Interaction of Human Blood Platelets with the 2′,3′‐Dialdehyde and 2′,3′‐Dialcohol Derivatives of Adenosine 5′‐Diphosphate and Adenosine 5′‐Triphosphate

Abstract

1. The 2',3'-dialdehyde derivative of ADP (oADP) at concentrations approaching the millimolar range induces human blood platelets to undergo the transition from discoid to globular morphology (the 'shape change') but is incapable of inducing aggregation.2. When incubated with platelets for 1 min before addition of the agonist, oADP acts as a competitive inhibitor of shape change and aggregation induced by ADP. Under these conditions secretion and hence aggregation induced by low concentrations of collagen ; and secretion and hence secondary aggregation induced by adrenaline, thrombin and vasopressin are also inhibited by this analogue. In addition, oADP stimulates the rate of primary aggregation induced by adrenaline and causes partial inhibition of primary aggregation induced by thrombin or vasopressin. When longer preincubation times are employed the extent of inhibition with respect to all agonists, except for high concentrations of collagen, is increased and the competitive character of the inhibition with respect to ADP is no longer apparent.3. Incubation of human platelets with the 2',3'-dialdehyde derivative of ATP (oATP) causes effects similar to those described for oADP except that the analogue neither induces platelet shape change, nor stimulates the rate of primary aggregation induced by adrenaline. In addition oATP fails to cause significant inhibition of platelet shape change induced by serotonin. The extent and character of inhibition caused by addition of oATP is not a function of the time of incubation.4. The 2',3'-dialcohol derivatives of ADP and ATP (orADP and orATP) effect the aggregation properties of human blood platelets in a manner generally resembling those observed for the 2',3'-dialdehyde analogues. However, orADP is only weakly effective in causing platelet shape change and stimulating the rate of primary aggregation induced by adrenaline and does not inhibit secretion induced by adrenaline, collagen, thrombin and vasopressin. The extent of inhibition by OI-ADP increases only slightly with increased time of incubation. 5.The data suggest that oADP acts as a partial agonist, and oATP as an antagonist, at the platelet ADP receptor, but that platelet membrane stabilisation also results from interaction with these dialdehyde analogues. Such membrane stabilisation does not complicate the interaction of platelets with orADP, which appears to act as a classical antagonist for the ADP receptor.Many agonists are capable of inducing platelet aggregation including adrenaline, thrombin, vasopressin and serotonin. In citrated plasma and under suitable conditions these agonists induce a biphasic response in which only the first, or reversible, phase is the direct result of platelet-agonist interaction. This initial interaction causes secretion of platelet constituents some of which are themselves inducers of aggregation and hence cause a further response associated ~~ -~ Ahhwviu/iorw. oATP and oADP. the 2',3'-dialdehyde derivatibe of ATP and ADP; orATP and orADP, the 2',3'-dialcohol derivative of AT...

Interaction of Selective Α‐adrenoceptor Agonists and Antagonists With Human and Rabbit Blood Platelets

“…Rabbit platelet-rich plasma was prepared as described by Wallis (1978) using either acid citrate-dextrose (10 mm citrate) or 14.7 mM trisodium citrate as anti-coagulant. The aggregatory response was monitored and quantitated using a Payton Model 300 dual-channel aggregometer as described previously (Pearce et al, 1978). When studies were performed with methanolic solutions of drugs, the final concentration of methanol in the system never exceeded 2% (v/v) and control studies demonstrated that the concentration added had no effect on the observed response.…”

“…Secretion by human platelets was estimated as described previously (Pearce et al, 1978) (Costa & Murphy, 1975). Secretion by rabbit platelets was estimated as described by Wallis (1978).…”

“…Human platelet-rich plasma was prepared from drugfree volunteers as described previously (Pearce, Wright, Egan & Scrutton, 1978). In all the experiments acid-citrate dextrose (10 mm citrate) was used as the anticoagulant.…”

“…Secretion by rabbit platelets was estimated as described by Wallis (1978). Collagen was prepared as described previously (Pearce et al, 1978 (Pearce et al, 1978;Egan, Fisher & Scrutton, 1979). All solutions were prepared in 0.1 M NaCl except for A-23187, prazosin hydrochloride, indomethacin and indoramin hydrochloride which were dissolved in methanol.…”

Effects of α2‐adrenoceptor agonists and of related compounds on aggregation of, and on adenylate cyclase activity in, human platelets

“…In most of the studies this response was assessed by measurement of changes in the turbidity of the platelet suspension using a Payton dual channel aggregometer interfaced with a Rikadenki DBE-2 dual channel recorder (Born & Cross, 1963;Pearce et al, 1978). All additions were made simultaneously except where the effect of compounds was examined on the response to a non-saturating dose of ADP in which case the compound was added 15 s before ADP.…”