Histamine is an Intracellular Messenger Mediating Platelet Aggregation

Abstract

Inhibition of human platelet aggregation by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), a novel antagonist of histamine binding, suggested that histamine might serve a critical role in cell function. Phorbol-12-myristate-13-acetate (PMA) or collagen was found to increase platelet histamine content in parallel with promotion of aggregation. Inhibitors of histidine decarboxylase (HDC) suppressed both aggregation and the elevation of histamine content, whereas DPPE inhibited aggregation only. In saponin-permeabilized platelets, added histamine reversed the inhibition by DPPE or HDC inhibitors on aggregation induced by PMA or collagen. The results indicate a role for histamine as an intracellular messenger, which in platelets promotes aggregation.

H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450

“…P450 inhibitors also block aggregation (Parnham et al, 1981), suggesting a close association between HIc and P450 in platelets. An important component of the evidence in favour of an intracellular role for histamine is based on the blunting of the platelet aggregatory response by specific inhibitors of histidine decarboxylase, the enzyme that generates histamine (Saxena et al, 1989). However, in our studies these inhibitors have consistently failed to block basal or ACTH-stimulated secretion of cortisol from isolated adrenal cells.…”

“…A low affinity (jaM) site in microsomes has been implicated in a second messenger role for histamine in platelets (Saxena et al, 1989); additional high and low affinity nuclear sites, of different ligand specificity, appear to play a growth-modulatory role in lymphocytes (Brandes et al, 1990;1991). H1c exhibits strong preference for certain novel, antioestrogen-like compounds, lesser affinity for HI ligands and very low affinity for H2 ligands (Brandes et al, 1990).…”

A role for intracellular histamine in ultrastructural changes induced in platelets by phorbol esters.

“…Finally, based on this and our previous reports, 8 we wish to speculate that a potential explanation for the observed elevated platelet histamine levels in patients with peripheral vascular disease 12 is a primary or secondary increase in its synthesis, or, perhaps, an aberrancy in its catabolism, resulting in a sensitizing action on platelets with consequent hyperaggregability.…”

“…DPPE inhibited the morphological changes induced by the action of PMA to both intact and permeabilized platelets, and this was reversed in the latter by histamine at a concentration similar to that produced by platelets in response to PMA. 8 The observation that high concentrations of DPPE (200 /xM) caused modest granular centralization while abolishing Intact platelets were stirred for 2 minutes In the presence of 12 to 15 jtg/ml saponln to achieve permeabilization. A. Permeabilized platelets were similar to intact platelets.…”

“…Both aggregation and histamine formation are attenuated in parallel by the HDC inhibitors, a-methylhistidine and a-fluoromethylhistidine. 8 Furthermore, A/,rV-diethyl-2-[4-(pheny1methyl)phenoxy]ethanarnine.HCI (DPPE), a histamine antagonist at a novel intracellular site, 9 blocks PMA-induced platelet aggregation but not histamine production. 8 ' 10 In permeabilized, but not intact, platelets the inhibitory effects of DPPE and of HDC inhibitors are reversed by histamine at concentrations consistent with those synthesized internally, 8 providing strong evidence that newly formed histamine modulates platelet activation.…”