title: Mechanisms of prostaglandin F2 alpha and histamine-induced contractions in human chorionic vasculature.
abstract: We investigated the signaling pathways modulating histamine- and prostaglandin F2 alpha (PGF2 alpha)-induced contractions of human chorionic vasculature. Neomycin, a phospholipase C (PLC) inhibitor, attenuated PGF2 alpha and histamine contractile responses 40 and 60%, respectively. AIF4-, a G protein stimulant, induced a strong contraction alone but blocked histamine- and PGF2 alpha-induced contractions. Staurosporine (100 nM), a protein kinase C (PKC) inhibitor, attenuated the PGF2 alpha-dependent contractions by 50% but did not affect the histamine response. However, higher nonspecific inhibitory concentrations of staurosporine (1-2 microM) abolished histamine and PGF2 alpha contractile responses, presumably by inhibiting other protein kinases. Although, the PKC phorbol 12-myristate 13-acetate (PMA) did not affect basal tension or PGF2 alpha-dependent contractions, the histamine response was attenuated by 30%. Sodium nitroprusside (SNP), a guanylyl cyclase stimulant, strongly attenuated histamine- and PGF2 alpha-induced contractions. Tension increases were similarly attenuated by forskolin and isobutylmethylxanthine (IBMX), which increase intracellular cyclic AMP. In vessel rings prelabeled with [3H]myoinositol, PGF2 alpha and histamine increased [3H]inositol phosphate (IP) production 400 and 100%, respectively, indicating that PLC is stimulated by both agonists. Neomycin inhibited histamine- and PGF2 alpha-induced increases in [3H]IP production 60 and 40%, respectively. Staurosporine (0.1-1 microM) and PMA did not affect histamine- or PGF2 alpha-stimulated IP production. AIF4-alone increased IP production but blocked histamine- and PGF(2 alpha)-dependent IP increases. These observations suggest that at least part of the contractile responses due to PGF2 alpha and histamine are associated with stimulation of PLC through an AIF4(-)-sensitive G protein. The role of PKC is variable, because PGF2 alpha but not histamine tension responses were attenuated by PKC inhibition. In addition, therapeutic agents that increase cyclic AMP and cyclic GMP attenuated histamine- and PGF2 alpha-induced contractions in human chorionic vasculature, although histamine responses were relatively more sensitive to these agents.
authors.affiliation: Department of Obstetrics/Gynecology, University of North Texas Health Science Center at Fort Worth 76107, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Quist
authors.forename: R
authors.initials: R
authors.lastname: Vasan
authors.forename: E
authors.initials: E
authors.lastname: Quist
mesh_terms: D017607:Aluminum Compounds / Q000494:pharmacology; D002823:Chorion / Q000098:blood supply* / Q000187:drug effects; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D005459:Fluorides / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D014661:Vasoconstriction
chemical_list: D017607:Aluminum Compounds; D006633:Histamine Antagonists; D007295:Inositol Phosphates; D006632:Histamine; D015237:Dinoprost; D005459:Fluorides; C032311:aluminum fluoride