D. J. Betteridge

Platelet function in patients with hypercholesterolaemia

Abstract. Platelets and plasma lipoproteins, particularly low density lipoprotein, have important roles in atherogenesis. Evidence from several sources suggests that important interactions occur between these individual components of the atherogeneic process. Here we review work from our own laboratory on platelet function in normal individuals and patients heterozygous for familial hypercholesterolaemia (FH). Data is presented on the role of platelet noradrenaline and also on altered cellular signalling in platelets from FH individuals who have plasma low density lipoprotein concentrations which are approximately double those seen in normal subjects.

Platelet transmembrane signalling responses to collagen in familial hypercholesterolaemia

Abstract Washed platelets from patients with familial hypercholesterolaemia (FH) were found to be more reactive towards collagen than those from control subjects. The dose required to achieve half maximum aggregation was found to be 0·6 ml‐1 for FH patients whilst that for control subjects was 1·25 μg ml‐1. In both types of platelet, intracellular Ca2+ levels, as monitored by the Ca2+‐dependent photoprotein, aequorin, rose on stimulation with collagen and then fell to basal levels, probably due to resequestration by the reticular system. This effect was not due to exhaustion of the supply of aequorin since sustained Ca2+ influx induced by the ionophore, A23187, gave a stable signal that did not return to baseline. Similarly, inositol 1,4,5, trisphosphate levels increased in the cytosol after stimulation and then fell to unstimulated values. When stimulated with collagen, platelets from FH patients showed a greater extent of cytoplasmic calcium mobilization (P < 0·05) when compared to controls, coupled with a greater extent of inositol phospholipid hydrolysis (P < 0·05). At doses of collagen sufficient to give either 100% or 50% aggregation, platelets from patients or control subjects showed the same amplitude of ATP release at either dose suggesting that the trigger for vesicle release is more sensitive in FH.

Platelet noradrenaline release in patients with familial hypercholesterolaemia.

Abstract. We have examined resting and thrombin (0.3 units ml‐1) induced release of noradrenaline by washed platelets from 15 normal subjects and eight patients with heterozygous familial hypercholesterolaemia.

Decreased sensitivity to adenosine in platelets from patients with familial hypercholesterolaemia - A change reversed by cholestyramine treatment

Abstract. Platelet‐rich plasma was obtained from patients with untreated heterozygous familial hypercholesterolaemia (FH), from FH patients treated with cholestyramine and from control subjects. Responsiveness of platelets to the aggregation inhibitors adenosine, its analogue N‐ethylcarboxamidoadeno‐sine (NECA) and prostaglandin 12 was decreased in FH. Patients on cholestyramine therapy showed normal responsiveness to adenosine and NECA. There were only minor changes in the binding of [3H]NECA to high‐affinity binding sites on platelet membranes from untreated FH or cholestyramine‐treated FH patients. The initial rate of cyclic AMP formation in response to a high concentration of NECA was severely decreased in platelets from FH patients. By contrast, the rate of cyclic AMP formation in response to forskolin or a high concentration of prostaglandin 12 was unchanged. These data point to a defect in the coupling of the platelet A2 adenosine receptor to adenylyl cyclase in untreated FH patients.

Influence of the alpha-adrenoreceptor naftopidil and doxazosin, on adrenaline-induced serotonin platelets: comparison with the antagonists, collagen and efflux by human effects of nifedipine.

Collagen (5 microg/ml) stimulation of washed platelets increased endogenous serotonin (5-HT) release to the medium from 13.88 1.39 to 188.67 26.37 pmol/108 platelets ( P < 0.001). Adrenaline (16 microM) also increased 5-HT release, from 11.0 1.46 to 110.6 29.9 pmol/108 platelets ( P < 0.02). Naftopidil enhanced collagen-induced 5-HT efflux; significant increases occurred with 2 microM (+71.6%, P < 0.01), 10 microM (+89.1%, P < 0.01) and 40 microM (+69.7%, P < 0.01). With 0.4 muM and 2 microM naftopidil, adrenaline-induced 5-HT release was enhanced, albeit non-significantly, whilst with 10 microM and 40 muM naftopidil release was reduced (40 microM,-58.5%, P < 0.05). Doxazosin increased collagen-induced 5-HT release, significant increases being recorded with 7.5 microM (+81.7%, P < 0.05) and 30 microM (+78.4%, P < 0.05). Adrenaline-induced 5-HT release was also increased by doxazosin, but not significantly. Collagen-stimulated 5-HT release was inhibited by nifedipine (7 microM,-38.8%, P < 0.05; 28 microM, -61.2%, P < 0.001). These data suggest that the-antagonists, naftopidil and doxazosin, and the Ca2+ channel blocker, nifedipine, influence agonist-induced platelet 5-HT release through different mechanisms. Thus naftopidil and doxazosin may possess 5-HT transporter-blocking activity. The observation that naftopidil inhibited, adrenaline-induced 5-HT release may indicate that naftopidil also inhibits adrenaline uptake and exchange with dense granular 5-HT, with consequent inhibition of 5-HT release and platelet aggregation. The data obtained with nifedipine are consistent with 5-HT release being reduced as a result of its inhibitory action on platelet Ca2+ mobilisation.

Collagen-induced Platelet Activation In Vitro Increases Plasma Catecholamine Concentration

Collagen-induced Platelet Activation In Vitro Increases Plasma Catecholamine Concentration C. C. T. Smith, B. N. C. Prichard & D. J. Betteridge To cite this article: C. C. T. Smith, B. N. C. Prichard & D. J. Betteridge (1992) Collagen-induced Platelet Activation In Vitro Increases Plasma Catecholamine Concentration, Platelets, 3:4, 217-218 To link to this article: http://dx.doi.org/10.3109/09537109209013186