International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress.

It is now more than 15 years since the molecular structures of the major prostanoid receptors were elucidated. Since then, substantial progress has been achieved with respect to distribution and function, signal transduction mechanisms, and the design of agonists and antagonists (http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=58). This review systematically details these advances. More recent developments in prostanoid receptor research are included. The DP(2) receptor, also termed CRTH2, has little structural resemblance to DP(1) and other receptors described in the original prostanoid receptor classification. DP(2) receptors are more closely related to chemoattractant receptors. Prostanoid receptors have also been found to heterodimerize with other prostanoid receptor subtypes and nonprostanoids. This may extend signal transduction pathways and create new ligand recognition sites: prostacyclin/thromboxane A(2) heterodimeric receptors for 8-epi-prostaglandin E(2), wild-type/alternative (alt4) heterodimers for the prostaglandin FP receptor for bimatoprost and the prostamides. It is anticipated that the 15 years of research progress described herein will lead to novel therapeutic entities.

Effect of the oestrous cycle, pregnancy and uterine region on the responsiveness of the isolated mouse uterus to prostaglandin F(2alpha) and the thromboxane mimetic U46619.

Previous studies in this laboratory have suggested that the isolated uterus from non-pregnant mice has a prostaglandin F and a thromboxane receptor population similar to that found in human myometrium. The aim of this study was to investigate any regional variation in myogenic activity ) and the and responsiveness to prostaglandin F(2alpha) (PGF(2alpha) thromboxane mimetic U46619 in the mouse uterus taken during different stages of the oestrous cycle and during pregnancy. Uterine samples from BKW mice were taken from different anatomical segments along the length of each uterine horn and set up for superfusion at 2 ml/min with Krebs solution (containing 1 microM indometacin) at 37 degrees C, and gassed with 95%O(2)/5%CO(2). Responses (area under the curve) are expressed as a percentage of the final contraction induced by hypotonic shock. Data are expressed as the means +/- s.e.m. of n=5-12 and were analysed using Student's paired t-test or two-way ANOVA with a Bonferroni post hoc test. Regional variation in myogenic activity was observed in all tissues studied except those taken during labour. These tissues displayed significantly greater myogenic activity than tissues taken at late gestation and at all stages of the oestrous cycle. Tissues from pregnant animals were generally more responsive to U46619 and PGF(2alpha) than tissues taken from non-pregnant animals. Tissues taken from the upper segment of the uterine horn were more responsive to both agonists during the oestrous cycle. The findings demonstrated that the hormonal milieu and site of excision are important for myogenic activity and responsiveness.

Sonographic investigation of flow patterns in the perfused human placenta and their modulation by vasoactive agents with enhanced visualization by the ultrasound contrast agent Albunex.

PURPOSE: Our objective was to demonstrate sonographically the flow distribution in the circulation of human placentae as well as the sensitivity of the human fetal capillary bed to vasoconstriction and dilatation. METHODS: Five human full-term placental lobules were maintained in vitro with fetal and maternal flow. Commercial ultrasound scanners were used for imaging. Albunex (1 ml bolus) was administered to the fetal "artery" to monitor patterns of flow. U46619 (1 ml, 10(-6) M; a thromboxane agonist and potent vasoconstrictor) and/or nitroglycerin (a potent vasodilator) were added to the fetal artery. RESULTS: Following the addition of U46619, mean "fetal pressures" rapidly rose from 23.2 +/- 0.8 to 118 +/- 2. 9 mm Hg (mean +/- standard error of mean; p < 0.001); venous flow rates decreased. As demonstrated by color Doppler imaging, flow markedly changed from a pattern of general distribution throughout the lobule to flow only near the chorionic plate. Color persistence was 94.4 +/- 6.5 seconds with Albunex after nitroglycerin and 39.8 +/- 3.4 seconds with Albunex after injection of U46619 (p < 0.001). Nitroglycerin had no effect when injected by itself but returned "constricted" flow to a "normal" pattern when injected after U46619. CONCLUSIONS: The contrast medium Albunex improved visualization of the fetal circulation throughout the lobule. Flow in the human placental capillary bed can be regionally manipulated throughout the placental lobule by vasomodulators and monitored by Albunex-enhanced sonographic examination.

Thromboxane modulating agents. 3. 1H-imidazol-1-ylalkyl- and 3-pyridinylalkyl-substituted 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid derivatives as dual thromboxane synthase inhibitor/thromboxane receptor antagonists.

The design of a series of dual thromboxane synthase inhibitor/thromboxane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid thromboxane receptor antagonist template is described. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinyl-methyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with thromboxane synthase inhibitory activity comparable with that of dazmegrel (7). In addition, 3-pyridinylalkyl substituents also make a significant contribution to thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting thromboxane synthase inhibition and thromboxane receptor blockade as measured by inhibition of U46619-induced platelet aggregation ex vivo.

Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces pulmonary hypertension.

We examined the pulmonary and systemic hemodynamic effects of administering soluble nitric oxide (NO) donor compounds (NO/nucleophile adducts, i.e., NONOates) directly into the trachea of animals with experimentally induced pulmonary hypertension. Steady-state pulmonary hypertension was created by using the thromboxane agonist U-46619. Yorkshire pigs were randomly assigned to one of four groups: group 1, intratracheal saline (control; n = 8); group 2, intratracheal sodium nitroprusside (n = 6); group 3, intratracheal ethylputreanine NONOate (n = 6); and group 4, intratracheal 2-(dimethylamino)-ethylputreanine NONOate (DMAEP/NO; n = 6). Pulmonary and systemic hemodynamics were monitored after drug instillation. Group 4 had significant reductions in pulmonary vascular resistance index (PVRI) at all time points compared with steady state and compared with group 1 (P < 0.05), whereas systemic vascular resistance index did not change. The mean change in mean pulmonary arterial pressure in group 4 was -33.1 +/- 1.2% compared with +6.4 +/- 1.3% in group 1 (P < 0.001), and the mean change in mean arterial pressure was -9.3 +/- 0.7% compared with a control value of -0.9 +/- 0.5% (P < 0.05). Groups 2 and 3 had significant decreases in both PVRI and systemic vascular resistance index compared with steady state and with group 1. In conclusion, intratracheal instillation of a polar-charged tertiary amine NONOate DMAEP/NO results in the selective reduction of PVRI. Intermittent intratracheal instillation of selective NONOates may be an alternative to continuously inhaled NO in the treatment of pulmonary hypertension.

A common low-affinity binding site for primary prostanoids on bovine aortic endothelial cells.

[3H]PGE2 and [3H]PGF2 alpha were shown to bind with similar binding capacity and dissociation constants to bovine aorta endothelial cells. The similarity in the binding parameters suggests that both agonists may bind to the same binding site. Displacement of [3H]PGE2 performed with PGE2, PGF2 alpha or U-46619, a thromboxane agonist, shows that all three prostanoids displaced the bound [3H]PGE2 with comparable potency (IC50 = 10(-7) M). These results indicated that the three different prostanoids, which serve as specific agonists to different prostanoid receptors, also compete for the same binding site in bovine endothelial cells with similar affinity. Comparison of the displacement of [3H]PGE2 or [3H]PGF2 alpha by a number of prostaglandin agonists and antagonists further supports the notion that the natural prostanoids bind with similar affinities to the same binding site. Thus, sulprostone, an EP1/EP3 agonist, displaced bound [3H]PGE2 and [3H]PGF2 alpha with IC50 of about 10(-7) M. On the other hand, thromboxane antagonists (BAY u-3405 and GR-32191B), EP1 specific antagonist (SC-19220) EP1/DP antagonist (AH-6809) and iloprost, a stable prostacyclin agonist, failed to displace bound [3H]PGE2 or [3H]PGF2 alpha at a concentration range of 10(-9)-10(-6) M. Gradual increase of sodium fluoride (NaF), a general activator of G binding proteins, or incubation of permeabilized cells with GTP gamma S resulted in a decrease in [3H]PGE2 binding, suggesting that the binding site represents a low-affinity common prostanoid receptor which, similar to other prostanoid receptors, is probably coupled with G binding proteins.