HISTAMINE H-1 AND ENDOTHELIN ET(B) RECEPTORS MEDIATE PHOSPHOLIPASE-D STIMULATION IN RAT-BRAIN HIPPOCAMPAL SLICES

Different neurotransmitter receptor agonists [carbachol, serotonin, no radrenaline, histamine, endothelin-1, and trans-(1S,3R)-aminocyclopent yl-1,3-dicarboxylic acid (trans-ACPD)], known as stimuli of phospholip ase C in brain tissue, were tested for phospholipase D stimulation in [P-32]P-i-prelabeled rat brain cortical and hippocampal slices. The ac cumulation of [P-32] phosphatidylethanol was measured as an index of p hospholipase D-catalyzed transphosphatidylation in the presence of eth anol. Among the six neurotransmitter receptor agonists tested, only no radrenaline, histamine, endothelin-1, and trans-ACPD stimulated phosph olipase D in hippocampus and cortex, an effect that was strictly depen dent of the presence of millimolar extracellular calcium concentration s. The effect of histamine (EC(50) 18 mu M) was inhibited by the H-1 r eceptor antagonist mepyramine with a K-i constant of 0.7 nM and was re sistant to H-2 and H-3 receptor antagonists (ranitidine and tioperamid e, respectively), Endothelin-1-stimulated phospholipase D (EC(50) 44 n M) was not blocked by BQ-123, a specific antagonist of the ET(A) recep tor. Endothelin-3 and the specific ET(B) receptor agonist safarotoxin 6c were also able to stimulate phospholipase D with efficacies similar to that of endothelin-1, and EC(50) values of 16 and 3 nM, respective ly. These results show that histamine and endothelin-1 stimulate phosp holipase D in rat brain through H-1 and ET(B) receptors, respectively.