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Increased aortic thromboxane production in experimental atherosclerosis
Prostaglandins, Leukotnenes and Medicme ‘1’ Longman Group UK Ltd 1987
INCREASED
AORTIC
(1987) 29, 71-77
THROMBOXANE PRODUCTION ATHEROSCLEROSIS
Peter Henrikssona,
Monika Stambergera
and Ulf Diczfalusyb.
Chemistry aDepartments of Medicine and bClinical Karoiinska Institutet, S-141 86 Huddinge, Sweden. (Reprint
IN EXPERIMENTAL
I,
Huddinge
Hospital,
requests to Peter Henriksson)
ABSTRACT It is of great importance to clarify the role of thromboxane and prostaIn order to study this we induced cyclin in the process of atherosclerosis. atherosclerosis in rabbits through cholesterol feeding (1% w/w> for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane 6 increased by 86 per cent in atherosclerotic vessels compared to control vesselsqp<0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-ketoprostaglandin F1 o showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (3196, ~~0.025). This suggests that an rather than a decreased prostacyclin increased thromboxane production production might be important for the progression of atherosclerosis. INTRODUCTION It is of utmost importance to elucidate the role of platelets and the vessel wall in the pathogenesis of atherosclerosis and cardiovascular catastrophes such as acute myocardial infarction (1). The products of cycle-oxygenation of give rise to two platelet active arachidonic acid, cyclic endoperoxides, prostanoids i.e. prostacyclin (PGI ) and thromboxane A (TXA ). PGI is formed in vascular endothelium and smoo? h muscle cells throug 6 out th& body &,3). It is a vasodilator and inhibits platelet activation (4). A reduced formation of prostacyclin has been reported in atherosclerotic vessels (5,6) and this has been proposed as a factor behind the genesis of thrombosis and atherosclerosis (7). TXA2 formed in blood platelets is a vasoconstrictor with proaggregating properties (8). TXA2 production has also been demonstrated in vascular tissue (9,10,11). A balance between these two antagonistic substances has earlier been suggested as a regulatory mechanism of normal haemostasis (12).
71
The aim of the present study was to investigate the rate of production of prostacyclin and thromboxane - measured through their stable metabolites thromboxane I3 (TXB ) and 6-keto-prostaglatidin-F (6-keto-PGFl o ) -in atherosclerotic iessels 5 nd non-atherosclerotic vessel d.”In vitro.
MATERIAL AND METHODS Series 1. Fourteen healthy male New Zealand White rabbits, aged 48 weeks, were fed standard rabbit pellets supplemented with 1% (w/w) cholesterol for 12 weeks. Eleven healthy male rabbits of the same age served as controls and received standard rabbit pellets without cholesterol. At the age of 60 weeks the rabbits were killed by a blow on the head. The aorta from the aortic valve to the renal artery was quickly removed, rinsed, cut longitudinally and put into ice-cold 0.1 M potassium phosphate buffer (pH 7.4, 5 ml/g wet weight). The aorta was incubated for 45 minutes in a shaking water bath at 37’C. The degree of macroscopic scale (Table I).
atherosclerosis
was estimated
on a five graded
Series 2. Nine healthy male New Zealand White rabbits aged 40 weeks were fed standard rabbit pellets supplemented with 1% (w/w). cholesterol for 3-9 weeks. Eight healthy male rabbits of the same age served as controls and received standard rabbit pellets without cholesterol. After 3,5,7 and 9 weeks on cholesterol diet, two cholesterol fed rabbits and two control rabbits were sacrificed, and the aorta was prepared, incubated and analyzed in the same manner as in series 1. Analysis of thromboxane
E3 and 6-keto-prostaglandin 2
F
Jc” 1.
in the diluted
aorta incubates were determined by and 6-keto-PGF o were purchased from New England Nuclear. The dilutions ?TXS 1:20 and 6-f
methods.
The atherosclerotic aortae and control aortae were compared Students t-test for unpaired samples. All values are given as mean + S.D.
using
RESULTS. Series 1. As shown in Table 1 the cholesterol-fed rabbits and the control rabbits had equal weights throughout the experiment, 3.1 + 0.5 kg and 3.1 + 0.2 kg, respectively. All of the cholesterol-fed rabbits had macroscopic ev‘idence of atheromatosis with a median of 25-50% (++) involvement of the aortic surface. None of the control rabbits had any macroscopic evidence of atheromatosis.
72
Table mc
I: Rabbit weight, aorta weight and atherosclerosis rabbits (n=lO> and controls (n=ll). Series 1.
n
Group
Rabbit
weight
Aorta
kg
weight g
10
3.120.5
1.18+0.17
044
Controls
11
3.120.2
0.8320.12
110
grading: 0 = 0%, + = l-2556,
in athero-
Atherosclerosis grading* ++++ 0 + ++ +++
Atherosclerosis
* Atherosclerosis ++++ = >75%.
grading
++ = 26-50%,
0
1
1
0
0
+++ = 51-75%,
The in vitro thromboxane production in atherosclerotic vessels measured as immunoreactive TXB , increased to 75.0 + 28.8 pmol/g wet weight compared to 56.0 + 8.4 pmol/g we? weight in the cont?ols (p < 0.05). This was also evident if the production of TXB was evaluated per aorta. The production was then 86.6 + 27.9 pmol/aorta in th% atherosclerotic group compared to 46.6 2 8.8 pmol/aorta in the controls (p < 0.0005) (Fig. 1). TX&/aortae pm01 ??
MO--
??
100--
?? ?? ??
0
60--
20-
. pco.ooo5 Atherosclerosis
Controls
Fig.1
Endogenous production of immunoreactive thromboxane B (TXB ) measured per aorta in controls (n=ll> and in the atherosclero a*IC gro ;fp (n=lO>. The bars represent means 2 SD.
73
The in vitro production of immunoreactive 6-keto-PGF o was 1.86 + 0.59 compa&ed to 2.00 q 0.46 nmol/g wet weight by the atherosclerotic vessels, nmol/g wet weight by the the vessels of the control rabbits (N.S.). If the 6xketoPGF oproduction was calculated per aorta, the atherosclerotic vessels had a tend&y to higher values (2.17 + 0.62 nmol/aorta) compared to the controls (1.65 + 0.42 nmol/aorta) (p < O.O25)(Fi<. 2).
6-keto-PGFla/aortae nmol 3.0 -
0
2x) --
0 T
0
f
0
0
0
1.0 -
p
40.025
Controls
Fig.2
Series
Atherosclerosis
Endogenous production of immunoreactive 6-keto-prostaglandin per aorta in the controls (n=ll) and in the atherosclerotic (n=lO). The bars represent means + S.D.
F o grou b
2.
In this series the cholesterol-fed rabbits had a lower mean weight with a greater variance than the controls, Table II. The TXB2 production showed a tendency to higher values in the cholesterol-fed rabbits, 65 + 21.5 pmol/g wet weight compared to 56.4 + 14.9 pmol/g wet weight in the controls. When the production per aorta was calculated, the cholesterol-fed rabbits had a production of 86.1 + 30.5 pmol/aorta compared to 64.3 + 14.6 pmol/aorta in the controls. This difference is significant at p < 0.05. The production of 6 keto PGF CYdid not differ significantly between cholesterol-fed rabbits and controls (1.+5 2 0.25 nmol/g wet weight and 2.02 + 0.3l/nmoi/g wet weight, respectively).
74
Table II Rabbit weight, production of immunoactive
Group
n
Rabbit weight kg
feeding period, atherosclerosis grading thromboxane 62 in the aortae. Series 2.
and
Feeding period weeks
Atherosclerosis grading* 0 + ++ +++ ++++
pmol/g
pmol/aortae
Thromboxane
B2
Cholesterol
9
2.8+0.6
6.2+_2.2
3311
1
6X0+21.5
86.1230.5
Control
8
3.220.2
5.022.1
8000
0
56.4514.9
64.3214.6
* Atherosclerosis ++++ = >75%.
the
grading: 0 = O%, + = l-25%,
++ = 26-5046, +++ = 51-75%,
DISCUSSION In the first study (series 1) we found no evidence of a dimished prostacyclin producing capacity in the atherosclerotic vessels compared to the controls in contrast to some earlier reports describing a decreased prostacyclin producing capacity in atherosclerotic vascular tissue (5,6). Our measurements show an increased thromboxane production in the atherosclerotic vessels compared to the control vessels. The rabbits in the first series were comparable with respect to body weight at the time of sacrifice. This permitted us to do a comparison of the total prostacyclin production per aorta. This comparison resulted in an increased total prostacyclin production in the atherosclerotic vessels compared to the controls (~~0.025). These results are in agreement with the results reported by Fitzgerald et al. who showed an increased prostacyclin production, measured as the excretion of the major urinary prostacyciin metabolite 2,3-dinor-6-ketoPGFl~, in patients with signs of atherosclerosis compared to healthy subjects I, -z\ The main finding from the first series is the increased thromboxane production in the atherosclerotic vessels compared to control vessels (p
75
the cholesterol-fed rabbits compared to controls. This makes it hazardous to compare the total production of thromboxane and prostacyclin per aorta in the two groups. However, the production of thromboxane and prostacyclin measured per wet weight of aortae was identical in the control groups in both studies and there was a tendency to a higher thromboxane production in the atherosclerotic vessels compared to the control vessels. This difference is, however, not significant. It should be noted, however, that the mean atherosclerotic involvement in the second series was lower than in the first one due to a mean cholesterol feeding of only 6.2 + 2.2 weeks compared to 12 weeks in the first series. If, in spite of the inhomogeneity of the rabbits in the second series, a comparison of the total thromboxane production is carried out this shows a significantly increased thromboxane production in the atherosclerotic vessels compared to the controls (~~0.05). In conclusion, we have found evidence of an increased thromboxane production in atherosclerotic vessels compared to healthy vessels in the rabbit. This increased thromboxane production may contribute to the progression of atherosclerosis and further studies are certainly justified.
ACKNOWLEDGEMENTS The invaluable advice of Assistant Professor Mats Hamberg, Department of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden and the kind support by Professor Rolf Blomstrand, Department of Clinical Chemistry I, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden is gratefully acknowledged. The study was financially supported by the SALUS Insurance Co. and the Swedish Society of Medical Sciences.
REFERENCES. Henriksson P, Edhag 0, Edlund A, Svensson B, Lantz 8, Nyquist 0, Sarby 6, Wennmalm A. A role -for platelets in the process of infarct extension? N Engl J Med 313: 1660,1985. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature (London) 263: 663, 1976. Smith WL, Dewitt DL Day JS. Purification, quantitation and localization of PGI synthase using monoclonal antibodiespp 87-92 in Adv Prostaglandin, ThrJmboxane and Leukotriene Research Vol 11 (Samuelsson 8 and Paoletti R eds) Raven Press, New York, 1983. Moncada S, Higgs EA, Vane JR. Human arterial and venous tissue generate prostacyclin (Prostaglandin X), a potent inhibitor of platelet aggregation. Lancet i: 18, 1977. Sinzinger H, Silberbauer K, Feigl W, Wagner 0, Winter M, Auerswald W. Prostacyclin activity is diminished in different types of morphologically controlled human atherosclerotic lesions. Thromb Haemost 42: 803, 1979.
76
6
Dembinska-Kiec A, Gryglewska T, Zmuda A, GrygIewski RJ. The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits. Prostaglandins 14: 1025, 1977.
7
Dusting GJ, Moncada S, Vane JR. Prostacyclin: Its biosynthesis, actions and clinical potential. P 59 In: Oates JA, ed. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 10, Raven Press, New York, 1982.
8
Hamberg M, Svensson J, Samuelsson B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Nat1 Acad Sci 72: 2994, 1975.
9
Hagen AA, thromboxane
10
Salzman PM, Salmon JA, Moncada S. Prostacyclin and thromboxane A2 synthesis by rabbit pulmonary artery.J Pharmacol. Exp Ther 215:240, 1980.
11
Tuvemo T, Strandberg K, Hamberg M, Samuelsson 6. Formation and action of prostaglandin endoperoxides in the isolated human umbilical artery. Acta Physiol Stand 96: 145,1976.
12
Moncada S, Vane JR. Role of prostacyclin 66, 1979.
13
FitzGeraId GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 310: 1065,1984.
14
Stuart MJ, Gerrard JM, White JG. Effect of cholesterol on production thromboxane B2 by platelets in vitro. N Engl J Med 302: 6, 1980.
15
Schwartz CJ. Thrombosis in the pathogenesis of sudden cardiac death and myocardial infarction. Pp l-14 in Adv Prostaglandin, Thromboxane and Leukotriene Research Vol 10 (Oates JA,ed) Raven Press, New York 1982.
White RP, Robertson JT. Synthesis of prostaglandins B2 by cerebral arteries.Stroke 10: 306, 1979.
77
in vascular
and
tissue. Fed Proc 38:
of
INCREASED
AORTIC
(1987) 29, 71-77
THROMBOXANE PRODUCTION ATHEROSCLEROSIS
Peter Henrikssona,
Monika Stambergera
and Ulf Diczfalusyb.
Chemistry aDepartments of Medicine and bClinical Karoiinska Institutet, S-141 86 Huddinge, Sweden. (Reprint
IN EXPERIMENTAL
I,
Huddinge
Hospital,
requests to Peter Henriksson)
ABSTRACT It is of great importance to clarify the role of thromboxane and prostaIn order to study this we induced cyclin in the process of atherosclerosis. atherosclerosis in rabbits through cholesterol feeding (1% w/w> for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane 6 increased by 86 per cent in atherosclerotic vessels compared to control vesselsqp<0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-ketoprostaglandin F1 o showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (3196, ~~0.025). This suggests that an rather than a decreased prostacyclin increased thromboxane production production might be important for the progression of atherosclerosis. INTRODUCTION It is of utmost importance to elucidate the role of platelets and the vessel wall in the pathogenesis of atherosclerosis and cardiovascular catastrophes such as acute myocardial infarction (1). The products of cycle-oxygenation of give rise to two platelet active arachidonic acid, cyclic endoperoxides, prostanoids i.e. prostacyclin (PGI ) and thromboxane A (TXA ). PGI is formed in vascular endothelium and smoo? h muscle cells throug 6 out th& body &,3). It is a vasodilator and inhibits platelet activation (4). A reduced formation of prostacyclin has been reported in atherosclerotic vessels (5,6) and this has been proposed as a factor behind the genesis of thrombosis and atherosclerosis (7). TXA2 formed in blood platelets is a vasoconstrictor with proaggregating properties (8). TXA2 production has also been demonstrated in vascular tissue (9,10,11). A balance between these two antagonistic substances has earlier been suggested as a regulatory mechanism of normal haemostasis (12).
71
The aim of the present study was to investigate the rate of production of prostacyclin and thromboxane - measured through their stable metabolites thromboxane I3 (TXB ) and 6-keto-prostaglatidin-F (6-keto-PGFl o ) -in atherosclerotic iessels 5 nd non-atherosclerotic vessel d.”In vitro.
MATERIAL AND METHODS Series 1. Fourteen healthy male New Zealand White rabbits, aged 48 weeks, were fed standard rabbit pellets supplemented with 1% (w/w) cholesterol for 12 weeks. Eleven healthy male rabbits of the same age served as controls and received standard rabbit pellets without cholesterol. At the age of 60 weeks the rabbits were killed by a blow on the head. The aorta from the aortic valve to the renal artery was quickly removed, rinsed, cut longitudinally and put into ice-cold 0.1 M potassium phosphate buffer (pH 7.4, 5 ml/g wet weight). The aorta was incubated for 45 minutes in a shaking water bath at 37’C. The degree of macroscopic scale (Table I).
atherosclerosis
was estimated
on a five graded
Series 2. Nine healthy male New Zealand White rabbits aged 40 weeks were fed standard rabbit pellets supplemented with 1% (w/w). cholesterol for 3-9 weeks. Eight healthy male rabbits of the same age served as controls and received standard rabbit pellets without cholesterol. After 3,5,7 and 9 weeks on cholesterol diet, two cholesterol fed rabbits and two control rabbits were sacrificed, and the aorta was prepared, incubated and analyzed in the same manner as in series 1. Analysis of thromboxane
E3 and 6-keto-prostaglandin 2
F
Jc” 1.
in the diluted
aorta incubates were determined by and 6-keto-PGF o were purchased from New England Nuclear. The dilutions ?TXS 1:20 and 6-f
methods.
The atherosclerotic aortae and control aortae were compared Students t-test for unpaired samples. All values are given as mean + S.D.
using
RESULTS. Series 1. As shown in Table 1 the cholesterol-fed rabbits and the control rabbits had equal weights throughout the experiment, 3.1 + 0.5 kg and 3.1 + 0.2 kg, respectively. All of the cholesterol-fed rabbits had macroscopic ev‘idence of atheromatosis with a median of 25-50% (++) involvement of the aortic surface. None of the control rabbits had any macroscopic evidence of atheromatosis.
72
Table mc
I: Rabbit weight, aorta weight and atherosclerosis rabbits (n=lO> and controls (n=ll). Series 1.
n
Group
Rabbit
weight
Aorta
kg
weight g
10
3.120.5
1.18+0.17
044
Controls
11
3.120.2
0.8320.12
110
grading: 0 = 0%, + = l-2556,
in athero-
Atherosclerosis grading* ++++ 0 + ++ +++
Atherosclerosis
* Atherosclerosis ++++ = >75%.
grading
++ = 26-50%,
0
1
1
0
0
+++ = 51-75%,
The in vitro thromboxane production in atherosclerotic vessels measured as immunoreactive TXB , increased to 75.0 + 28.8 pmol/g wet weight compared to 56.0 + 8.4 pmol/g we? weight in the cont?ols (p < 0.05). This was also evident if the production of TXB was evaluated per aorta. The production was then 86.6 + 27.9 pmol/aorta in th% atherosclerotic group compared to 46.6 2 8.8 pmol/aorta in the controls (p < 0.0005) (Fig. 1). TX&/aortae pm01 ??
MO--
??
100--
?? ?? ??
0
60--
20-
. pco.ooo5 Atherosclerosis
Controls
Fig.1
Endogenous production of immunoreactive thromboxane B (TXB ) measured per aorta in controls (n=ll> and in the atherosclero a*IC gro ;fp (n=lO>. The bars represent means 2 SD.
73
The in vitro production of immunoreactive 6-keto-PGF o was 1.86 + 0.59 compa&ed to 2.00 q 0.46 nmol/g wet weight by the atherosclerotic vessels, nmol/g wet weight by the the vessels of the control rabbits (N.S.). If the 6xketoPGF oproduction was calculated per aorta, the atherosclerotic vessels had a tend&y to higher values (2.17 + 0.62 nmol/aorta) compared to the controls (1.65 + 0.42 nmol/aorta) (p < O.O25)(Fi<. 2).
6-keto-PGFla/aortae nmol 3.0 -
0
2x) --
0 T
0
f
0
0
0
1.0 -
p
40.025
Controls
Fig.2
Series
Atherosclerosis
Endogenous production of immunoreactive 6-keto-prostaglandin per aorta in the controls (n=ll) and in the atherosclerotic (n=lO). The bars represent means + S.D.
F o grou b
2.
In this series the cholesterol-fed rabbits had a lower mean weight with a greater variance than the controls, Table II. The TXB2 production showed a tendency to higher values in the cholesterol-fed rabbits, 65 + 21.5 pmol/g wet weight compared to 56.4 + 14.9 pmol/g wet weight in the controls. When the production per aorta was calculated, the cholesterol-fed rabbits had a production of 86.1 + 30.5 pmol/aorta compared to 64.3 + 14.6 pmol/aorta in the controls. This difference is significant at p < 0.05. The production of 6 keto PGF CYdid not differ significantly between cholesterol-fed rabbits and controls (1.+5 2 0.25 nmol/g wet weight and 2.02 + 0.3l/nmoi/g wet weight, respectively).
74
Table II Rabbit weight, production of immunoactive
Group
n
Rabbit weight kg
feeding period, atherosclerosis grading thromboxane 62 in the aortae. Series 2.
and
Feeding period weeks
Atherosclerosis grading* 0 + ++ +++ ++++
pmol/g
pmol/aortae
Thromboxane
B2
Cholesterol
9
2.8+0.6
6.2+_2.2
3311
1
6X0+21.5
86.1230.5
Control
8
3.220.2
5.022.1
8000
0
56.4514.9
64.3214.6
* Atherosclerosis ++++ = >75%.
the
grading: 0 = O%, + = l-25%,
++ = 26-5046, +++ = 51-75%,
DISCUSSION In the first study (series 1) we found no evidence of a dimished prostacyclin producing capacity in the atherosclerotic vessels compared to the controls in contrast to some earlier reports describing a decreased prostacyclin producing capacity in atherosclerotic vascular tissue (5,6). Our measurements show an increased thromboxane production in the atherosclerotic vessels compared to the control vessels. The rabbits in the first series were comparable with respect to body weight at the time of sacrifice. This permitted us to do a comparison of the total prostacyclin production per aorta. This comparison resulted in an increased total prostacyclin production in the atherosclerotic vessels compared to the controls (~~0.025). These results are in agreement with the results reported by Fitzgerald et al. who showed an increased prostacyclin production, measured as the excretion of the major urinary prostacyciin metabolite 2,3-dinor-6-ketoPGFl~, in patients with signs of atherosclerosis compared to healthy subjects I, -z\ The main finding from the first series is the increased thromboxane production in the atherosclerotic vessels compared to control vessels (p
75
the cholesterol-fed rabbits compared to controls. This makes it hazardous to compare the total production of thromboxane and prostacyclin per aorta in the two groups. However, the production of thromboxane and prostacyclin measured per wet weight of aortae was identical in the control groups in both studies and there was a tendency to a higher thromboxane production in the atherosclerotic vessels compared to the control vessels. This difference is, however, not significant. It should be noted, however, that the mean atherosclerotic involvement in the second series was lower than in the first one due to a mean cholesterol feeding of only 6.2 + 2.2 weeks compared to 12 weeks in the first series. If, in spite of the inhomogeneity of the rabbits in the second series, a comparison of the total thromboxane production is carried out this shows a significantly increased thromboxane production in the atherosclerotic vessels compared to the controls (~~0.05). In conclusion, we have found evidence of an increased thromboxane production in atherosclerotic vessels compared to healthy vessels in the rabbit. This increased thromboxane production may contribute to the progression of atherosclerosis and further studies are certainly justified.
ACKNOWLEDGEMENTS The invaluable advice of Assistant Professor Mats Hamberg, Department of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden and the kind support by Professor Rolf Blomstrand, Department of Clinical Chemistry I, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden is gratefully acknowledged. The study was financially supported by the SALUS Insurance Co. and the Swedish Society of Medical Sciences.
REFERENCES. Henriksson P, Edhag 0, Edlund A, Svensson B, Lantz 8, Nyquist 0, Sarby 6, Wennmalm A. A role -for platelets in the process of infarct extension? N Engl J Med 313: 1660,1985. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature (London) 263: 663, 1976. Smith WL, Dewitt DL Day JS. Purification, quantitation and localization of PGI synthase using monoclonal antibodiespp 87-92 in Adv Prostaglandin, ThrJmboxane and Leukotriene Research Vol 11 (Samuelsson 8 and Paoletti R eds) Raven Press, New York, 1983. Moncada S, Higgs EA, Vane JR. Human arterial and venous tissue generate prostacyclin (Prostaglandin X), a potent inhibitor of platelet aggregation. Lancet i: 18, 1977. Sinzinger H, Silberbauer K, Feigl W, Wagner 0, Winter M, Auerswald W. Prostacyclin activity is diminished in different types of morphologically controlled human atherosclerotic lesions. Thromb Haemost 42: 803, 1979.
76
6
Dembinska-Kiec A, Gryglewska T, Zmuda A, GrygIewski RJ. The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits. Prostaglandins 14: 1025, 1977.
7
Dusting GJ, Moncada S, Vane JR. Prostacyclin: Its biosynthesis, actions and clinical potential. P 59 In: Oates JA, ed. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 10, Raven Press, New York, 1982.
8
Hamberg M, Svensson J, Samuelsson B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Nat1 Acad Sci 72: 2994, 1975.
9
Hagen AA, thromboxane
10
Salzman PM, Salmon JA, Moncada S. Prostacyclin and thromboxane A2 synthesis by rabbit pulmonary artery.J Pharmacol. Exp Ther 215:240, 1980.
11
Tuvemo T, Strandberg K, Hamberg M, Samuelsson 6. Formation and action of prostaglandin endoperoxides in the isolated human umbilical artery. Acta Physiol Stand 96: 145,1976.
12
Moncada S, Vane JR. Role of prostacyclin 66, 1979.
13
FitzGeraId GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 310: 1065,1984.
14
Stuart MJ, Gerrard JM, White JG. Effect of cholesterol on production thromboxane B2 by platelets in vitro. N Engl J Med 302: 6, 1980.
15
Schwartz CJ. Thrombosis in the pathogenesis of sudden cardiac death and myocardial infarction. Pp l-14 in Adv Prostaglandin, Thromboxane and Leukotriene Research Vol 10 (Oates JA,ed) Raven Press, New York 1982.
White RP, Robertson JT. Synthesis of prostaglandins B2 by cerebral arteries.Stroke 10: 306, 1979.
77
in vascular
and
tissue. Fed Proc 38:
of