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PROSTAGLANDIN E 1 AND HUMAN PLATELETS
111 a
high birth-rate and diminishing local resources. Is there they are always more content with their
any evidence that
lot than urban industrialised societies ? The behaviour of some newly emergent nations makes one wonder. Reed Paper Group Medical Service, Maidstone, Kent.
TERRY COATES.
PROSTAGLANDIN E 1 AND HUMAN PLATELETS
SIR,-Prostaglandin
E
1
(P.G.E 1) inhibits platelet
adhesiveness, aggregation, and electrophoretic mobility in Vitro.1Since it can be safely infused into man in small doses3 we have studied its effects on human platelets. Sterile solutions of P.G.E 1 in isotonic saline solution (supplied
by Prof. S. Bergstrom, Karolinska Institute, Stockholm) were injected into a cubital vein at a rate of 0-2 g. per kg. per min. for The maximum total amount administered was 250 jjtg., and the minimum was 160 fLg. (the infusion being stopped because of side-effects). The subjects were 9 male volunteers aged 25-68. Shortly after the beginning of the infusion, each subject noticed facial flushing and a feeling of constriction in the chest. In 8 there was a slight fall in bloodpressure (B.P.) (up to 10 mm. Hg diastolic), but in 1 subject the infusion was stopped when the systolic pressure fell to 70 mm. Hg. 1 subject also experienced severe nausea, giddiness, and abdominal discomfort. All the symptoms disappeared within 5 minutes of the end of the infusion, except in the subject with severe hypotension, whose B.P. remained low for 30 minutes. Two different batches of P.G.E 1 were used, 4 subjects receiving one and 4 the other; the symptoms experienced were similar in the two groups. Venous blood-samples, taken with disposable plastic syringes from the arm which was not being used for the infusion, were obtained immediately before the infusion of P.G.E 1, at the end of the infusion, and at intervals up to 2 hours afterwards. 9-ml. samples of blood were transferred to siliconised glass tubes containing 1 ml. of 3-8% solution (w/v) of trisodium citrate. For the aggregation and electrophoretic experiments,- platelet-rich plasma (P.R.P.) and platelet-poor plasma (P.P.P.) were prepared by centrifugation at 150 g for 10 minutes and 750 g for 15 minutes respectively. Platelet adhesiveness was measured in whole blood by a modification of the technique of Payling Wright,4duplicate platelet-counts being performed before and after 40 minutes’ rotation, the observer counting the cells being unaware of the Platelet aggregation was source and timing of the sample. measured by a modification of the turbidimetric method of Bom.17 Platelet electrophoretic mobility was measured in a horizontal capillary apparatus 8 by the technique described by Hampton and Mitchell.99 up to 15 minutes.
Platelet adhesiveness.-In the 4 subjects treated with the first batch of P.G.E 1 mean platelet adhesiveness fell from 36% before the infusion to 11 % at the end of the infusion 30 minutes later platelet adhesiveness was still (P<0’02). reduced in each patient (mean 19%), but after a further hour it had returned to its initial value. In the 4 subjects given P.G.E 1 from the second batch the mean values were 35% before, and 39% immediately after, the infusion. Platelet aggregation.-The effects of adenosine diphosphate (A.D.P.) in a final concentration of 0-5 and 1-0 pg. per ml. were studied in P.R.P. samples from 5 subjects (3 treated with the first and 2 treated with the second batch of P.G.E 1). There was no significant difference between the samples taken before and after the infusion. Platelet electrophoretic mobility.-The platelet electro1. 2.
3. 4. 5. 6. 7. 8. 9.
Kloeze, J. in Proceedings of Nobel Symposium II. Stockholm, 1966. Emmons, P. R., Hampton, J. R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Br. med.J. 1967, ii, 468. Bergastrom, S., Carlson, L. A., Ekelund, L.-G., Oro, L. Acta physiol. scand. 1965, 64, 332. Payling Wright, H. J. Path. Bact. 1941, 53, 255. Emmons, P.R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Lancet, 1965, ii, 603. Born, G. V. R. J. Physiol., Lond. 1962, 162, 67p. Emmons, P. R., Mitchell, J. R. A. Lancet, 1965, i, 71. Bangham, A. D., Flemans, R., Heard, D. H., Seaman, G. V. F. Nature, Lond. 1958, 182, 642. Hampton, J. R., Mitchell, J. R. A. Br. med. J. 1966, i, 1074.
phoretic-mobility changes induced by A.D.P. were measured in 5 subjects (2 treated with the first, and 3 treated with the second batch of P.G.E 1). These subjects showed the characteristic biphasic mobility changes,9 a 7% increase in platelet mobility being induced by 0-05 g. per ml. of A.D.P., and a 6% decrease in mobility by 0-5 g. per ml. Immediately after the p.G.E 1, the addition of A.D.P. failed to produce any change in mobility; in 2 of the subjects the platelet response to A.D.P. was still strikingly decreased 30 minutes after the infusion, and in 1 subject the mobility response remained impaired at 1 hour. In all 5 subjects the response had returned to normal 2 hours after the P.G.E 1. These experiments show that some aspects of the invitro behaviour of human platelets can be influenced by the intravenous administration of P.G.E 1; we cannot deduce that their behaviour in vivo is affected, but our studies with rabbitssuggest that it would be. However, the undesirable side-effects produced by P.G.E 1 in 2 of our subjects, together with the need to administer it by intravenous infusion, will limit its potential use as an antithrombotic agent in man. It is not clear why one of the batches of p.G.E 1 that we used should have strikingly affected platelet adhesiveness while the other did not. However, the mechanism of action of P.G.E 1 on platelets remains unknown, although in some respects its effects resemble those of other vasoactive compounds.10 Our present studies show that platelet behaviour is modified for a considerably longer period than the time for which free P.G.E 1 is known to remain in the circulation (it is rapidly broken down in the lungs, and the bulk of a single injection of P.G.E 1 has disappeared from the blood after 10 minutes 11). We do not know whether the more prolonged action of P.G.E 1 on platelet behaviour indicates that one of its breakdown products is the active material, or whether it induces some change in the cells which has its own time-course and, once induced, is independent of the level of circulating P.G.E 1. Since the mechanism by which the prostaglandins act in respect of other types of cell behaviour is via modifications in the level of 3’5’ cycle adenosine monophosphate (A.M.P.) in the cell, it is possible that changes in platelet cyclic A.M.P. activity could be induced by a brief exposure to P.G.E 1 which would persist after the P.G.E 1 itself had disappeared. This aspect of the action of P.G.E 1 is now being studied. R. S. E. is now at the department of
medicine, Royal Post-
tn-arhtatf Mitral Scool T.nnclnn W 12
Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford. of Medicine, General Hospital, Nottingham NGI 6HA.
R. S. ELKELES J. R HAMPTON M. J. G. HARRISON.
Department
J. R. A. MITCHELL.
ANALGESIA FOR BURNS SIR,-Dr. Sachs and Mr. Watson (April 5, p. 718) remark on the use of neuroleptanalgesia in the management of burns. In our unit, which is the centre for the north of Israel, our experience with this form of analgesia has been very favourable. Many of the potential difficulties of general anarsthesia are avoided, including the necessity of fasting, the production of nausea and vomiting which further precludes feeding, and the high incidence of cardiac arrest which is increased by endotracheal intubation. On Passover night, 1968,12 30 burned patients were received by our casualty department after a major fire. 22 of these were admitted, and, altogether, 168 changes of burn dressings were done under neuroleptanalgesia, using a Hampton, J. R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Cardiovasc. Res. 1967, 1, 101. 11. Granstrom, E. Progr. Biochem. Pharmac. 1967, 3, 89. 12. Birkhan, H. J., Mahler, D., Hirshowitz, B., Monies, I. Harefuah, 1969, 2, 57. 10.
high birth-rate and diminishing local resources. Is there they are always more content with their
any evidence that
lot than urban industrialised societies ? The behaviour of some newly emergent nations makes one wonder. Reed Paper Group Medical Service, Maidstone, Kent.
TERRY COATES.
PROSTAGLANDIN E 1 AND HUMAN PLATELETS
SIR,-Prostaglandin
E
1
(P.G.E 1) inhibits platelet
adhesiveness, aggregation, and electrophoretic mobility in Vitro.1Since it can be safely infused into man in small doses3 we have studied its effects on human platelets. Sterile solutions of P.G.E 1 in isotonic saline solution (supplied
by Prof. S. Bergstrom, Karolinska Institute, Stockholm) were injected into a cubital vein at a rate of 0-2 g. per kg. per min. for The maximum total amount administered was 250 jjtg., and the minimum was 160 fLg. (the infusion being stopped because of side-effects). The subjects were 9 male volunteers aged 25-68. Shortly after the beginning of the infusion, each subject noticed facial flushing and a feeling of constriction in the chest. In 8 there was a slight fall in bloodpressure (B.P.) (up to 10 mm. Hg diastolic), but in 1 subject the infusion was stopped when the systolic pressure fell to 70 mm. Hg. 1 subject also experienced severe nausea, giddiness, and abdominal discomfort. All the symptoms disappeared within 5 minutes of the end of the infusion, except in the subject with severe hypotension, whose B.P. remained low for 30 minutes. Two different batches of P.G.E 1 were used, 4 subjects receiving one and 4 the other; the symptoms experienced were similar in the two groups. Venous blood-samples, taken with disposable plastic syringes from the arm which was not being used for the infusion, were obtained immediately before the infusion of P.G.E 1, at the end of the infusion, and at intervals up to 2 hours afterwards. 9-ml. samples of blood were transferred to siliconised glass tubes containing 1 ml. of 3-8% solution (w/v) of trisodium citrate. For the aggregation and electrophoretic experiments,- platelet-rich plasma (P.R.P.) and platelet-poor plasma (P.P.P.) were prepared by centrifugation at 150 g for 10 minutes and 750 g for 15 minutes respectively. Platelet adhesiveness was measured in whole blood by a modification of the technique of Payling Wright,4duplicate platelet-counts being performed before and after 40 minutes’ rotation, the observer counting the cells being unaware of the Platelet aggregation was source and timing of the sample. measured by a modification of the turbidimetric method of Bom.17 Platelet electrophoretic mobility was measured in a horizontal capillary apparatus 8 by the technique described by Hampton and Mitchell.99 up to 15 minutes.
Platelet adhesiveness.-In the 4 subjects treated with the first batch of P.G.E 1 mean platelet adhesiveness fell from 36% before the infusion to 11 % at the end of the infusion 30 minutes later platelet adhesiveness was still (P<0’02). reduced in each patient (mean 19%), but after a further hour it had returned to its initial value. In the 4 subjects given P.G.E 1 from the second batch the mean values were 35% before, and 39% immediately after, the infusion. Platelet aggregation.-The effects of adenosine diphosphate (A.D.P.) in a final concentration of 0-5 and 1-0 pg. per ml. were studied in P.R.P. samples from 5 subjects (3 treated with the first and 2 treated with the second batch of P.G.E 1). There was no significant difference between the samples taken before and after the infusion. Platelet electrophoretic mobility.-The platelet electro1. 2.
3. 4. 5. 6. 7. 8. 9.
Kloeze, J. in Proceedings of Nobel Symposium II. Stockholm, 1966. Emmons, P. R., Hampton, J. R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Br. med.J. 1967, ii, 468. Bergastrom, S., Carlson, L. A., Ekelund, L.-G., Oro, L. Acta physiol. scand. 1965, 64, 332. Payling Wright, H. J. Path. Bact. 1941, 53, 255. Emmons, P.R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Lancet, 1965, ii, 603. Born, G. V. R. J. Physiol., Lond. 1962, 162, 67p. Emmons, P. R., Mitchell, J. R. A. Lancet, 1965, i, 71. Bangham, A. D., Flemans, R., Heard, D. H., Seaman, G. V. F. Nature, Lond. 1958, 182, 642. Hampton, J. R., Mitchell, J. R. A. Br. med. J. 1966, i, 1074.
phoretic-mobility changes induced by A.D.P. were measured in 5 subjects (2 treated with the first, and 3 treated with the second batch of P.G.E 1). These subjects showed the characteristic biphasic mobility changes,9 a 7% increase in platelet mobility being induced by 0-05 g. per ml. of A.D.P., and a 6% decrease in mobility by 0-5 g. per ml. Immediately after the p.G.E 1, the addition of A.D.P. failed to produce any change in mobility; in 2 of the subjects the platelet response to A.D.P. was still strikingly decreased 30 minutes after the infusion, and in 1 subject the mobility response remained impaired at 1 hour. In all 5 subjects the response had returned to normal 2 hours after the P.G.E 1. These experiments show that some aspects of the invitro behaviour of human platelets can be influenced by the intravenous administration of P.G.E 1; we cannot deduce that their behaviour in vivo is affected, but our studies with rabbitssuggest that it would be. However, the undesirable side-effects produced by P.G.E 1 in 2 of our subjects, together with the need to administer it by intravenous infusion, will limit its potential use as an antithrombotic agent in man. It is not clear why one of the batches of p.G.E 1 that we used should have strikingly affected platelet adhesiveness while the other did not. However, the mechanism of action of P.G.E 1 on platelets remains unknown, although in some respects its effects resemble those of other vasoactive compounds.10 Our present studies show that platelet behaviour is modified for a considerably longer period than the time for which free P.G.E 1 is known to remain in the circulation (it is rapidly broken down in the lungs, and the bulk of a single injection of P.G.E 1 has disappeared from the blood after 10 minutes 11). We do not know whether the more prolonged action of P.G.E 1 on platelet behaviour indicates that one of its breakdown products is the active material, or whether it induces some change in the cells which has its own time-course and, once induced, is independent of the level of circulating P.G.E 1. Since the mechanism by which the prostaglandins act in respect of other types of cell behaviour is via modifications in the level of 3’5’ cycle adenosine monophosphate (A.M.P.) in the cell, it is possible that changes in platelet cyclic A.M.P. activity could be induced by a brief exposure to P.G.E 1 which would persist after the P.G.E 1 itself had disappeared. This aspect of the action of P.G.E 1 is now being studied. R. S. E. is now at the department of
medicine, Royal Post-
tn-arhtatf Mitral Scool T.nnclnn W 12
Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford. of Medicine, General Hospital, Nottingham NGI 6HA.
R. S. ELKELES J. R HAMPTON M. J. G. HARRISON.
Department
J. R. A. MITCHELL.
ANALGESIA FOR BURNS SIR,-Dr. Sachs and Mr. Watson (April 5, p. 718) remark on the use of neuroleptanalgesia in the management of burns. In our unit, which is the centre for the north of Israel, our experience with this form of analgesia has been very favourable. Many of the potential difficulties of general anarsthesia are avoided, including the necessity of fasting, the production of nausea and vomiting which further precludes feeding, and the high incidence of cardiac arrest which is increased by endotracheal intubation. On Passover night, 1968,12 30 burned patients were received by our casualty department after a major fire. 22 of these were admitted, and, altogether, 168 changes of burn dressings were done under neuroleptanalgesia, using a Hampton, J. R., Harrison, M. J. G., Honour, A. J., Mitchell, J. R. A. Cardiovasc. Res. 1967, 1, 101. 11. Granstrom, E. Progr. Biochem. Pharmac. 1967, 3, 89. 12. Birkhan, H. J., Mahler, D., Hirshowitz, B., Monies, I. Harefuah, 1969, 2, 57. 10.