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Effects of the non-selective beta-adrenoceptor blocking agent, carteolol, on platelet function, blood coagulation and viscosity
EFFECTS OF THE NON-SELECTIVE BETA-ADREXOCEPTOR BLOCKING AGEp?'i', CARTEOLOL, ON PLATELET FUNCTION,BLOOD COAGULATION AND VISCOSITY.
w* Small, J.T. Douglas, +G.W. Aherne, Korna Orr, G.D.O. Lowe, C. D. Forbes and C. R. M. Prentice. University Department of Medicine, Royal Infirmary,Glasgow. and *Department of Biochemistry, University of Surrey. (Received 16.11.1981; in revised form 14.1.1982. Accepted by Editor D. Ogston)
ABSTRACT We have studied the effect of a new beta-adrenergic blocker, carteolol, on platelet function, blood coagulation and viscosity in IO healthy male volunteers. Following carteolol (5 mg orally) we were able to demonstrate significant inhibition of platelet aggregation to ADP (p
_.....
Key Words: Carteolol, beta-adrenoceptor blocker,platelet functicn
351
.-_. -; i__.-_)
:,m--q@J~ _w_-
:;c . ;
*
Ten healthy male volunteers (age range 22-45, mean = 23.2 years) with normal biochemistry, haematolcgy and resting electrocardiogram were fasted overnight. After 75 minutes at rest blood was drawn without a tourniquet from an antecubital vein for estimation of baseline platelet function, coagulation indices and blood viscosity. The volunteers were then given 5 mgms of carteolol orally and the same tests were repeated at 2, 5 and 24 hours post ingestion. Blood was anticoagulated with 3.8% trisodiumcitrate (9:l vol) to obtain titrated plasma for platelet and coagulation studies. Platelet aggregation was performed by the method of Born (10) using a Bryston aggregometer and a Vitatron recorder. All tests were performed in duplicate and completed within 2 hours of venepuncture. ADP and adrenaline (Z&1) and collagen (2 ug/ml) were used as the aggregation stimuli. The initial rate of aggregation (degree of light transmission per second) was measured by drawing a line through the maximum gradient of the aggregation curve. Platelet count was measured by tne Coulter thrombocounter (Coulter Electronics Ltd, England). Plasma betathromboglobulin (BTG) was measured by radioimmunoassay (RIA) using the kit supplied by the Radiochemical Centre, Amersham. Prothrombin time (PI) and partial thromboplastin time @TT) were measured using standard methods. Factor VIII coagulant activity (FVIIIc) was measured b a one stage assay (11). Factor VIII related antigen (FVIII R:A 'iwas measured by the Laurel1 Yocket" electroimmunoassay (12B . Serum fibrinogen degradation products (FDP's) were measured by the tanned red cell haemagglutination inh?_bitionimmunoassay using the Wellcome FDP kit. Fibrinogen was measured by the thrombin time method (13) using a Dade Fibrometer and standards. Plasma fibrinopeptide A was measured by an RIA using the kit supplied by Imco, Stockholm and carteolol in plasma was estimated by an RIA. Blood was anticoagulated with EDTA (2 g/l) for measurement of lasma viscosity (Coulter Harkness Capillary Viscometer, 25oCP and blood viscosity on raves LS 30 rotational viscometer, shear rates 0.95 and 94 (c 1 37OC) with correction for microhaematocrit (Hawksleymicroset' centrifuge, 13000 g for 5 minutes). Bleeding time was performed in duplicate using a disposable template bleeding time device (Simplate II, General Diagnostics) with an arm cuff pressure of 40 mm Hg. The Wilcoxon matched pairs signed rank test was used to compare changes from baseline measurements and results are expressed as mean f SET/I. RESULTS. We observed significant inhibition of the initial rate of platelet aggregation to ADP (~(0.05) and adrenaline (p
21.75* 3.72
ADP
BTG (ng/ml)
2
*9.15
9.56
+
38.2 + 6.1
236.3 + 14.9
32.75k4.19
** significant at p
42.2 f 8.0
5.9 + 0.48
233.4 i15.8
26.7 f 3.63
2.90
2.24
f 1.75
5
22.grjk4.34 *15.95t
14.97~2.91
9.34 + 1.27
* significant at ~(0.05
43.4 + 5.2
6.9 + 0.46
215.4 il7.70
Platelet count (X 109/l)
Bleeding Time (mins)
32.60* 4.05
Collagen (2pg/ml) %/set
(+M) %/xc
16.7
* 3.32
0
0
Adrenaline (2@) %/set
Initial Rate of Platelet Aggregation
Plasma Carte0101 (ng/ml)
HOURS
Platelet tests following carteolol (MEAN f SEM)
TABLE I.
+ 0.01
34.6
7.0
219.7
* 5.0
+ 0.90
f12.G
33.15 2 5.20
20.05 2 3.75
14.02 2 2.47
1.75
24
T I i__--___----,
T
/
\
/
/
\
/ 3<0
\ \
01
\
/
/
/ Meaq ? SEM
‘\
B
n*lO
NS
/ / 3 2
5
”
Time - ho&s
FIG. 1. The inhibition of the initial rate of adrenaline (2 urn)induced aggregation with time (Hrs), showing maximum inhibition corresponding to highest concentration of carteolol recorded. To check that diurnal variation could not account for these changes we also performed the same platelet aggregation studies on 5 of the above subjects under similar conditions without cart eolol and found no significant difference between the baseline and the 5 hour samples (see Table II). TABLE II. Platelet Aggregation without carteolol (MEAN * SEM) Hours
I
5
0
Initial rate of PA Adrenaline (2 @)
14.1
+ 2.51
ADP
20.4
2 3.69
(2W)
Collagen (2 pg/ml)
42.3 2 3.62
13.5
2 5.63
30 ,f 9.35 37.2
+
2.51
?.._ 5JJ
. k3 T-
. In
.
.
$
?
throz’oo-1 +obulin remained unchanged after a__d ‘oofa P:Latelet cotxi$ carteolol. X significant shortening of the bleeding time (2S.05) at the 5 hour period was also recorded. Coagulation tests (~/r;lT/FVIIiC/FVIII RAG/fibrin0 en/FDP and fibrinopeptide a) were unaltered following carteolol 7see Table III). Whole blood viscosity at high and low shear rates, corrected and UT,corrected for microhaematocrit, was also unchanged (see Table IV) Plasma viscosity was significantly increased at the 5 hour period (p(3.02). ”
“I
DISCUSSIOFI. These pilot studies demonstrate that carteolol in the minimum therapeutic oral dose has an inhibitory action on platelet aggregation induced by both adrenaline and ADP but no effect on platelet release as measured by plasma levels of BTG. Beta-blockers do not appear to influence platelet factor 3 availability (6,14, 15) but to our knowledge there have been no previous reports on the effect of beta-blockers on BTG. Inhibition of Cl4 serotonin release induced by aggregating agents has been observed after preincubation of platelets with propranolol in vitro (5). However under resting conditions in normal subjects, without any platelet aggregation stimuli, one could not anticipate any significant decrease in platelet release and the fact that there was no change in BTG during the 24 hour period was therefore not surprising.
Antagonism of platelet function by beta-adrenergic blockers was first noted in 1955 (16) since when there have been numerous conflicting studies. Most of the studies have been performed on the non selective blocker propranolol, but other beta-blockers have been shown to have antiplatelet actions (15) although the selective beta-blocker practolol appears to have no effect (6, Investigators have disagreed on the effects of propranolol, 15). some showing no significant anti-aggregator potential (14, 17) while others have shown the opposite (2,5,6 7 . The mechanism of the antiplatelet effect of beta-blockers is not clear. Itap e3rs not to be due to its role in the blockade of beta-receptors P6, 18) but since propranolol has known membrane stabilising action and is highly bound to platelet membrane phospholipid (6, 19) this may be a possible mode of action. A number of drugs with this stabilising action on biological membranes have been documented as possessing antiaggregatory effects (20). Carteolol has no membrane action of note and propranolol has been shown to reduce platelet aggregation in vivo in doses where no such membrane stabilising action would be expected (2). Thus, it is unlikely that the antiplatelet effect of carteolol is related to membrane stabilising activity. Beta-blockers have been shown to antagonise calcium transport both in myocardial cells (21) and within the platelet (6). As calcium ions are essential for aggregation of platelets this effect on calcium could explain how the platelet action is mediated.
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Propranolol has apparently no effect on the bleeding tire (:8) -cu+we have demonstrated a reduction in the bleeding time at the 5. It is also known that beta-blockade can at least partiallyirhihit the rise of FVIII mediated by stress or adrenaline infusion (25) but has no effect on baseline coagulation activity (25). We have confirmed this last observation and further note that carteolol does not affect fibrinopeptide i levels - an index of thrombin activity. Dintenfass et al (27) found lower blood viscosity in patients with coronary artery disease who were taking a course of betablockers, but we have not (28). Our work has shown carteolol to have no effect on blood viscosity in normal volunteers; Reinhart et al (29) also observed no effect on single dose propranolol on viscosity. These actions of carteolol, in which platelet aggregation is inhibited without changes in other haemostatic variables merit further study. Perhaps the improvement in prognosis of patients placed on beta-blockers following m ocardial infarction as shown by the recent studies on Timolol (8'5and Metoprolol (9) may be at least partly mediated via an antiplatelet effect. ACKNOWLEDGEMENT. We wish to thank Be&Pharmaceuticals for supplying carteolol and also giving support to the project. REFERENCES. 1.
CARVALHO, A.C.A., COLMAN, R.W., LEES, R.S. Platelet function in hyperlipoproteinaemia. N. Eng. J. Med. 290: 434-438. 1974.
2.
FRISHMAN, W.H., CHRISTODOULOU, J., WEKSLER, B., SMITHEN, C., KILLIP, T., SCHEIDT, S. Abrupt Propranolol withdrawal in angina pectoris; effects on platelet aggregation andexercise tolerance. Am. Heart J. s: 169-1'79.1978.
3.
SAGEL, J., COLWELL, J.A., CROOK, L., LAIMINS, M. Increased platelet aggregation in early diabetes mellitus. Ann Intern M&. 82: 733-738. 1975.
4.
HAFT, J.L., KRANZ, P.D., ALBERT, F.J., FANI, K. Intravascular platelet aggregation in the heart induced by norepinephine. Circulation. 45: 698-708. 1972.
5.
RUBEGNI,M., PROVVEDI, D., BELLINI, P.S. Letter- Beta blocking agents and platelet aggregation. JAEY..'22C?:4%?. -1974.
T _ .
WEKSLER, B-B., GILLICK, M., PINK, J. Effects of propranolol on platelet function. Blood Q: 135-195. 1977.
7.
MULTICENTRE INTERNATIONAL STUDY GROUP. Improvement in prognosis of myocardial infarction by longterm beta-adrenoreceptor blockade using practolol. Br. Med. J. 1: 735-740. 1975.
8.
NOR~~~GIAN~~TICE~IT~ STUDY GROUP. Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. M. Ena. J. Med. 304: eOl-807. 1981.
9.
HJALM4RSON, B., ELMFELDT, D., HERLITZ, J., HOLMBERG, S., HALE;(,I., NYBERG, G., RYDEN, L., SWEDBERG, K., VEDIN, A., WILHELMSEN, L., WILKELMSSON, C. Effect on mortality of metoprolol in acute myocardial infarction. Lancet -2: 823826. 1981.
10.
BORN, G.V.R. Aggregation of blood platelets reversal. Nature. 1%: 972. 1962.
11.
BRECKENRIDGE, R .T., RATNOFF, 0-D. Studies on the nature of the circulatory anticoagulant directed against the antihaemophilic factor: with notes on any assay for antihaemophilic factor. Blood 20: _ 137. 1962.
?Jy
ADP and its
12. LAURELL, C.B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Analytical Biochemistry. 12: 45-49. 1966. 13.
CLAUSS, A. Gerinnungsphysiologische Schnellmethode sur Bestimmung des Fibrinogens. Acta Haematologica. 17: 237246. 1957.
14.
LEON, R., TIARKS, C.Y., PECHET, L. Some observations on the in vivo effect of propranolol on platelet aggregation and release. Am. J. Haematol. -5: 117-121. 1978.
15.
ZAWILSKA, K., KOMARNICKI, M., MANKA, B. Proceedings: Effect of beta-blockers on human blood platelets in vivo. Thromb. Diath. Haemorrh. 2: 336. 1975.
16.
MCCLURE, P.D., INGRAM, G.I.C., VAUGHAN, R.J. Platelet changes after adrenaline infusion with and without adrenaline blockers. Thromb. Diath. Haemorrh. 13: 136. 1965. -
17.
KEBER, I., JERSE, M., KEBER, D., STEGNER, M. The influence of combined treatment with propranolol and acetylsalicylic acid on platelet aggregation in coronary artery disease. ,Br. J. Clin. Pharmacol. 1 (3): 287-291. 1979.
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3 ,
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BOULLIN, D.J., ZL~T~?F:, P.A. Characterisation of receotors mediating 5HT and catecholamine - induced platelet aggregation assessed by the action sf z and B-blockers, butyrophenones, 5-HT antagonists and chlorpromazine. Br.J. Pharmacol. 62
(4) 537-542.
1978.
13.
BCISSEAU M.. DACHAXY-PRIGENT J DUFOURCQ, J. LUSSAN, Propranolbl, chior$omazine and platelet meib;ane; a fl;orescence study of the drug-membrane interaction. :Thromb. m. 14: 15-22. 1979.
20.
MILLS, D.C.B., ROBERTS, G.C.K. Membrane active drug and the aggregation of human blood platelets. Nature. Jan. 35-38. 1967.
21.
FLECKENSTEIN, A. Specific inhibitors and promotors of calcium action in the excitation - contraction coupling of heart muscle and their role in the prevention or production of myocardial lesions. In: Harris, P., Opie, L. eds. Calcium and the Heart. New York: Academic Press. 135-188. 1971. __
22.
McSORLEY, P.D., WARREN, D.J. Effects of propranolol and metoprolol on the peripheral circulation. Br. Med.J. 2: 1598. 1978.
23.
CORRALL, R.J.M., WEBBER, R.G., RIER, B.M. Increase in coagulation factor VIII activity in man following acute hypopgycaemia. Medication via an adrenergic mechanism. Br. J. Haematol. 3: 301-305. 1980.
24.
INGRAii,G.I.C. Increase in antihaemophiliac globulin activity following infusion of adrenaline. J. Physiol. 1s: 217224. 19Gl.
25.
COHEN, R.J., EPSTEIN, S.E., COHEN, L.S., DENNIS, L.H. Alterations of fibrinolysis and blood coagulation induced by exercise and the role of beta-adrenergic stimulation. Lancet 2: 1264-1266. 1968.
26.
BUTLER, M.J., SMITH, M., IRVING, M.H., GORDON, Y.B., RATHY, S.M., RIVERS, J.W., HAWKEY, C. The influence of beta-adrenergic blockade upon baseline blood coagulation and fibrinolytic activity and upon the response to venous occlusion. Thromb. Diath. Haemorrh. 31: 169-180. 1975.
27.
DINTENFASS, L., LAKE, B. Beta blockers and blood viscosity (Letter). Lancet 1: 1026. 1976.
28.
LOWE, G.D.O., DRUMMOND, M-M., LORIMER, A.R., HUTTON, I., FORBES, C.D., PRENTICE,C.R.M., BARBENEL, J.C. Relation between extent of coronary artery disease and blood viscosity. Br. Med. J. 280: 673-674. 1980.
29.
REINHART, W., STAUBLI, M., STRAUB, P.W. The effect of a single dose of propranolol on human erythrocytes in viva. Europ. J. Clin. Invest. 65-68. 1981.
w* Small, J.T. Douglas, +G.W. Aherne, Korna Orr, G.D.O. Lowe, C. D. Forbes and C. R. M. Prentice. University Department of Medicine, Royal Infirmary,Glasgow. and *Department of Biochemistry, University of Surrey. (Received 16.11.1981; in revised form 14.1.1982. Accepted by Editor D. Ogston)
ABSTRACT We have studied the effect of a new beta-adrenergic blocker, carteolol, on platelet function, blood coagulation and viscosity in IO healthy male volunteers. Following carteolol (5 mg orally) we were able to demonstrate significant inhibition of platelet aggregation to ADP (p
_.....
Key Words: Carteolol, beta-adrenoceptor blocker,platelet functicn
351
.-_. -; i__.-_)
:,m--q@J~ _w_-
:;c . ;
*
Ten healthy male volunteers (age range 22-45, mean = 23.2 years) with normal biochemistry, haematolcgy and resting electrocardiogram were fasted overnight. After 75 minutes at rest blood was drawn without a tourniquet from an antecubital vein for estimation of baseline platelet function, coagulation indices and blood viscosity. The volunteers were then given 5 mgms of carteolol orally and the same tests were repeated at 2, 5 and 24 hours post ingestion. Blood was anticoagulated with 3.8% trisodiumcitrate (9:l vol) to obtain titrated plasma for platelet and coagulation studies. Platelet aggregation was performed by the method of Born (10) using a Bryston aggregometer and a Vitatron recorder. All tests were performed in duplicate and completed within 2 hours of venepuncture. ADP and adrenaline (Z&1) and collagen (2 ug/ml) were used as the aggregation stimuli. The initial rate of aggregation (degree of light transmission per second) was measured by drawing a line through the maximum gradient of the aggregation curve. Platelet count was measured by tne Coulter thrombocounter (Coulter Electronics Ltd, England). Plasma betathromboglobulin (BTG) was measured by radioimmunoassay (RIA) using the kit supplied by the Radiochemical Centre, Amersham. Prothrombin time (PI) and partial thromboplastin time @TT) were measured using standard methods. Factor VIII coagulant activity (FVIIIc) was measured b a one stage assay (11). Factor VIII related antigen (FVIII R:A 'iwas measured by the Laurel1 Yocket" electroimmunoassay (12B . Serum fibrinogen degradation products (FDP's) were measured by the tanned red cell haemagglutination inh?_bitionimmunoassay using the Wellcome FDP kit. Fibrinogen was measured by the thrombin time method (13) using a Dade Fibrometer and standards. Plasma fibrinopeptide A was measured by an RIA using the kit supplied by Imco, Stockholm and carteolol in plasma was estimated by an RIA. Blood was anticoagulated with EDTA (2 g/l) for measurement of lasma viscosity (Coulter Harkness Capillary Viscometer, 25oCP and blood viscosity on raves LS 30 rotational viscometer, shear rates 0.95 and 94 (c 1 37OC) with correction for microhaematocrit (Hawksleymicroset' centrifuge, 13000 g for 5 minutes). Bleeding time was performed in duplicate using a disposable template bleeding time device (Simplate II, General Diagnostics) with an arm cuff pressure of 40 mm Hg. The Wilcoxon matched pairs signed rank test was used to compare changes from baseline measurements and results are expressed as mean f SET/I. RESULTS. We observed significant inhibition of the initial rate of platelet aggregation to ADP (~(0.05) and adrenaline (p
21.75* 3.72
ADP
BTG (ng/ml)
2
*9.15
9.56
+
38.2 + 6.1
236.3 + 14.9
32.75k4.19
** significant at p
42.2 f 8.0
5.9 + 0.48
233.4 i15.8
26.7 f 3.63
2.90
2.24
f 1.75
5
22.grjk4.34 *15.95t
14.97~2.91
9.34 + 1.27
* significant at ~(0.05
43.4 + 5.2
6.9 + 0.46
215.4 il7.70
Platelet count (X 109/l)
Bleeding Time (mins)
32.60* 4.05
Collagen (2pg/ml) %/set
(+M) %/xc
16.7
* 3.32
0
0
Adrenaline (2@) %/set
Initial Rate of Platelet Aggregation
Plasma Carte0101 (ng/ml)
HOURS
Platelet tests following carteolol (MEAN f SEM)
TABLE I.
+ 0.01
34.6
7.0
219.7
* 5.0
+ 0.90
f12.G
33.15 2 5.20
20.05 2 3.75
14.02 2 2.47
1.75
24
T I i__--___----,
T
/
\
/
/
\
/ 3<0
\ \
01
\
/
/
/ Meaq ? SEM
‘\
B
n*lO
NS
/ / 3 2
5
”
Time - ho&s
FIG. 1. The inhibition of the initial rate of adrenaline (2 urn)induced aggregation with time (Hrs), showing maximum inhibition corresponding to highest concentration of carteolol recorded. To check that diurnal variation could not account for these changes we also performed the same platelet aggregation studies on 5 of the above subjects under similar conditions without cart eolol and found no significant difference between the baseline and the 5 hour samples (see Table II). TABLE II. Platelet Aggregation without carteolol (MEAN * SEM) Hours
I
5
0
Initial rate of PA Adrenaline (2 @)
14.1
+ 2.51
ADP
20.4
2 3.69
(2W)
Collagen (2 pg/ml)
42.3 2 3.62
13.5
2 5.63
30 ,f 9.35 37.2
+
2.51
?.._ 5JJ
. k3 T-
. In
.
.
$
?
throz’oo-1 +obulin remained unchanged after a__d ‘oofa P:Latelet cotxi$ carteolol. X significant shortening of the bleeding time (2S.05) at the 5 hour period was also recorded. Coagulation tests (~/r;lT/FVIIiC/FVIII RAG/fibrin0 en/FDP and fibrinopeptide a) were unaltered following carteolol 7see Table III). Whole blood viscosity at high and low shear rates, corrected and UT,corrected for microhaematocrit, was also unchanged (see Table IV) Plasma viscosity was significantly increased at the 5 hour period (p(3.02). ”
“I
DISCUSSIOFI. These pilot studies demonstrate that carteolol in the minimum therapeutic oral dose has an inhibitory action on platelet aggregation induced by both adrenaline and ADP but no effect on platelet release as measured by plasma levels of BTG. Beta-blockers do not appear to influence platelet factor 3 availability (6,14, 15) but to our knowledge there have been no previous reports on the effect of beta-blockers on BTG. Inhibition of Cl4 serotonin release induced by aggregating agents has been observed after preincubation of platelets with propranolol in vitro (5). However under resting conditions in normal subjects, without any platelet aggregation stimuli, one could not anticipate any significant decrease in platelet release and the fact that there was no change in BTG during the 24 hour period was therefore not surprising.
Antagonism of platelet function by beta-adrenergic blockers was first noted in 1955 (16) since when there have been numerous conflicting studies. Most of the studies have been performed on the non selective blocker propranolol, but other beta-blockers have been shown to have antiplatelet actions (15) although the selective beta-blocker practolol appears to have no effect (6, Investigators have disagreed on the effects of propranolol, 15). some showing no significant anti-aggregator potential (14, 17) while others have shown the opposite (2,5,6 7 . The mechanism of the antiplatelet effect of beta-blockers is not clear. Itap e3rs not to be due to its role in the blockade of beta-receptors P6, 18) but since propranolol has known membrane stabilising action and is highly bound to platelet membrane phospholipid (6, 19) this may be a possible mode of action. A number of drugs with this stabilising action on biological membranes have been documented as possessing antiaggregatory effects (20). Carteolol has no membrane action of note and propranolol has been shown to reduce platelet aggregation in vivo in doses where no such membrane stabilising action would be expected (2). Thus, it is unlikely that the antiplatelet effect of carteolol is related to membrane stabilising activity. Beta-blockers have been shown to antagonise calcium transport both in myocardial cells (21) and within the platelet (6). As calcium ions are essential for aggregation of platelets this effect on calcium could explain how the platelet action is mediated.
-l~-;--
>-,
_./_.__i_~_-
_a.
?.
1,-T
;:-_
y-
.___
--
__-..z_:-
__.,.~___..
I__-.
--
._:
.z...__‘,
-
-
\.
.>.-
Propranolol has apparently no effect on the bleeding tire (:8) -cu+we have demonstrated a reduction in the bleeding time at the 5
CARVALHO, A.C.A., COLMAN, R.W., LEES, R.S. Platelet function in hyperlipoproteinaemia. N. Eng. J. Med. 290: 434-438. 1974.
2.
FRISHMAN, W.H., CHRISTODOULOU, J., WEKSLER, B., SMITHEN, C., KILLIP, T., SCHEIDT, S. Abrupt Propranolol withdrawal in angina pectoris; effects on platelet aggregation andexercise tolerance. Am. Heart J. s: 169-1'79.1978.
3.
SAGEL, J., COLWELL, J.A., CROOK, L., LAIMINS, M. Increased platelet aggregation in early diabetes mellitus. Ann Intern M&. 82: 733-738. 1975.
4.
HAFT, J.L., KRANZ, P.D., ALBERT, F.J., FANI, K. Intravascular platelet aggregation in the heart induced by norepinephine. Circulation. 45: 698-708. 1972.
5.
RUBEGNI,M., PROVVEDI, D., BELLINI, P.S. Letter- Beta blocking agents and platelet aggregation. JAEY..'22C?:4%?. -1974.
T _ .
WEKSLER, B-B., GILLICK, M., PINK, J. Effects of propranolol on platelet function. Blood Q: 135-195. 1977.
7.
MULTICENTRE INTERNATIONAL STUDY GROUP. Improvement in prognosis of myocardial infarction by longterm beta-adrenoreceptor blockade using practolol. Br. Med. J. 1: 735-740. 1975.
8.
NOR~~~GIAN~~TICE~IT~ STUDY GROUP. Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. M. Ena. J. Med. 304: eOl-807. 1981.
9.
HJALM4RSON, B., ELMFELDT, D., HERLITZ, J., HOLMBERG, S., HALE;(,I., NYBERG, G., RYDEN, L., SWEDBERG, K., VEDIN, A., WILHELMSEN, L., WILKELMSSON, C. Effect on mortality of metoprolol in acute myocardial infarction. Lancet -2: 823826. 1981.
10.
BORN, G.V.R. Aggregation of blood platelets reversal. Nature. 1%: 972. 1962.
11.
BRECKENRIDGE, R .T., RATNOFF, 0-D. Studies on the nature of the circulatory anticoagulant directed against the antihaemophilic factor: with notes on any assay for antihaemophilic factor. Blood 20: _ 137. 1962.
?Jy
ADP and its
12. LAURELL, C.B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Analytical Biochemistry. 12: 45-49. 1966. 13.
CLAUSS, A. Gerinnungsphysiologische Schnellmethode sur Bestimmung des Fibrinogens. Acta Haematologica. 17: 237246. 1957.
14.
LEON, R., TIARKS, C.Y., PECHET, L. Some observations on the in vivo effect of propranolol on platelet aggregation and release. Am. J. Haematol. -5: 117-121. 1978.
15.
ZAWILSKA, K., KOMARNICKI, M., MANKA, B. Proceedings: Effect of beta-blockers on human blood platelets in vivo. Thromb. Diath. Haemorrh. 2: 336. 1975.
16.
MCCLURE, P.D., INGRAM, G.I.C., VAUGHAN, R.J. Platelet changes after adrenaline infusion with and without adrenaline blockers. Thromb. Diath. Haemorrh. 13: 136. 1965. -
17.
KEBER, I., JERSE, M., KEBER, D., STEGNER, M. The influence of combined treatment with propranolol and acetylsalicylic acid on platelet aggregation in coronary artery disease. ,Br. J. Clin. Pharmacol. 1 (3): 287-291. 1979.
_r
;^a
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-
A-
‘>,
-“-
,.,-
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.\--.
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