HISTAMINE H-1-RECEPTOR-MEDIATED CYCLIC-GMP PRODUCTION IN GUINEA-PIG LUNG-TISSUE IS AN L-ARGININE-DEPENDENT PROCESS

Histamine produces a rapid and massive increase of the c-GMP level of guinea-pig lung tissue. The EC50 value for this in vitro response is found to be 27-mu-M and the c-GMP level is maximally 9-fold elevated by 100-mu-M histamine. The response is stereoselectively inhibited by the enantiomers of chlorpheniramine, indicating H-1-receptor involvement. Preincubation of lung tissue with 200-mu-M NCDC, a phospholipase C inhibitor, reduces the histamine (100-mu-M) responses to 16 +/- 3% (N = 6) of the control c-GMP production. Inhibition of protein kinase C by 50-mu-M H-7 does not significantly attenuate the H-1-receptor response, whereas omittance of extracellular Ca2+ results in almost complete inhibition of the c-GMP production. The histamine-induced c-GMP response is inhibited by hemoglobin, methylene blue and the antioxidants butylated hydroxytoluene and nordihydroguaretic acid, indicating the involvement of a nitric oxide-dependent activation of soluble guanylate cyclase. This suggestion is supported by the concentration-dependent inhibition of the c-GMP production by N(G)-monomethyl-L-arginine (NMA). At a concentration of 20-mu-M NMA the histamine (100-mu-M) response is inhibited to 34 +/- 8% (N = 6) of the control response. This inhibition is reversed to 127 +/- 20% (N = 6) by the exogenous addition of 1 mM L-arginine. These findings show that after an initial H-1-receptor-mediated, phospholipase C-dependent, Ca2+-mobilization the enzymatic conversion of L-arginine to nitric oxide is stimulated. This nitric oxide production is finally responsible for the activation of soluble guanylate cyclase, leading to the production of c-GMP.