Histamine H1-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 microM and the c-GMP level is maximally 9-fold elevated by 100 microM histamine. The response is stereoselectively inhibited by the enantiomers of chlorpheniramine, indicating H1-receptor involvement. Preincubation of lung tissue with 200 microM NCDC, a phospholipase C inhibitor, reduces the histamine (100 microM) responses to 16 +/- 3% (N = 6) of the control c-GMP production. Inhibition of protein kinase C by 50 microM H-7 does not significantly attenuate the H1-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 NG-monomethyl-L-arginine (NMA). At a concentration of 20 microM NMA the histamine (100 microM) 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 H1-receptor-mediated, phospholipase C-dependent, Ca(2+)-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.