dinoprost and 9-(tetrahydro-2-furyl)-adenine

5-HT is known to be a potent vasospasmogenic agonist in various arteries. However, in veins the vasomodulating actions of 5-HT, and the underlying mechanisms, remain to be fully clarified. Here, we characterized the actions by which 5-HT affects electrical and mechanical activities in the rabbit jugular vein.. Membrane potential and isometric tension were measured in endothelium-intact and -denuded preparations. Localization of 5-HT receptor subtypes was examined immunohistochemically.. 5-HT induced a transient then a small, sustained smooth muscle cell hyperpolarization in endothelium-intact strips. In endothelium-denuded strips, 5-HT induced only a sustained hyperpolarization, and this was changed to a depolarization by the selective 5-HT(7) receptor inhibitor SB269970. This depolarization was inhibited by the 5-HT(2A) receptor blocker sarpogrelate. 5-HT induced a relaxation of PGF(2α) -induced contracted strips that was similar in endothelium-intact and -denuded preparations. The latter relaxation was changed to contraction by SB269970 and this contraction was inhibited by sarpogrelate. Immunoreactive responses against endothelial and smooth muscle 5-HT(2A) receptors and smooth muscle 5-HT(7) receptors were identified in the vein. The 5-HT-induced relaxation of the PGF(2α) contraction was inhibited by the cAMP-dependent protein kinase inhibitor Rp-cAMPS and by the AC inhibitor SQ22536.. These results indicate that 5-HT activates both smooth muscle 5-HT(7) receptors (to produce relaxation) and smooth muscle 5-HT(2A) receptors (to produce contraction) in rabbit jugular vein. We suggest that in this particular vein, the 5-HT(2A) receptor-induced depolarization and contraction are masked by the 5-HT(7) receptor-induced responses, possibly via actions mediated by cAMP.

Topics: Adenine; Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprost; Endothelium, Vascular; Glyburide; Immunohistochemistry; Isometric Contraction; Jugular Veins; Male; Membrane Potentials; Muscle, Smooth, Vascular; Nitric Oxide; Phenols; Rabbits; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Succinates; Sulfonamides; Vasodilation

Prostaglandin F(2alpha) (PGF(2alpha)) and interleukin-1beta (IL-1beta) levels are elevated in inflamed dental pulp. The roles of IL-1beta and PGF(2alpha) in the pathogenesis of pulpal inflammation await investigation. We found that IL-1beta stimulated PGF(2alpha) production of human dental pulp cells. IL-1beta and PGF(2alpha) (0.5-10 mumol/L) also induced IL-8 production and mRNA expression in pulp cells. Aspirin inhibited IL-1beta-induced PGF(2alpha), but not IL-8 production. PGF(2alpha)-induced IL-8 production and mRNA expression were inhibited by U0126 (an inhibitor of mitogen-activated protein kinase kinase [MEK1/2]) inhibitor), whereas SQ22536 (an adenylate cyclase inhibitor) enhanced this event. These results indicate that IL-1beta-induced IL-8 production in pulp cells is not mainly via direct activation of cyclooxygenase and PGF(2alpha) generation. PGF(2alpha)-induced IL-8 production is possibly via activation of MEK/extracellular signal-regulated kinase signaling, but not by activation of adenylate cyclase. IL-1beta and PGF(2alpha) might involve the pathogenesis of pulpal inflammation via induction of IL-8 production.

Topics: Activating Transcription Factor 1; Adenine; Butadienes; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Dental Pulp; Dinoprost; Extracellular Signal-Regulated MAP Kinases; Humans; Interleukin-1beta; Interleukin-8; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Nitriles; Protein Kinase Inhibitors; Pulpitis

The Na+/Ca2+ exchanger (NCX) may be an important modulator of Ca2+ entry and exit. The present study investigated whether NCX was affected by prostacyclin and nitric oxide (NO) released from the vascular endothelium, as NCX contains phosphorylation sites for PKA and PKG.. Rat aortic rings were set up in organ baths. Tension was measured across the ring with a force transducer.. Lowering extracellular [Na+] ([Na+]o) to 1.18 mM induced vasoconstriction in rat endothelium-denuded aortic rings. This effect was blocked by the NCX inhibitor KB-R7943 (2-2-[4-(4-nitrobenzyloxy)phenyl] ethyl isothiourea methanesulphonate; 1 microM). In endothelium-intact aortic rings, decreasing [Na+]o did not constrict the aortic rings significantly, but after treatment with the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 1 microM) or the NOS inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester; 50 microM), a vasoconstriction that was similar in size to that in endothelium-denuded preparations was evident. The vasorelaxation induced by the NO donor sodium nitroprusside sodium nitroprusside dihydrate (30 nM) was the same in the endothelium-denuded aortic rings preconstricted with either low Na+ (1.18 mM), the thromboxane A2 agonist U46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha); 0.1 microM) or high K+ (80 mM).. The results suggest that the endothelium inhibits NCX operation via guanylate cyclase/NO. This is stronger than for other constrictors such as phenylephrine and may relate to concomitant NCX-stimulated NO release from the endothelium. This finding may be important where NCX operates in reverse mode, such as during ischaemia, and highlights a new mechanism whereby the endothelium modulates Ca2+ homoeostasis in vascular smooth muscle.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Aorta, Thoracic; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Guanylate Cyclase; In Vitro Techniques; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Oxadiazoles; Potassium; Prostaglandin-Endoperoxide Synthases; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium; Sodium-Calcium Exchanger; Thiourea; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

To clarify the vasodilatory mechanism of unoprostone isopropyl (unoprostone), a PG F2alpha related compound used for treatment of glaucoma, we have investigated the effect of this drug and its metabolites on isolated rabbit ciliary artery in vitro.. Under the dissecting microscope, ciliary arteries were prepared from albino rabbit eyes and mounted in a myograph system. The effects of unoprostone isopropyl and other agents were investigated using isometric tension recording methods.. Unoprostone induced a dose-dependent relaxation in ciliary arteries that were pre-contracted with high-K solution, 10 microM histamine or 10 microM PG F2alpha. Neither unoprostone metabolite M1 or M2 had a relaxant effect on the precontracted vessels. Relaxation was unaffected by inhibition of adenylyl cyclase with SQ 22536, guanylyl cyclase with ODQ, or maxi-K channels with iberiotoxin. Pretreatment with unoprostone did not affect histamine-induced transient contractions in Ca2+ -free solution. However, SKF96365, a general Ca2+ channel blocker, evoked relaxation similar to unoprostone with respect to amplitude and rate of onset.. Unoprostone, but not its metabolites M1 and M2, relaxed pre-contracted rabbit ciliary artery. The mechanism of vascular smooth muscle relaxation by unoprostone differs from that of IOP reduction and does not depend on adenylyl cyclase, guanylyl cyclase, or maxi-K channels. Relaxation may be mediated by inhibition of Ca2+ entry, possibly through capacitative Ca2+ channels.

Topics: Adenine; Adenylyl Cyclase Inhibitors; Animals; Antihypertensive Agents; Ciliary Arteries; Dinoprost; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanylate Cyclase; Histamine; Isometric Contraction; Large-Conductance Calcium-Activated Potassium Channels; Male; Muscle, Smooth, Vascular; Oxadiazoles; Peptides; Potassium Channels, Calcium-Activated; Quinoxalines; Rabbits; Vasodilation