Modulation of human platelet adenylate cyclase by prostacyclin (PGX).

https://science.sciencemag.org/content/sci/177/4047/401.full.pdf

Studies on the mechanism of hormone action

Effects of prostacyclin (PGX) on cyclic AMP concentrations in human platelets

Blood platelets as a model for monoamine-containing neurones.

Studies on the role of adenosine 3',5'-monophosphate in the hepatic actions of glucagon and catecholamines.

Divergent effects of epinephrine and prostaglandin E1 on the level of cyclic AMP in human blood platelets

Diagnostic specificity of sucrose hemolysis test for paroxysmal nocturnal hemoglobinuria.

1. Clonal theories of disease, particularly progressive clonal growth and selection in tumorogenesis, were briefly cited. 2. Evidence for the clonal nature of PNH was presented. Correlation of red cell hemolysis with (a) G-6-PD type in two female G-6-PD mosaics with PNH and with (b) erythrocyte acetylcholinesterase deficiency, provides strong evidence for the clonal theory of PNH. 3. Possible pitfalls in defining "hidden PNH clones" in other diseases by the use of PNH hemolytic tests were discussed. 4. The potential of PNH as a study model for clonal evolution in human disease was emphasized.

Paroxysmal nocturnal hemoglobinuria (PNH) as a clonal disorder.

platelet adenyl cyclase. This was noted several years ago by R.E.Scott and his colleagues(Butcher et a1,1967;Scott, 1970),and has been confirmed since by at least three other groups of investigators(Wo1fe and ShulmanIl969;Marquis et al,l969;Moskowitz et a1,1970). The order of potency of different prostaglandins,to the extent that this has been studied,is the same as their order of potency as inhibitors of platelet aggregation. With the exception of the fluoride ion,to be mentioned laterlagents which do not inhibit aggregation are not known to be capable of stimulating platelet adenyl cyclase. The second line of evidence derives from studies with intact platelets. As expected from their effect on adenyl cyclase,the prostaglandins increase the steady state level of cyclic AMP in these cells(Fig.l)(Robison et a1,1969). The greater potency of PGEl over PGE2 is in line with their known potencies as inhibitors of aggregation(Weeks et all 1969;Robison et a1,1969). Other investigators(Moskowitz et all 1970;Vigdahl et all 1969)have used 3H-adenine or 14Cadenosine to label endogenous ATP,and have obtained essentially similar results: the prostaglandins were found to stimulate the incorporation of radioactivity into cyclic AMP,reflecting an increased rate of synthesis of the cyclic nucleotide in the intact cells. Conversely,several agents which stimulate platelet aggregation have been shown to produce a fall in the level of cyclic AMP in these cells. These are epinephrine (Moskowitz et alIl970;Robison et alIl969;Salzman & Neri, 1969;Marquis et a1,1970)and adenosine diphosphate(ADP), (Salzman & Neri,l969;Cole et alIl970a),both of which are thought to play an important role in regulating platelet function in vivo(Mustard ti Packham,l970). The effect of epinephrine is mediated by adrenergic a-receptors, First,the prostaglandins are potent stimulants of

Effects of Prostaglandins on Function and Cyclic Amp Levels of Human Blood Platelets

Summary. No evidence was found to support the claimed role of lipid peroxidation in the pathogenesis and haemolysis in paroxysmal nocturnal haemoglobinuria (PNH) including iron-induced episodes of gross haemoglobinuria. Therapy with the antioxidant vitamin E failed to influence the course of two patients with PNH. Three separate techniques for inducing lipid peroxidation failed to lower AChE of normal and PNH red cells and to induce susceptibility to in vitro PNH haemolytic tests in normal cells whether iron was added to the test system or not. Under peroxidatic stress, PNH cells did not generate abnormally high amounts of lipid peroxides as measured by malonaldehyde formation. Similar results were obtained with human red cells with induced high concentrations of protoporphyrin IX. Such studies do not, however, vitiate the concept that lipid peroxidation may play an important role in biologic ageing and cell destruction.

Anita B. Arnold

Papers

Divergent effects of epinephrine and prostaglandin E1 on the level of cyclic AMP in human blood platelets

Diagnostic specificity of sucrose hemolysis test for paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) as a clonal disorder.

Effects of Prostaglandins on Function and Cyclic Amp Levels of Human Blood Platelets

Studies of the role of red cell membrane peroxidation in paroxysmal nocturnal haemoglobinuria (PNH).