HISTAMINE MODULATION OF CA2+ HOMEOSTASIS IN HUMAN NEUTROPHILS

The influence of histamine on the basal intracellular free Ca2+ concen tration ([Ca2+]i) and agonist-induced increases of [Ca2+]i was studied in Fura-2-loaded neutrophils. Histamine was unable to change the basa l [Ca2+]i at concentrations (10(-6)-10(-4) M) that have been shown to cause a rapid increase in [Ca2+]i in a variety of cell types. Histamin e, in contrast, was found to inhibit dose-dependently the rise in [Ca2 +]i induced by two neutrophil receptor agonists, N-formylmethionyl-leu cylphenylalanine (fMLP) and serum-opsonized zymosan particles. The his tamine inhibition was shown to be specific for H-2 receptor activation by blocking experiments with selective H-1 and H-2 receptor antagonis ts. In the absence of extracellular Ca2+, histamine failed to inhibit the agonist-induced rise in [Ca2+]i, indicating that histamine does no t affect the release of Ca2+ from internal pools. Forskolin, which mim ics the biochemical effects of H-2 receptor activation by directly sti mulating adenylate cyclase, also decreased the Ca2+ transients induced by receptor agonists. Similarly, 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, reduced the Ca2+ response of activated neutrophils. These data suggest that in human neutrophils (1) no funct ional H-1 receptors are present or alternatively H-1 receptors are not coupled to cellular Ca2+ metabolism, and (2) H-2 receptors modulate t he receptor-triggered Ca2+ flux via the cAMP second messenger system.