dinoprost and phosphoramidon

E2-isoprostanes are recently discovered compounds that are produced in vivo from free radical-catalysed peroxidation of arachidonic acid. One such compound whose formation is favoured by this mechanism is isoprostaglandin E2 type III (iPE2-III, also named 8-iso-prostaglandin E2 or 15-E2t-isoprostaglandin). The aim of this study was to evaluate the vasomotor properties of iPE2-III in isolated human internal mammary artery. In organ bath, iPE2-III was approximately 10 times more potent than isoprostaglandin F2alpha-III and 27 times more potent than prostaglandin E2, whereas both isoprostaglandin F3alpha-III and 15-epi-isoprostaglandin F2alpha-II induced weak contractions. The responses to iPE2-III were inhibited in a concentration-dependent manner by the thromboxane A2 receptor antagonist GR 32191 (3.10(-9) to 3.10(-7) M). Indomethacin, a cyclooxygenase inhibitor and phosphoramidon, an endothelin converting enzyme inhibitor, did not affect iPE2-III response. These data shows that iPE2-III is a more potent vasoconstrictor of human internal mammary arteries than isoprostaglandin F2alpha-III. These effects are mediated by TP receptors, but involve neither cyclooxygenase products nor endothelins. iPE2-III production may induce more pronounced vasomotor effects than isoprostaglandin F2alpha-III in situations of oxidative stress, and in particular may modulate internal mammary artery tone following coronary bypass surgery.

Topics: Aged; Biphenyl Compounds; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; F2-Isoprostanes; Female; Glycopeptides; Heptanoic Acids; Humans; Indomethacin; Isoprostanes; Male; Mammary Arteries; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Organ Culture Techniques; Vasoconstrictor Agents

To investigate whether prostaglandin F2 alpha (PGF2 alpha) stimulates the release of tachykinins and whether the tachykinins play a role in the PGF2 alpha-induced bronchial contraction, we examined the contractile response to PGF2 alpha in the presence or absence of a neutral endopeptidase (NEP) inhibitor phosphoramidon in the guinea pig main bronchus in vitro. Because NEP effectively cleaves tachykinins, we hypothesized that the inhibition of NEP would enhance a PGF2 alpha-induced bronchial contraction if PGF2 alpha stimulates the release of tachykinins. Phosphoramidon significantly enhanced the concentration-response curve to PGF2 alpha. And it also significantly enhanced 10(-5) M PGF2 alpha-induced contraction. The enhancement was significantly attenuated in tissues where the tachykinins had been depleted by treatment with capsaicin. Furthermore, the enhancement of contraction was also significantly attenuated in the presence of tachykinin antagonist FK-224 (10(-5) M). Tetrodotoxin, a sodium-channel blocker that blocks nerve conduction, did not affect the enhancement. From these results we conclude that 1) PGF2 alpha causes the release of tachykinin-like substances, 2) these substances play a role in bronchial contraction in tissues where NEP activity is inhibited, and 3) nerve conduction is not necessary for the release of these substances in the guinea pig bronchus.

Topics: Animals; Bronchi; Bronchoconstriction; Capsaicin; Dinoprost; Glycopeptides; Guinea Pigs; In Vitro Techniques; Male; Peptides, Cyclic; Protease Inhibitors; Tachykinins; Tetrodotoxin

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.

Topics: Anaphylaxis; Animals; Antigens; Dinoprost; Diphenhydramine; Glycopeptides; Guinea Pigs; Histamine; In Vitro Techniques; Indazoles; Leukotriene D4; Muscle Contraction; Muscle, Smooth; Neprilysin; Prostaglandin D2; SRS-A; Trachea