ah-23848 and sulotroban

The effects of thromboxane B2 (TxB2) and of two thromboxane mimetics, dl-(9,11), (11,12)-dimethano-TxA2 (ONO 11006) and 9,11-dideoxy-11,9-epoxymethano prostaglandin F2 alpha (U46619) on the cardiac response to adrenergic nerve stimulation in isolated guinea-pig atria were evaluated. All the agonists dose dependently reduced the positive inotropic effect induced by field stimulation, U46619 being the most active. The inhibitory effect of U46619 was reduced by the thromboxane receptor antagonists, sulotroban and AH 23848B. U46619 did not significantly reduce the positive inotropic effect induced by exogenous noradrenaline. However U46619 was unable to modify the tritium overflow induced by field stimulation in preparations preloaded with [3H]noradrenaline. In addition to this influence on adrenergic neurotransmission, U46619 also had a direct positive inotropic effect on cardiac contractility, which was antagonized by AH 23848B. These results indicate that U46619 reduces the cardiac response to sympathetic nerve stimulation and that is also has a direct stimulatory effect on cardiac muscle.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Norepinephrine; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Sympathetic Nervous System; Synaptic Transmission; Thromboxane A2; Thromboxane B2

We studied the effects of the thromboxane (Tx)A2-receptor antagonists AH 23848 and BM 13.177 in small isolated human uteroplacental arteries.. Fetal stem villous arteries and maternal intramyometrial arteries were dissected from placental specimens and from myometrial biopsies obtained at cesarean or from nonpregnant women after hysterectomy. Vascular ring preparations were prepared and mounted in organ baths, and isometric tension was recorded.. AH 23848 produced competitive, concentration-dependent inhibition of responses to the TxA2-mimic U46619 in all vessel types tested. Mean (+/- standard error of the mean) pA2 values (the negative logarithm of the concentration of antagonist needed to double the half maximum response [EC50] value for U46619) were 8.69 +/- 0.16 in the stem villous arteries, 9.58 +/- 0.33 in intramyometrial arteries from term pregnant women, and 9.25 +/- 0.47 in intramyometrial arteries from nonpregnant women. In stem villous arteries, the pA2 value for BM 13.177 was 6.15 +/- 0.13, whereas these values in intramyometrial arteries could not be assessed. However, the concentrations needed to produce inhibition of U46619-induced contractions were considerably higher for BM 13.177 than for AH 23848. Both drugs inhibited responses to prostaglandin (PG)F2 alpha and PGE2 in stem villous arteries, while leaving responses to vasopressin in intramyometrial arteries unaffected. No differences in the effects of the two antagonists were found between intramyometrial arteries from nonpregnant and term pregnant women.. Our results suggest that TxA2-receptor antagonists effectively inhibit responses to TxA2 in human uteroplacental arteries, and such drugs may represent an interesting therapeutic approach in preeclampsia.

Topics: Adult; Arteries; Biphenyl Compounds; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Muscle Contraction; Placenta; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxanes; Uterus; Vasoconstriction; Vasopressins