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 (O2-) 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 O2- formation via H2-receptors. We have studied the effects of lipophilic arpromidine-derived guanidines, which are potent, full H2-receptor agonists in the guinea pig atrium, on O2- 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 O2- 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 mumol/l inhibited and, at concentrations above 30 mumol/l, enhanced formyl peptide-induce O2- formation in neutrophils. In HL-60 cells, guanidines per se activated O2- formation. The stimulatory effects of guanidines on O2- formation were not inhibited by H1- or H2-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 Gi/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 O2- formation.
Hagelüken
A
A
Institut für Pharmakologie, Freie Universität Berlin, Germany.
Burde
R
R
Nürnberg
B
B
Harhammer
R
R
Buschauer
A
A
Seifert
R
R
D001711:Biotransformation / Q000187:drug effects; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006632:Histamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D037342:Pertussis Toxin; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D002316:Cardiotonic Agents; D006146:Guanidines; D007093:Imidazoles; D010566:Virulence Factors, Bordetella; D006632:Histamine; C060591:arpromidine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins