The release of nucleotides, 5‐hydroxytryptamine and enzymes from human blood platelets during aggregation

Mills, D. C. B.; Robb, I. A.; Roberts, G. C. K.

doi:10.1113/jphysiol.1968.sp008484

Cited by 310 publications

(124 citation statements)

References 35 publications

(45 reference statements)

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“…This suggests either that centralization of the platelet granules may not be necessary for the release process or that, in rabbit platelet-rich plasma, the concentration of aggregating agents normally employed does not induce the complete reaction. The latter suggestion is supported by two observations: Herrman & Frank (1966) studied the response of rabbit platelets to aggregating agents in the absence of anticoagulants, and found biphasic responses of those that occur in human platelet-rich plasma produced by the release of the granular contents (see Mills et al 1968). Also, if rabbit platelets are exposed 154 PLATELET MICROTUBULES AND AGGREGATION 155 to high concentrations of thrombin and other proteolytic enzymes which produce aggregation, they selectively discharge adenine nucleotides and 5-hydroxytryptamine from granular sites, and this process is prevented by prior treatment with colcemid or vinblastine (Sneddon, 1971), suggesting that the movement of the granules may be the first step in their eventual discharge during the platelet release reaction (Grette, 1962) and that their movement requires the presence of intact microtubules.…”

Section: Discussionsupporting

confidence: 51%

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

Sneddon¹

1971

The Journal of Physiology

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1. An inhibitory action of the mitosis inhibitors colchicine, colcemid and vinblastine on blood platelet aggregation has been demonstrated. 2. The inhibitory action of low concentrations of these drugs was surmountable by increasing the concentration of the aggregating agents adenosine diphosphate (ADP) or thrombin. High concentrations completely inhibited aggregation. 3. The presence of a circumferential bundle of microtubules has been demonstrated in rabbit platelets. 4. After exposure to aggregating doses of ADP and thrombin the microtubules move to the centre of the cell, ‘trapping’ the platelet intracellular organelles in a relatively clear cytoplasm. 5. Concentrations of the antimitotic agents which reduce platelet aggregation depolymerize the platelet microtubules and prevent the rearrangement of the platelet organelles during aggregation. 6. It is suggested that the microtubules are not essential for platelet aggregation but are intimately involved in the movement of intracellular granules. This may be a preliminary stage in the eventual discharge of the granules during the platelet ‘release reaction’.

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Section: Discussionsupporting

confidence: 51%

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

Sneddon¹

1971

The Journal of Physiology

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“…The significance of this platelet-bound fraction is not known, but Table 3 shows that its release may increase plasma levels. It does not seem likely that the quantity of substance lost from platelets would be sufficient to produce a general increase in plasma levels or pharmacological action, but such changes may occur in a local situation where platelets accumulate in quantity and, in fact, release of substances from platelets in vitro has been observed by Mills, Robb & Roberts (1968).…”

Section: Release Of Guanethidine By Plateletsmentioning

confidence: 99%

The accumulation of guanethidine by human blood platelets

Boullin

O'Brien

1969

British J Pharmacology

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1. When human blood platelets were incubated aerobically in plasma containing 2 x 10-7 to 10-3M radioactive guanethidine for 10 min to 6 hr, the drug was accumulated against a concentration gradient until concentration ratios (platelet/plasma) of up to 80: 1 were obtained. 2. The decline in rate of uptake after 3 hr appeared to result from a decrease in platelet viability, because accumulation was reduced by prolonged incubation before addition of guanethidine. 3. Uptake was energy-dependent because it was inhibited by cold and ouabain. 4. Sodium ions were essential for guanethidine uptake and retention of 5-hydroxytryptamine (5-HT). 5. Accumulation was inhibited by 5-HT, desipramine, cocaine, dexamphetamine, bretylium, tyramine and noradrenaline; bethanidine, p-chlorophenylalanine and (-)-a-methyldopa were inactive. 6. Guanethidine was tightly bound to platelets, only 10% being lost from labelled cells during 60 min incubation in drug-free plasma; but efflux was increased by addition of amphetamine. 7. The binding sites for guanethidine seemed to be different from those for 5-HT since guanethidine accumulation was independent of 5-HT levels, and neither guanethidine uptake or release were affected by reserpine. 8. Guanethidine was not metabolized by platelets or plasma in vitro. 9. We consider that, if our results regarding uptake, binding and release of guanethidine are confirmed in vivo, and also found to apply to other pharmacologically active agents, then the eventual loss of a platelet-bound substance may increase pharmacological action by raising plasma levels.Although there is considerable information concerning the mechanisms of uptake and sites of storage of 5-hydroxytryptamine (5-HT) and noradrenaline (NA) by blood platelets, the fact that platelets can also accumulate a wide variety of other substances such as procaine, histamine, reserpine, quinidine, amino-acids, sugars Guanethidine uptake by platelets and diuretic drugs has only recently been demonstrated (Solomon & Zieve, 1967;Zieve & Solomon, 1967.Recent work indicates that in several respects the blood platelet resembles the sympathetic nerve ending. Although 5-HT is the'predominant amine in platelets and sympathetic nerves contain only NA, both structures preferentially accumulate the respective amine by an energy-dependent mechanism and store it in sub-cellular vesicles which show a dense core under the electron microscope (for references see Potter, 1967;Pletscher, 1968). As the uptake of guanethidine by sympathetic nerves is well established (for references see Boullin, 1968), it was thought that blood platelets might also take up guanethidine. This paper shows that this is the case: guanethidine is concentrated to a considerable degree by an energy-dependent process. As the ratio of the concentration of guanethidine in platelets to that in the incubation medium may exceed 50: 1, the possibility that platelet-bound guanethidine may be of clinical significance is discussed.Some of these experiments have been reported in preliminary communica...

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“…1-ml samples were decanted into 0.2 ml cold 0.1 M EDTA pH 7.4, with rapid mixing. After centrifugation aliquots were removed for the determination of radioactivity [23].…”

Section: [14c]serotonin Releasementioning

confidence: 99%

On the Interrelationship of Prostaglandin Endoperoxide G₂ and Cyclic Nucleotides in Platelet Function

Claesson

Malmsten

1977

European Journal of Biochemistry

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The prostaglandin endoperoxide Gz caused rapid aggregation and release of ADP and [14C]serotonin in human platelets. Since the presence of the ADP phosphorylating system creatine phosphate/ creatine phosphokinase markedly inhibited the aggregation caused by the endoperoxide, this effect seemed to be mediated mainly by ADP, which is instantaneously released by the endoperoxide.The prostaglandin G2 counteracted the increasing effect of prostaglandin El on the adenosine 3' : 5'-monophosphate (CAMP) levels in platelet-rich plasma. This effect of prostaglandin G2 was only observed when ADP was released by the endoperoxide. This finding indicates that the effect of prostaglandin G2 on the cAMP levels in platelet-rich plasma is principally mediated by ADP. The rapid release of ADP by prostaglandin GZ and the time courses for the effects of the endoperoxide and ADP on the level of cAMP give further evidence for this hypothesis. ADP also caused primary aggregation in the presence of indomethacin, and prostaglandin synthesis inhibitors did not influence the decreasing effect of ADP on the cAMP levels. NZ,OZ -Dibutyrylguanosine 3 ' : 5'-monophosphate did not influence the aggregation and release-reaction caused by ADP and no changes of the cGMP levels were observed after addition of prostaglandin Gz.The blood platelets play an important role for normal hemostasis in human beings. Platelet adhesion to exposed subendothelium and platelet aggregation will plug an injury to the vessel wall and initially stop the bleeding. There is also increasing evidence that the platelets are involved in pathological obstruction of vessels e.g. in myocardial infarction. The mechanism by which the platelets, which are normally separate from each other in the circulation, are transformed in such a way that they aggregate and secrete ADP and serotonin ('the release reaction') is in many parts unknown.It has been shown that cAMP [I] and its dibutyryl derivative [2,3] inhibit platelet aggregation and the release-reaction caused by agents such as ADP, collagen or epinephrine. It was also reported by several groups that prostaglandin El and to some extent high concentrations of prostaglandin E2 inhibit platelet aggregation [4 -71. However, prostaglandin EZ in low concentrations enhanced the aggregation induced by a submaximal dose of ADP [8]. Since prostaglandin El and high concentrations of prostaglandin E2 increased the level of cAMP in platelets Trivial Names and Abbreviations. Prostaglandin El, 1 la,l5(S)-dihydroxy-9-ketoprosta-l3(trans)-enoic acid; prostaglandin endoperoxide Gz, 15-hydroperoxy-9cx,l la-peroxidoprosta-5,13-dienoic acid; Bt2-CAMP: N6,,0z-dibutyryladenosine 3': 5'-rnonophosphoric acid; Bt2-cGMP: N*,O'-dibutyrylguanosine 3' : 5'-monophosphoric acid.while low concentrations of prostaglandin E2 as well as ADP, collagen and epinephrine decreased the content of cAMP in platelets, it was suggested that a decrease of the cAMP level is necessary in order for the aggregation and the release-reaction to occur [8].The unstable prostagland...

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The release of nucleotides, 5‐hydroxytryptamine and enzymes from human blood platelets during aggregation

Cited by 310 publications

References 35 publications

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

The accumulation of guanethidine by human blood platelets

On the Interrelationship of Prostaglandin Endoperoxide G₂ and Cyclic Nucleotides in Platelet Function

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The release of nucleotides, 5‐hydroxytryptamine and enzymes from human blood platelets during aggregation

Cited by 310 publications

References 35 publications

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

Effect of mitosis inhibitors on blood platelet microtubules and aggregation

The accumulation of guanethidine by human blood platelets

On the Interrelationship of Prostaglandin Endoperoxide G2 and Cyclic Nucleotides in Platelet Function

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On the Interrelationship of Prostaglandin Endoperoxide G₂ and Cyclic Nucleotides in Platelet Function