CATIONIC AMPHIPHILIC ARPROMIDINE-DERIVED GUANIDINES AND A HISTAMINE TRIFLUOROMETHYL-TOLUIDIDE DERIVATIVE MAY ACTIVATE PERTUSSIS-TOXIN-SENSITIVE G-PROTEINS BY A RECEPTOR-INDEPENDENT MECHANISM

Formyl peptides activate superoxide anion (O-2(-)) formation in human neutrophils and in HL-60 cells via pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins), and histamine (HA) mediates inhibition of O-2(-) formation via H-2-receptors. We have studied the effects of lipophilic arpromidine-derived guanidines, which are potent, full H-2-receptor agonists in the guinea pig atrium, on O-2(-) formation and on activation of G-proteins in HL-60 membranes and on purified G-proteins. We have also studied the effects of a HA trifluoromethyl-toluidide derivative (HTMT), a cationic-amphiphilic HA derivative which activates O-2(-) formation in HL-60 cells through a mechanism which is independent of known HA receptor subtypes, on G-protein activation. Guanidines, at concentrations, up to 30 mu mol/l inhibited and, at concentrations above 30 mu mol/l, enhanced formyl peptide-induce O-2(-) formation in neutrophils. In HL-60 cells, guanidines per se activated O-2(-) formation. The stimulatory effects of guanidines on O-2(-) formation were not inhibited by H-1- or H-2-receptor antagonists. In HL-60 membranes, guanidines and HTMT, activated high-affinity GTPase in a PTX-sensitive manner. These substances also increased GTP hydrolysis effected by transducin and G(i)/G(o)-proteins. Our data suggest that lipophilic guanidines and HTMT may act as receptor-independent activators of PTX-sensitive G-proteins, resulting in stimulation of O-2(-) formation.