Cyclic GMP System in Epidermis: II. Histamine Stimulates Cyclic GMP Formation

In search of hormones and drugs which might elevate the intracellular level of cyclic GMP in pig epidermis, we have tested the effects of carbachol, concanavalin A, prostaglandin F2α, insulin, epinephrine, Vitamin A acid and histamine. Only histamine was found to cause consistent activation of the cyclic GMP system. Epidermal slices incubated in Hank's balanced salt solution with histamine exhibited 2- to 4-fold increases in intracellular cyclic GMP concentrations. Histamine's effect on cyclic GMP was not due to contamination by the 1000-fold higher level of cyclic AMP. The time course after histamine addition showed maximal response for cyclic GMP at 1min and for cyclic AMP at 5min. Leakage of cyclic GMP into the media was much more marked than that of cyclic AMP. Maximal histamine activation of the cyclic GMP system required a 1mM concentration, whereas that for the cyclic AMP system required only a 100 μM final concentration. 3-Isobutyl, 1-methylxanthine (IBMX) highly potentiated the effect of histamine on both cyclic nucleotides, but the synergistic effect was more marked in relation to cyclic GMP accumulation. Histamine activation of the cyclic AMP system was specifically inhibited by an (H2) inhibitor. Although both (H1) and (H2) inhibitors significantly reduced histamine activation of the cyclic GMP system, the inhibition by the (H1) inhibitor was predominant. These results indicate that the pig epidermis has a weak but distinct histamine-guanylate cyclase system