Disease relevance of U 44069

• Treatment of membranes with either cholera or pertussis toxins, which inhibited markedly the receptor-mediated stimulation of the GTPase activities of Ns and Ni respectively, had no or only a small effect, respectively, on the GTPase activity stimulated by PAF and U44069 [1].
• Acute, stable pulmonary hypertension was induced in instrumented unanesthetized sheep by infusing a PGH(2) analog, U-44069 [2].

High impact information on U 44069

• Microsomes of human seminal vesicles oxygenated arachidonate, U-44069, U-46619, U-51605, and PGH(2), similar to CYP4F8 [3].
• Oxabicycloheptane analogs of prostaglandin endoperoxide, U-44069 and U-46619, induced spectral changes in human P450 3A4 with K(s) values of 240 +/- 20 and 130 +/- 10 microM, respectively [4].
• In contrast, the TxA2 receptor blocker 13-APA significantly enhanced NC activity and even reversed the inhibitory effect of U44069 at equimolar (10(-7)M) concentrations [5].
• The U44069-induced EA constriction was insensitive to the vasodilator action of diltiazem at concentrations from 10(-8) to 10(-6) mol/L, but at 10(-5) mol/L, diltiazem increased the EA diameter significantly, albeit modestly [6].
• The thromboxane A2 (TXA2) mimetic U44069 has been demonstrated to reduce the GFR and filtration fraction of the normal isolated perfused rat kidney markedly, suggesting a predominant constriction of preglomerular vessels [6].

Chemical compound and disease context of U 44069

• In contrast, injecting the thromboxane A2 mimetic U44069 during the endotoxin recovery period triggered pulmonary vasoconstriction and pulmonary hypertension similar in magnitude to the responses triggered by U44069 before endotoxin had been administered [7].

Biological context of U 44069

• Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M) [8].
• L-640,035 (1 and 3 mg/kg i.v.) inhibited platelet aggregation induced in this model by U-44069 but not by ADP [9].
• U-46619 and U-44069 are among the most potent microvascular permeability factors described to date for the conjunctiva; their potency is exceeded only by that reported for leukotrienes D4 and E4 [10].
• In thoracotomized guinea pigs, i.v. (+)-S-145 (31.6 micrograms/kg) and increasing i.v. doses of U44069 increased mean arterial blood pressure, total peripheral resistance, left ventricular end-diastolic pressure and left ventricular peak positive dP/dt (LV + dP/dt) and depressed cardiac output (P < .05) [11].
• Intravenous (+)-S-145 inhibited U44069-induced decreases in circulating platelet count (ID50 = 4.2 + 4.1, - 2.0 micrograms/kg) [11].

Anatomical context of U 44069

• Fresh human pulmonary artery rings, with and without an intact endothelium, were mounted in organ baths containing Krebs' solution and precontracted with U44069 (0.3 microM) [12].
• PGI2 consistently relaxed the middle cerebral artery contracted by the prostaglandin endoperoxide analogue U-44069, whereas the basilar artery was almost unaffected [13].
• In vitro, PGD2, 9 alpha, 11 beta-PGF2 and a TxA2 mimic, U-44069, produced concentration-dependent contractions of the guinea pig isolated trachea with pD2s of 6.4, 6.0 and 7.2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)[14]
• The presence and the possible mechanism of action of the inhibitory nonadrenergic, noncholinergic nerve system (i-NANC) were investigated in guinea pig pulmonary artery (PA) precontracted with U44069 (a thromboxane analog) [15].
• 3 Responses produced by 5-HT or U-44069 were similar in the presence and absence of the epithelium in control guinea-pigs [16].

Associations of U 44069 with other chemical compounds

• Nifedipine also reversed the U44069-induced AA constriction (81 +/- 7%), but failed to inhibit the EA constriction at concentrations from 10(-9) to 10(-6) mol/L [6].
• The variations in the formation of 3H-PA in this patient on different occasions broadly paralleled the variations in the initial rates of ADP and U44069 aggregation and in epinephrine aggregation seen in PRP [17].
• 5. In vessel rings submaximally contracted with the thromboxane analogue U44069 (2 microM), the selective alpha 2-adrenoceptor agonist UK14304 induced concentration-dependent relaxation, which was abolished by removal of endothelium [18].
• When L-640,035 was administered intravenously to guinea-pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U-44069 (ED50 0.16 mg kg-1), leukotriene D4 (ED50 0.25 mg kg-1) and 5-HT (ED50 3.4 mg kg-1) but not histamine (ED50 greater than 10 mg kg-1) was observed [19].
• Intravenous injections of the TXA2 receptor mimics, U-46619 [(15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta5Z,13E-dienoic acid] and U-44069 (9,11-dideoxy-11 alpha,9 alpha-epoxymethano PGF2 alpha), produced dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance [20].

Gene context of U 44069

• A high-resolution NMR spectroscopy was used to determine the conformational changes and solution 3D structure of U44069, a PGH(2) analogue, bound to one of the COX-downstream synthases-an engineered thromboxane A(2) synthase (TXAS) [21].
• Moreover, ANG II (10(-11) - 10(-7) M) augmented platelet responses to the TxA2 mimetic, U44069 [22].
• Both 5-hydroxy-tryptamine and beta-thromboglobulin release were greater with patients' platelets than with those of controls in response to adrenaline, ADP and U44069 [23].
• Treatment with another PGH(2) analogue, U44069, produced a peak at 387 nm and a trough at 432 nm in the spectrum (Type I), while treatment with tranylcypromine, a PGIS inhibitor, produced a peak at 434 nm and a trough at 412 nm (Type II) [24].
• 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A2 agonist U44069 in order to amplify the responses; or (ii) exposed to N(omega)-nitro-L-arginine (100 micromol/L) plus LY 53857 (0.1 micromol/L; a 5-HT2 receptor antagonist shown previously to inhibit relaxation) [25].

Analytical, diagnostic and therapeutic context of U 44069

• The effects of a thromboxane A2 (TxA2)-endoperoxide analogue, U-44069 (0.16 micrograms/min. i.a.) on blood flows to the total wall, the mucosal (= mucosa+submucosa), and muscularis (= muscularis+serosa) layers of the canine jejunum, were determined utilizing radiolabelled microspheres (diam = 13.75 microns) [26].
• When administered to the IPRK, 10(-6) M U-44069 caused a 82 +/- 3% decrease in glomerular filtration rate (GFR) and a 80 +/- 4% decrease in filtration fraction but reduced renal perfusate flow (RPF) only 13 +/- 8% (P less than 0.005) [27].

References