterial blood pressure.There was an immediate marked sustained decrease in the height of contraction alongwith a slight fall in blood pressure following injection of sodium pentobarbital, whilePersantin produced only a minimal temporary decrease in contractility with essentiallyno change in blood pressure.

blood ptvissure, total peripheral resistance,coronary resistance, coronary arteriovenousoxygen difference, and coronary oxygen utili-zation. Cardiac oxygen consumption, cardiacwork, cardiac output, cardiac rate, aud car-diac efficiency were not changed significantly.

The electrocardiograms following intra-venous (200 jug./Kg.) injections of Persantinwere essentially unchanged with the excep-tion of the alteration in heart rate.

In two experiments, the electrolyte pat-terns (Na, K, Mg, Cl) of the arterial andcoronary venous blood were determined be-fore and after intracoronary and intravenousinjections of Persantin. The changes ob-served following Persantin were minimal,with no consistent change in pattern, exceptthat sodium (in the coronary A'enous blood)appeared to show a consistent tendency todecrease slightly.

Circulation Research, Volume X, Januarj/ 1961



ownloaded from


NEW CORONARY VASOSlLAtfOR 41

DOGS WITH CHRONIC CORONARYINSUFFICIENCY: DECREASED LUMEN OFTHE MAIN BRANCHES OF THE LEFTCORONARY ARTERY PRODUCED BYCASEIN RINGSCoronary Blood Flow

In table 1, (column 2) the values for coro-nary blood flow on three dogs with narrowedcoronary arteries (produced by casein rings)are illustrated. In this group of animals thecontrol flow is less than the control flow ob-served in the normal animals** since the lumenof the coronary vessels has been markedlynarrowed. Nevertheless, intravenous injec-tions of Persantin still increased at least by75 per cent the coronary blood flow in theseanimals. However, the magnituds of the flowincrease was considerably less than that ob-served in the normal animals. A"graphic"representation of the typical type of.responseof the drug on coronary blood flow .is dem-on trated in figure 9.

Coronary ResistanceThe control resistance in these animals was

considerably elevated -over the. resistancedemonstrated in the normal animals. Thisresulted from the obstructive casein rings'placed around the left anterior descendingand circumflex- ^branches. In spite of., thereduced lumen of the main arteries, the ooro-nary resistance was observed to decrease fol-lowing Persantin (table 1).Coronary Arteriovenous Oxygen Difference

A decrease in coronary arteriovenous oxy-gen difference was also observed in these ani-mals following injections of Persantin (table1, column 2). However, the degree of nar-rowing of the coronary (A-V) O2 was lessthan that observed in the normal animals-,because the coronary venous oxygen contentand saturation could not increase as greatlyas was possible in the normaLdogs. •

Related Circulatory' Dynamics :

Slight increases in cardiac oxygen consump-tion as well as minimat'Jingreases in cardiacoutput and cardiac rate" were observe®-, whilecardiac work, mean arterial blood pressure?'and ' cardiac efficiency 'decr eased "slightly'3'(table 1, Column 2).- C&ron&rys#xygeri'utili-e

zation and totals peripheral resistance also de-creased, but to a lesser,, extent, than in the

Circulation Research, Volume X, January lgen

N s

- I ©

W3

ina cae N

o 3

§>

a u

•i.

.2 =

•^7

'1 l

.se-

OJ o w 00 w q © H w . H , os >o ̂

N O Q N

CM t o CO 00

O C 1 C 1 0 3iH N (M H »O t-\

onoI A

w > o ( M ot » (M CO TH (M

t V

©com(Min©Oii>-cooo©©{M©OlOminiMJtfMOOHOfOfOCOWMM

in I-IT(H O

1 <SI Oj te o

'. V

«.iH OV OC O . i H > tO o

J OS O ~

IOlOfHOJCQ0O3NCOI> ^ H CO CO CO 00xy-O^HHDIOCOIOtOlOCOH

CO

+-

• * o.' "" ' o o o

SHt>Ht>CO-M«HH^H00t>fi0tO o oo

O O5 OJ55 OOOOMBOOriOSt- ? gtosowow&iiMOffiixo^wmot1

M<M(MHmHNHH NN N H CO (M m H

"7

to^=,o^ca^ooco^coo«N13««+!r H r H i — I H N I M H H CM r-i —• ° • • - ^ ^5



ownloaded from


42 WEST, BELLET, MANZOLI, MttLLER

200 —

I—>—I— - I - - I -8 10 15 £0Control

FIGURE 9

Effects of intravenous injection of Persantin inthe presence of coronary artery (left anteriordescending and circumflex) narrowing. Note thatcoronary blood flow increases but the effect isless than in the normal dog or in the dog withcoronary artery ligation. Blood pressure decreasedwhile heart rate increased.

normal dogs. As seen in the normal dogs,the heart rate was the most variable param-eter in this group of dogs.

DOGS WITH MYOCARDIAL INFARCTION:CORONARY ARTERY LIGATIONCoronary Blood Flow

The control coronary blood flow in thisgroup of animals was found to be lower thanthe flow in the normal dogs, but not as low asin the dogs with coronary insufficiency (nar-rowed arteries). Following Persantin, coro-nary blood flow increased markedly (165 percent). This increase in flow was greater thanthat observed in the dogs with coronary in-sufficiency and equal to that obtained in thenormal dogs (table 1, column 3). However,the total flow was considerably below thatobserved in the normal control animals. Atypical response is illustrated in figure 10.

Coronary ResistanceIn this group of dogs, the coronary resis-

tance was found to be greater than in thenormal dogs, but not as high as in the dogswith coronary narrowing. However, Per-santin decreased the resistance in this groupof animals more than in the dogs with coro-nary narrowing. The magnitude of the changewas within the range of the response seen inthe normal dogs (table 1, column 3).

250 -

200

150

100 —

5 0 -

» « C-BP(»L./M1N)) b - ^ M.fl.B.R(MM.HS)—~ H.R.fDEflTS/MlM)

_ / ^

Conttol

PERSflNTIN

2—I—T—1—r—I— - I - - I -

6 8 10 15 20Minwtes

FIGURE 10

Effects of intramenous injection of Persantin inthe presence of coronary artery (left anteriordescending) ligation and healed myocardial in-farction. There is an immediate sustained rise incoronary blood flow which resembles that seenin the normal dog, but somewhat less marked(see text). Blood pressure was noted to decreaseslightly while heart rate increased slightly.

Coronary Arteriovenous Oxygen Difference

Persantin decreased markedly the coro-nary arteriovenous oxygen difference in thisgroup of animals by increasing the coronaryvenous oxygen content and saturation. Thedegree of response was greater than in thedogs with coronary narrowing and equal tothat observed in the normals (table 1,column 3).

Related Circulatory Dynamics

Persantin produced minimal increases incardiac oxygen consumption, cardiac work,and cardiac output, while at the same time itdecreased slightly mean arterial blood pres-sure, cardiac rate, and cardiac efficiency.Total peripheral resistance was decreasedmoderately, while coronary oxygen utiliza-tion was markedly decreased. Heart rate wasthe most variable of the parameters meas-ured.

DiscussionCoronary vasodilators may be divided into

two main groups: (1) those which increasethe coronary blood flow but at the same timeproduce a stimulating effect upon the heartmuscle and increase cardiac work (epineph-

Circulation Research, Volume X, January 196!



ownloaded from


NEW CORONABY VASODILATOR 43

rine and other sympathomimetic amines, nico-tine, and aminophylFine), and (2) thosewhich tend to increase coronary blood flowwithout a significant increase in cardiac work.The latter is accomplished in the presenceof a decrease in coronary vascular resistance.To this group belong the nitrites. There isconsiderable evidence, chiefly- in- the- ex-perimental animal, that the nitrites, mainlynitroglycerin, increase coronary blood flow.6'14"17 Kecent studies have confirmed these ob-servations in the normal human subject.18

However, in subjects with coronary arterydisease, coronary blood flow and myocardialoxygen consumption were only slightly in-creased following nitroglycerin; the coronaryresistance remained essentially fixed, andcoronary blood flow and myocardial consump-tion remained either unchanged or actuallydecreased.19

It would appear from the data obtainedabove that Persantin might also belong tothe second group, namely, that in which thereis an increase in coronary blood flow withoutan increase in cardiac contractility or cardiacwork. The maximum dose to accomplish thiseffect was 200 yu.g./Kg., intravenously. It is ofconsiderable interest that this increase incoronary flow occurred not only in the normalanimal but also in the animal with coronaryinsufficiency, which often was of a severegrade.

The mode of action of this preparation inincreasing coronary blood flow has not beenentirely elucidated. There is some sugges-tive evidence that it manifests a direct effectin producing vascular dilatation. This effectis more pronounced in certain vascular de-pots, especially the coronary arteries. Thereis some evidence that it manifests an effecton nucleoside metabolism of the heart mus-cle,5 and, in addition, an increase in ATPin the myocardium has been observed in thepresence of hypoxia.3

In view of these findings in the experimen-tal animal, the use of Persantin merits a morethorough investigation in the human subject.The dose which would result in the optimumincrease in coronary blood flow and the bloodCirculation Reaearoh, Volume Xf January 19SZ

level required to accomplish this end arebeing investigated at the present time.

SummaryThe effect of a new coronary vasodilator

(Persantin), which produces a marked in-crease in coronary blood flow (up to 159 percent in normal animals) without increasingcardiac contractility or cardiac work, hasbeen studied in the experimental animal. Thisis associated with a marked decrease in coro-nary resistance. There is an increase in thecoronary venous oxygen content and a de-crease in the coronary A-V oxygen difference;the cardiac output is only slightly affected.Increase in the coronary blood flow has alsobeen observed in dogs in which coronary in-sufficiency has been produced by coronaryligation and by narrowing of the lumen ofthe coronary artery by the application ofcasein rings. This was accompanied by nosignificant increase in cardiac work.

References1. FISCHER, F. G., AND ROCH, J.: tjber Pyriinido-

pyrimidine. Liebigs Aim. Chem. 572: 217,1951.

2. KADATZ, R.: Die pharmakologischen Eigenschaf-ten der lieuen coronarerweiternden Substanz 2,6-Bis-(diaethanolamino)-4, 8-dipiperidino-pyri-mido-(5, 4-d) pyrimidin. Arzneim-Forsch. 9:39, 1959.

3. HOCKERTS, T. H., AND BOGELMANN, G.: Unter-

suchungen iiber die Wirkung von 2, 6-Bis-(dia-ethanolamino)-4, 8-dipiperidino-pyrimido-(5, 4-d) pyrimidin auf Herz und Kreislauf. Arz-neim-Forsch. 9: 47, 1959.

4. GRABNER, G., KAINDL, F., AND KRAUPP, O.: Die

Wirkung von 2, 6-Bis-(diaethanolamino) -4, 8-dipiperidino-pyrimido- (5, 4-d) pyrimidin aufHerztatigkeit und Coronarkreislauf narkoti-sierter Hunde. Arzneim-Forsch. 9: 45, 1959.

5. BRETSCHNEIDER, H. J., FRANK, A., BERNARD, U.,

KOCHSIEK, K., AND SCHELER, F.: Die Wirkung

eines Pyrimidopyrimidin-Derivates auf dieSauerstoffversorgung des Herzmuskels. Arz-neim-Forsch. 9: 49, 1959.

6. FOLTZ, E. L., PAGE, B. G., SHELDON, W. F.,

WONG, S. K., TUDDENHAM, W. J., AND WEISS,

A. J.: Factors in variation and regulation ofcoronary blood flow in intact anesthetizeddogs. Am. J. Physiol. 162: 521, 1950.

7. LlTVAK, J. , SlDERIDES, L. E. , AND VlNBERG, A.

M.: Experimental production of coronary ar-tery insufficiency and occlusion. Am. HeartJ. 53: 505, 1957.



ownloaded from


44 j . M4NZQLI,, MttLLEB.

8. WEST, J. W., GUZMAN, S. V., AND BELLET, S.:Cardiac effects of intracoronary arterial in-jections of nicotine. Circulation Research 6:389, 1958.

9. WEST, J. W., KOBATASHI, T., AND GUZMAN, S. V.:

Coronary artery catheterization in the intactdog. Circulation Research 6: 383, 1958.

10. VAN SLTKE, D. D., AND NEILL, J. M.: Determina-

tion of gases in blood and other s61utions byvacuum extraction and manometric nieasure-ment. J: Biol. Chem. 61: 523, 1924.

11. BONIFACE, K. J., BROWE, O. J., AND WALTON,

R. P.: Resistance strain gauge arches for di-rect measurements of heart contractile forieein animals. Proc. Soc. Biol. & Med. 84::u

263,1953.

12. COTTEN, M. DEV. : Circulatory changes affectingmeasurements of heart force in situ with straingauge arches. Am. J. Physiol. 174: 365, 1953.

13. HERRMANN, G. E.: Experimental heart disease:I. Methods of dividing hearts, with sectionaland proportional weights and ratios for twohundred normal dogs' hearts. Am. Heart J.1: 213, 1925.

14. ESSEX, H. E., WEGRIA, R. G., HERRICK, J. F.,AND MANN, F. C.: Effect of certain drugs on

tjte coifOnsry bipod.'flow,, of the trained dog.Am. Heart J. 19:" 554, 1940.

15. BOYER,,N. H., AND GREEN, H. D,: Effects ofnitrites and £anthines on the*' coronary inflowand -'blood-pressurei- in. anesthetized 'dogs'.' <hiti.HeartJ'J. 21: 199, 1941.

16. ECKSTEIN,^ . W., NE^BERRY, W. B., MCBACHEN,J. A., AND.SMITH, G.: Studies on the anti-adrenergie effects of hitroglycerin on the dogheart. Circulation 4: 534, 1951.'

17. SA:RNOia?/jSi-J., CASE, R. B.,: AND MACRU, B.:

'!3)?^r^a';i^ns on the vasodilating properties off,urine; I.,.Comparison of the effec|v,.of humanurine and nitroglycerin on coroiuiry resistanceand mydca'fflial "biyg'en cdnsumption in' theisolated Supported heart preparation. Circu-Jation ResBOrooofe':: 522;id958.

18. BRACHFIELD,VN., tJ^OZER,. (J . , AND ,GORI<IN, R.:Action of nitroglycer.iji, on the coronary circula-tion iii normal and in mild cardiac subjects.Circulation 19: 697, 1959:1"

19. GORLIN,''R;, BRACarlEEDy JJ., MACliEOD, C , AND

BOPP, P.: EiJect of nitroglycerin on the coro-nary circulation in patients with coronaryartery disease or increased left ventricularwork. Circulation 19: 70*5, 1959.

Circulation Research,, Volume X, January 19G&



ownloaded from


James W. West, Samuel Bellet, Ugo C. Manzoli and Ottto F. MüllerCardiac Dynamics in the Dog

Effects of Persantin (RA8), A New Coronary Vasodilator, on Coronary Blood Flow and

Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 1962 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

doi: 10.1161/01.RES.10.1.351962;10:35-44Circ Res.

http://circres.ahajournals.org/content/10/1/35World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circres.ahajournals.org//subscriptions/

is online at: Circulation Research Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer about this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. Further informationEditorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculation Research Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



ownloaded from

http://circres.ahajournals.org/content/10/1/35

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circres.ahajournals.org//subscriptions/


effects of persantin (ra8), a new coronary vasodilator, on...

Documents