prostaglandin-d2 and vapiprost

1. Arachidonic acid (0.01-1 microM) induced relaxation of precontracted rings of rabbit saphenous vein, which was counteracted by contraction at concentrations higher than 1 microM. Concentrations higher than 1 microM were required to induce dose-dependent contraction of vena cava and thoracic aorta from the same animals. 2. Pretreatment with a TP receptor antagonist (GR32191B or SQ29548, 3 microM) potentiated the relaxant effect in the saphenous vein, revealed a vasorelaxant component in the vena cava response and did not affect the response of the aorta. 3. Removal of the endothelium from the venous rings, caused a 10 fold rightward shift in the concentration-relaxation curves to arachidonic acid. Whether or not the endothelium was present, the arachidonic acid-induced relaxations were prevented by indomethacin (10 microM) pretreatment. 4. In the saphenous vein, PGE2 was respectively a 50 and 100 fold more potent relaxant prostaglandin than PGI2 and PGD2. Pretreatment with the EP4 receptor antagonist, AH23848B, shifted the concentration-relaxation curves of this tissue to arachidonic acid in a dose-dependent manner. 5. In the presence of 1 microM arachidonic acid, venous rings produced 8-10 fold more PGE2 than did aorta whereas 6keto-PGF1alpha and TXB2 productions remained comparable. 6. Intact rings of saphenous vein relaxed in response to A23187. Pretreatment with L-NAME (100 microM) or indomethacin (10 microM) reduced this response by 50% whereas concomitant pretreatment totally suppressed it. After endothelium removal, the remaining relaxing response to A23187 was prevented by indomethacin but not affected by L-NAME. 7. We conclude that stimulation of the cyclo-oxygenase pathway by arachidonic acid induced endothelium-dependent, PGE2/EP4 mediated relaxation of the rabbit saphenous vein. This process might participate in the A23187-induced relaxation of the saphenous vein and account for a relaxing component in the response of the vena cava to arachidonic acid. It was not observed in thoracic aorta because of the lack of a vasodilatory receptor and/or the poorer ability of this tissue than veins to produce PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Aorta, Thoracic; Arachidonic Acid; Biphenyl Compounds; Calcimycin; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Endothelium; Epoprostenol; Heptanoic Acids; In Vitro Techniques; Indomethacin; Ionophores; Male; Muscle Contraction; Muscle Relaxation; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Saphenous Vein; Thromboxanes; Venae Cavae

1. Cumulative concentration-response curves (CRC) to prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2alpha (0.01-30 microM) and to the thromboxane A2 (TXA2) receptor agonist U-46619 (0.01-30 microM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical field stimulation. 2. All the agonists tested contracted the detrusor muscle. The rank order of agonist potency was: PGF2alpha > U-46619 > PGE2 whereas weak contractile responses were obtained with PGD2 and PGE1. Any of the agonists tested was able to induce a clear plateau of response even at 30 microM. 3. The selective TXA2 antagonist, GR 32191B (vapiprost), antagonized U-46619-induced contractions with an apparent pK(B) value of 8.27+/-0.12 (n = 4 for each antagonist concentration). GR 32191B (0.3 microM) did not antagonize the contractile responses to PGF2alpha and it was a non-surmountable antagonist of PGE2 (apparent pK(B) of 7.09+/-0.04; n = 5). The EP receptor antagonist AH 6809 at 10 microM shifted to the right the CRC to U-46619 (apparent pK(B) value of 5.88+/-0.04; n = 4). 4. Electrical field stimulation (20 Hz, 70 V, pulse width 0.1 ms, trains of 5 s every 60 s) elicited contractions fully sensitive to TTX (0.3 microM) and atropine (1 microM). U-46619 (0.01-3 microM) potentiated the twitch contraction in a dose-dependent manner and this effect was competitively antagonized by GR 32191B with an estimated pK(B) of 8.54+/-0.14 (n = 4 for each antagonist concentration). PGF2alpha in the range 0.01-10 microM (n = 7), but not PGE2 and PGE1 (n = 3 for each), also potentiated the twitch contraction of detrusor muscle strips (23.5+/-0.3% of KCl 100 mM-induced contraction) but this potentiation was unaffected by 0.3 microM GR 32191B (n = 5). 5. Cumulative additions of U-46619 (0.01-30 microM) were without effect on contractions induced by direct smooth muscle excitation (20 Hz, 40 V, 6 ms pulse width, trains of 2 s every 60 s, in the presence of TTX 1 microM; n = 3). Moreover, pretreatment of the tissue with 0.3 microM U-46619 did not potentiate the smooth muscle response to 7 microM bethanecol (n = 2). 6. We concluded that TXA2 can induce direct contraction of human isolated urinary bladder through the classical TXA2 receptor. Prostanoid receptors, fully activated by PGE2 and PGF2alpha are also present. All these receptors are probably located post-junctionally. The rank order of agonist potency and the fact that GR 32191B, but not AH6809, antagonized respon

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Biphenyl Compounds; Dinoprost; Dinoprostone; Electric Stimulation; Heptanoic Acids; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Prostaglandin Antagonists; Prostaglandin D2; Receptors, Prostaglandin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Thromboxane; Thromboxane A2; Urinary Bladder; Xanthenes; Xanthones

Current evidence suggests that thromboxane plays a role in pathophysiologic processes in the lung. Efforts to find effective, specific therapy to modify these effects have led to the development of a new class of thromboxane receptor blockers. This present investigation examined the selectivity and duration of the inhibitory effects of one of these novel agents in the pulmonary vascular bed of anesthetized cats.. Prospective, randomized, controlled study with repeated measures.. University research laboratory.. Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium.. The effects of GR32191, a thromboxane receptor antagonist, were investigated under constant-flow conditions in the intact-chest cat, using a triple-lumen, 6-Fr, balloon perfusion catheter that was placed by means of fluoroscopic guidance. Data were analyzed using a paired or unpaired t-test or analysis of variance. A p < .05 was considered statistically significant.. Aortic, left atrial, and left lobar arterial pressures were measured. After administration of GR32191 (0.25 and 1.0 mg/kg iv), pulmonary vasoconstrictor responses to U46619, a thromboxane mimic, were significantly decreased. Blockade was overcome with higher doses of the thromboxane mimic. GR32191 was without significant effect on the responses to prostaglandin (PG) D2, PGF2 alpha, serotonin, the calcium-channel agonist BAY K8644, or norepinephrine. Additionally, GR32191 did not alter baseline vascular pressures. Responses to U46619 returned to 50% of control value 90 mins after administration of 0.25 mg/kg of U46619. Responses to GR32191 returned to 50% of control value 180 mins after administration of 1.0 mg/kg of GR32191. These data suggest that GR32191 selectively blocks thromboxane A2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed of the cat.. These results are consistent with the hypothesis that discrete thromboxane A2 receptors, unrelated to receptors activated by PGF2 alpha or PGD2, are present in the feline pulmonary vascular bed. Specific thromboxane receptor antagonists, such as GR32191, could be useful therapeutic agents in the treatment of pulmonary hypertensive and thromboembolic disorders.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Biphenyl Compounds; Blood Pressure; Cats; Dinoprost; Heptanoic Acids; Norepinephrine; Prospective Studies; Prostaglandin D2; Pulmonary Circulation; Random Allocation; Receptors, Thromboxane; Serotonin; Vasoconstriction

The effects of hydrogen peroxide (H2O2) on human airway smooth muscle tone were determined in vitro. Treatment with H2O2 led to transient concentration-related contractions in the organ bath, amounting to 118 +/- 14 mg (mean +/- SE; n = 12) at 1 mM H2O2, and to greater and more prolonged contractions under superfusion conditions, amounting to 451 +/- 71 mg (n = 17) at 1 mM H2O2. Epithelial removal augmented the response to H2O2 in both systems. Addition of catalase (500 U/ml) abolished the effects of H2O2. Pretreatment of superfused tissues with indomethacin (3 microM) shifted the concentration-effect curve to H2O2 rightward and almost abolished the response to 1 mM H2O2 in epithelium-intact preparations (n = 16; P < 0.05); the response in epithelium-denuded tissues was also significantly inhibited (n = 16; P < 0.05). Pretreatment of the tissues with the TP prostanoid-receptor antagonist GR-32191B (1 microM) also inhibited the contractile effect of H2O2 in epithelium-intact and -denuded tissues. In separate experiments, H2O2 resulted in concentration-related generation of prostaglandin (PG) D2 from isolated airway preparations. The amount of PGD2 released was not different in tissues with intact epithelium compared with those without (n = 9; NS). We conclude that H2O2 exerts on isolated human airways a contractile effect that is augmented by epithelium removal and is largely mediated by prostanoids. The source of PGD2 does not appear to be the epithelium, which we suggest serves mainly as a barrier against H2O2-mediated bronchoconstriction.

Topics: Aged; Biphenyl Compounds; Cyclooxygenase Inhibitors; Epithelium; Female; Heptanoic Acids; Humans; Hydrogen Peroxide; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Receptors, Prostaglandin; Receptors, Thromboxane; Respiratory Physiological Phenomena; Respiratory System

The rank orders of potency of prostaglandin D2, prostaglandin F2 alpha, 9 alpha,11 beta-prostaglandin F2 and the stable thromboxane A2 mimetics U-46619 and ONO-11113 were determined in guinea-pig trachea and human bronchus in vitro. In both tissues the thromboxane mimetics were markedly more potent than the other prostanoids with EC50 values in the nanomolar range. The prostanoid antagonists BW-245C, EP-092 and GR-32191 attenuated the contractile responses to all of the prostanoid agonists and TXA2 mimetics tested in guinea-pig tracheal spirals, although agonist selectivity was seen. Contractile responses to methacholine in the guinea-pig trachea were unaffected by any of the antagonists employed. BW-245C antagonised the effects of all prostanoid agonists tested in human bronchial spirals, the pA2 values obtained were similar to those seen in the guinea-pig trachea when U-46619 and 9 alpha,11 beta-PGF2 were employed as the agonists. However, significant differences were found between the two tissues when PGD2 and PGF2 alpha were tested against BW-245C. EP-092 produced pA2 values against prostanoid agonists in the human bronchus similar to those seen in the guinea-pig trachea, as did GR-32191. It is concluded that whilst the contractile responses of guinea-pig and human airways smooth muscle to prostaglandin D2, and the other prostanoids are mediated predominantly via thromboxane (TP) receptors, it can be inferred that other receptor populations may contribute to the contractile response. The presence of these minor subpopulations may account for the agonist selectivity seen both within and between tissues from different species.

Topics: Animals; Biphenyl Compounds; Bronchi; Dinoprost; Dose-Response Relationship, Drug; Guinea Pigs; Heptanoic Acids; Humans; Hydantoins; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Prostaglandins, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxanes; Trachea

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Animals; Asthma; Biphenyl Compounds; Bronchi; Dinoprost; Guinea Pigs; Heptanoic Acids; Histamine; Humans; Male; Methacholine Compounds; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2