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.
Leurs
R
R
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Brozius
M M
MM
Jansen
W
W
Bast
A
A
Timmerman
H
H
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D048448:Phenylcarbamates; D011969:Receptors, Histamine H1 / Q000502:physiology*; D015398:Signal Transduction
D002219:Carbamates; D006633:Histamine Antagonists; D048448:Phenylcarbamates; D011969:Receptors, Histamine H1; C025508:2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate; D009569:Nitric Oxide; D006632:Histamine; D001120:Arginine; D006152:Cyclic GMP