These drugs lower plasma lipids but they also inhibit platelet aggregation in wh ich
TXA2 plays a major part and prolong shortened platelet survival (Gilbert & Mustard,
1963; Robinson & LeBeau, 1967; Glynn, Murphy & Mustard, 1967; Steele, Battock &
Genton, 1975; Lin & Smith, 1976; Favis & Colman, 1978). The sensitivity ofplatelets
from patients with familial hyperbetalipoproteinaemia is lessened by these drugs,
possibly through etTects on platelet membrane lipids and hence membrane fluidity
(Carvalho, Colman & Lees , 1974; Colman, Bennett, Sheridan, Cooper & Shattil,
1976; Colman, 1978). Clofibrate has also been reported to decrease prostacyclin
synthesis by human veins (Sinzinger, Clopath & Silberbauer, 1979).
Suloctidil is a vascular antispasmotic drug that inhibits platelet aggregation in vitro
and after oral administration to animals or man (Roba, Claeys & Lambelin, 1976; de
Gaetano, Miragliotta, Roncucci, Lansen & Lambelin, 1976; Stelzer, Bums &
This drug is unusual in that its etTects are not apparent in vitroand are only manifest
24 to 48h after it is administered; however, the etTects persist for several days
(O'Brien, Etherington & Shuttleworth, 1978; Knudsen & Gormsen, 1979). Unlike the
other drugs that have been considered, it inhibits the primary phase ofADP-induced
platelet aggregation (O'Brien et al., 1978; David, Monfort, Herion & Raskinet, 1979).
platelets (Johnson & Heywood, 1979). It prolongs the bleeding time and has been
shown to prolong shortened platelet survival in rats (Wilkinson, Hawker & Hawker,
1979). Ticlopidine inhibits intimal proliferation in de-endothelialized rabbit aortae
(Reece & Walton, 1979). The biochemical reactions that are atTected by ticlopidine or
its metabolities have not been determined.
This vitamin is an antioxidant that has inhibitory etTects on platelet aggregation that
result from activation of the arachidonate pathway (Kurokawa, Kimura, Nagai &
Mitsuo, 1971; Fong, 1976; Steiner & Anastasi, 1976). It may atTect the calcium flux
within platelets that is involved in contractile processes (Butler, Gerrard, Peiler,
Inhibitory etTects on platelet functions have been demonstrated with many other
as imipramine, arnitriptyline, and chlorpromazine; nitrofurantoin; glyccryl
guaiacolate; pyridinolcarbamate; nitroprusside (Pfister & Imhof, 1979; Mehta &
Mehta, 19-79) and many others. The vasodilator nitroglycerin has recently been
shown to induce prostacyclin production by cultured human cndothelial cells (Levin,
DR UG ACTION ON PLATELET AN D VESSEL WA LL FUNCTJON 205
A great variety of combinat ions of drugs have been used to inhib it plat elet func tions
or plat elets and coagul ation (Packha m & M ustard , 1977; Mu sta rd & Packham, 1978 ).
Sinc e seve ra l mech an ism s may be involved in thrombosis, th is appears to be a
Many drugs in hibit plat elet reactions but none o f them blocks all of th e pathways
th at contrib ute to thrombus formatio n. Drugs th at on ly inhibit th e gene ra tion of
TXA z by plat elets cannot be expec ted to in hib it types of thrombosis to whic h thi s
com po und mak es only a min or contributio n. When th ro mbin an d fibrin for ma tion
pla y th e pr incip al role in th rombus formation, heparin or ora l anticoagulants ma y
ha ve beneficial effects . The prosta glan din s th at in hibit plat elet react ions because
th ey stim ulate adeny late cyc1ase are not suitable for long term admi nis tra tion.
on platelet fun ctions rem a in to be est ablished. One un sol ved problem is th e reason
why some of the drugs suc h as sulphi npy ra zo ne, dipyridamole and clofibrate,
prolong shortened platel et surviva l in man, particul arl y in condition s involvi ng
thromboembolic proce sses. It may be th at some of th e benecial effects of drugs that
affect plat elets will eve ntua lly be shown to invo lve mod ification of other ce llula r
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DRUG ACT ION ON PLATELET AN D VESSELWALL FUNCTION 211
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Ciba-Geigy Pharmaceuticals Division,
Three drugs continue to be under intensive clinical assessment to determine whether
sulphinpyrazone. The most recent trials to be completed are those relating to
sulphinpyrazone (Anturane Reinfarction Trial Research Group, 1980), aspirin
(Aspirin Myocardial Infarction Study Research Group, 1980) and aspirin
alone or in combination with dipyridamole (Persantine-Aspirin Reinfarction Study
Research Group, 1980). None of these drugs were invented for use after stroke or
myocardial infarction and much effort has gone into their investigation in animal
models thought to have some bearing on the development or the consequences of
vessel disease in man . In this review attention will be paid to data derived from in
vivo animal models in which either thrombus formation and changes in the intima
and media ofthe vasculature occur as a result of direct injury to the endothelium, or
in which platelet aggregation follows from the administration of a known platelet
agonist. For the most part discussion of the effect of these drugs on the heart will
derive from var iants ofthe well-known coronary ligation models.
During the examination of a range of phenylbutazone analogues for uricosuric
uricosuric substance, the sulphoxide (Bums, Yu , Ritterbrand, Perel & Gutman,
1957). This substance was called sulphinpyrazone. The reverse transformation is now
known in man and a number of animal species and will be referred to later in this
214 A. M . WHITE & K . D. BUTLER
Inhibition of'pkuelet thrombiform ed as a result ofdirect electrical or mechanical
A favoured method for examining the ability of drugs to inhibit mural thrombus
formation utilises the exposed microcirculation of the hamster cheek pouch
(Berman, 1961; Begent & Born, 1970). In aversion ofthis model Lewis & Westwiek
(1977) placed a glass micropipette filled with IM KCl in contact wun the wall of a
cheek pouch arteriole 40-60 IJm in diameter and then applicd positive square wave
d.c. pulses in order to produce white bodies of platelets adhering to the vessel wall.
The amount of white body formation was assessed by counting the total number of
thrombi adhering during the Irrst 4 min after stimulation. A graded response could be
produced by varying the duration ofstimulation. Following the oral administration
ofsulphinpyrazone 18 hand I h prior to vascular damage there was a reduction in the
amount of white body formation . Statistical significance was achieved at doses of
20 mg kg" and 60 mg kg-I when the plasma concentrations ofsulphinpyrazone were
stated to be 60 lJg mi-I and 82 lJg mi-I respectively. In experiments where arteries on
the surface of the cerebral cortex of rabbits were exposed and damaged by pinching
with forceps (Honour & Ross-Russell, 1962; Honour & MitcheII, 1964) a dose of
sulphinpyrazone of 40 mg kg-I (i.v.) suppressed white body formation for 7 min,
while a second bolus injection of 60 mg kg-I stopped white body formation
completely over a 4 h observation period (Adams & MitcheII, 1979). Heparin did not
inhibit the platelet response to injury.
Inh ibition ofplatelet thrombiformed as a result of imm unological injury to the
To examine one aspect of this action of su1phinpyrazone, work in the authors'
laboratory has concentrated on the examination of the drug in the sub-Iethal
Forssman reaction (Butler & White, 1980). In brief, drugs are administered to guinea
pigs prior to the i.v. administration ofForssman antiserum at a sub-lethal dose and
inhibited the thrombocytopenia and the sequestration of platelets in the lungs. The
plasma concentration would have been about 50 lJg ml! (Butler, Dieterle, Maguire,
Pay, Wallis & White, 1980). Aspirin had no efTect at all at the same dose (Butler &
sulphinpyrazone has also been shown to be efTective. In the case of kidney
transplants, dogs were presensitized by full th ickness skin grafts and then underwent
cross-renal transplantation (Sharma, Moore, Merrick & Smith, 1972). The test group
until anoxia ofthe kidney occurred. Urine flow was used as a test ofkidney function .
The mean function time among thirteen animals in the control group was 7.5 h
whereas in the treated group ofl3 animals the mean time ofgraft function was 33.1 h.
Platelet aggregation and vascular injury were absent in the treated group in the
Similar results have been obtained using heart transplants (Sharma, Rosensweig,
EXPERIMENTAL MODELS AND PLATELET REG ULATORY DR UGS 215
Chatterjee, Moore & de Champlain, 1973; Vaessen, Benthuis, Hesse & Lameizer,
1977; Jamieson, Burton & Reitz, 1980) but in the third of these studies it was of
interest to note that sulphinpyrazone in combination with azathioprine appeared
more effective than other inhibitors of prostagiandin synthesis such as ibuprofen and
indomethacin . Could these results indicate a 'protective' effect ofsulphinpyrazone on
the endothelium as weil as an antiplatelet act ivity? Such a protective effect has been
c1aimed in cultured human umbilical vein cells by direct mea surement (Harker ,
Wall , Harlan & Ross , 1979) but could not be seen in cultured cells from pig aorta
Inhibition ofthe developm ent ofexperimental arteriosclerosis and atherosclerosis
In the rat , 'early' atherosclerotic lesion s were produced by a combination of
cholesterol feeding and an immunological challenge. Sub sequent to treatment over
daily) has been c1aimed to reduce intimal hyperplasia in the lower abdominal aorta,
iliac and femoral arteries (Harker, et al., 1979). Cairncross, Bassett & Martin (1979)
have recently shown that the morphological changes in the coronary vasculature of
rats exposed to unpredictable stress for 50 days were markedly reduced when
sulphinpyrazone (8 mg kg-1 daily) was administered orally for the whol e 50 da ys.
Likewis e, in rabbits, a da ily dose of 67 mg kg-I p.o . for 14 days after removing the
endothelium from the iliac artery by balloon catheter cau sed a 30% reduction in the
thickness ofthe neointima (Baumgartner & Studer, 1976).
In contrast to these positive results, no effect of the drug could be seen on intimal
hyperplasia in the aortic arch , the thoracic aorta and the abdominal aorta ofminipigs
over a period of 4 weeks after initial ballooning. The dose of sulphinpyrazone was
30 mg kg-I given twice da ily (Clopath et al., 1980). In the same way no effect of
sulphinpyrazone could be seen on intimal hyperplasia in rabbit aorta when
continuous damage was cau sed by an indwelling catheter (Moore & Ihnatowycz,
Direct infusio n of'platelet agonists and understanding ofthe prolonged action of
In rats rendered hyperl ipidaemic by a ten-week period on a high lipid diet ,
thrombosis was induced in the hep atic veins by intravenous injection of Sityphosa
lipopolysaccharide. Sulphinpyrazone (about 1000 mg kg") administered by gastric
lavage 2 h before the injection of endotoxin led to a 66% reduction in hepatic infarcts
(Renaud & Lecompte, 1970). In a similar fashion sulphinpyrazone (100 mg kg-I
i.v.) given at various times up to I min prior to the infusion of endotoxin into rabbits
protected the animals against its lethai effects and reduced the number of platelet
aggregates seen in the microcirculat ion (Evans & Mustard, 1968).
Experiments in this laboratory have involved the use of the Arthus rea ction in
guinea pigs and therefore in vivo platelet aggregation resulting from the presence of
circulating and localised Ag/Ab complexes (Butler, Pay , Roberts & White, 1979).
, i.v.) I h before the antigenie challenge significantly
(Butler, Wallis & White, 1979) and is due to the production of the pot ent thioether
metabolite mentioned abo ve (Butler et al., 1980). Sim ilarl y, the prolonged inhibition
of collagen-induced thrombocytopenia first seen by Buchanari , Rosenfeld & Hirsh
(1978) in rabb its after the administration of 100 mg kg-I (i.v.) has been explained in
216 A. M. WHITE & K. D. BUTLER
this way (pedersen & Jakobsen, 1979). The prolonged action of this drug in man
(Butler et al., 1980) is also due to the production of the thioether (Maguire, Pa y,
Turney, Wallis, Weston, White, Williams & Woods, 1980).
EjJects on models 0/cardiac arrythmia
Kelliher, Dix, Jurkiewicz & Lawrence (1980) studied the efTect of sulphin pyrazone
100 mg kg-1 (i.v.) in anaesthetised cats. The drug was given I h before tying abruptl y
the left anterior de scending coronary artery and its efTects were observed on
arrythmia and death, on heart rate and blood pressure and on infarct size. A
significant reduction was detected in the incidence of ventricular tach ycardia during
a 30 min period immediately following occlusion in those cats which did not
fibrillate . Similar results to these, and in addition, a reduction in the duration of
ventricular tachycardia were seen in cats which were additionally bilaterally
vagotomised. Even though vagotomy nearly doubled the incidence of ventricular
In studies in dogs involving occlusion-reperfusion techniques which reliably
produce a ventricular fibrillation (VF), sulphinpyrazone (30 mg kg-1 p.o. for seven
days) produced a marked reduction in VF from 58% to 17% accompanied by a
slight decrease in mortality (75 % to 50%) (Povalski, Ol son , Koria & Furness, 1980).
There was no efTect on infarct size. Mo schos, Escobinas & Jorgensen (1980) , also in
dogs, showed after administering sulphinpyrazone (300 mg/dog) for seven days, that
The antiarrythmic efTects ofsulphinpyrazone do not appear to be related to efTects
on the systemic circulation or on the reaction of the circulation to cardiac function
subsequent to an ischaemic episode. Moschos, Escobinas & Jorgensen (1979)
measured aortic pressure and concluded that drug treatment failed to produce an y
changes. Similarly heart rate and blood pressure of intact or vagotomised cats were
not afTected by sulphinpyrazone before coronary artery occlusion and bradycardia
and the hypotensive response to occlusion of non-vagotornised cats were sim ila r in
(Davenport, Goldstein & Capurro, 1979).
In the work of Folts & Beck (1980) dogs with 70% stenosis of the left circumflex
artery showed cyclical reductions in coronary blood flow wh ich probably reflect the
presence of platelet plugs in the narrowed lumen. Sulphinpyrazone (30 mg kg-I
abolished the cyclical flow disruptions, caused a reappearance of the reactive
claimed to cause a reduction in heart rate but to be without any efTect on blood
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