dinoprost and vapiprost

This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F(2)-isoprostane metabolites 15-keto-15-F(2t)-IsoP, 2,3-dinor-15-F(2t)-IsoP, and 2,3-dinor-5,6-dihydro -15-F(2t)-IsoP in comparison with 15-F(2t)-IsoP on the rat thoracic aorta. 15-keto-15-F(2t)-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD(2) value of 5.80 +/- 0.05, whereas 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP had no effect. The parent compound 15-F(2t)-IsoP was more potent (pD(2) value: 6.46 +/- 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F(2t)-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F(2t)-IsoP, with a significant decrease in the E(max) values for GR32191 10(-7) M. Pretreatment with 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no alteration of 15-F(2t)-IsoP concentration-response curves. In contrast, 15-keto-15-F(2t)-IsoP pretreatment competitively inhibited the response to 15-F(2t)-IsoP. When concentration ratios of EC(50) values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA(2) value of 6.13. 15-keto-15-F(2t)-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10(-8) M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no vasodilation. In conclusion, among the F(2)-isoprostane metabolites, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F(2t)-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Biphenyl Compounds; Dinoprost; Endothelium, Vascular; F2-Isoprostanes; Heptanoic Acids; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Potassium Chloride; Prostaglandin Antagonists; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

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

Isoprostaglandin F(2alpha) type-III (formerly known as 8-iso-prostaglandin F(2alpha)) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F(2alpha) type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F(2alpha) type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. In organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F(2alpha) type-III stimulation. The responses to isoprostaglandin F(2alpha) type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2beta,3beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3x10(-9) to 3x10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3x10(-5) M), an EP(1)-DP receptor antagonist had no effect on isoprostaglandin F(2alpha) type-III-induced contractions. The maximal responses to isoprostaglandin F(2alpha) type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E(max): 147+/-20% vs. 213+/-19% in control group, P<0.05). Isoprostaglandin F(2alpha) type-III stimulated thromboxane B(2) release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F(2alpha) type-III response. In conclusion, this study shows that (1) isoprostaglandin F(2alpha) type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F(2alpha), (2) the contractions induced by isoprostaglandin F(2alpha) type-III are mediated by TP receptor but not EP(1)-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F(2alpha) type-III. Isoprostaglandin F(2alpha) type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situatio

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Benzoquinones; Biphenyl Compounds; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Female; Flavanones; Flavonoids; Heptanoic Acids; Humans; In Vitro Techniques; Leukotrienes; Lipoxygenase Inhibitors; Male; Mammary Arteries; Middle Aged; Prostaglandin Antagonists; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Thromboxane; Thromboxane B2; Vasoconstriction; Vasoconstrictor Agents; Xanthenes; Xanthones

The newly revived coronary bypass graft, the radial artery (RA), is more spastic than the internal mammary artery. Thromboxane A2 is a potent vasoconstrictor for arterial grafts. This study was therefore designed to determine whether the specific thromboxane A2 (TP) receptor antagonist, GR32191B, is effective in inhibition of prostanoid or nonprostanoid receptors in the RA.. The effect of GR32191B was studied in human RA segments, taken from coronary bypass patients, in organ chambers. Two effects of GR32191B were tested: (1) the relaxation induced by GR32191B in the RA precontracted with the TP receptor agonists U46619 and PGF2alpha or nonprostanoid vasoconstrictors (noradrenaline [NA], angiotensin II [AII], and K+ ) and (2) the inhibitory effect of GR32191B on TP receptor agonists and nonprostanoid vasoconstrictors.. In U46619 (10 nm, n=7) and PGF2alpha (1 microm, n=7) precontracted RA, GR32191B induced 100% relaxation (10-100 microm ) but not after precontraction with nonprostanoid stimuli (5.8% for K+, 25 mm, n=6, 24.4% for NA, 3 microm, n=8, and 53.2% for AII, 3 nm, n=5) (P<0.001). Treatment with GR32191B (30 nm ) significantly depressed the contraction with U46619 (from 160.1+/-11.0% to 116.8+/-13.1%, P<0. 05) or PGF2alpha (from 91.3+/-12.3% to 42.2+/-9.2%, P<0.01). The contraction was further abolished by 3 microm GR32191B. However, GR32191B at 3 microm did not significantly inhibit the contraction induced by either NA, AII, or K+.. GR32191B is a highly potent and specific TP receptor antagonist for the human RA. It may be particularly useful in inhibiting TXA2-mediated vasoconstriction and therefore in reducing the complications related to vasospasm in this graft.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Biphenyl Compounds; Coronary Artery Bypass; Dinoprost; Heptanoic Acids; Humans; In Vitro Techniques; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Prostaglandin Antagonists; Radial Artery; Thromboxane A2; Vasoconstrictor Agents

1. 5-HT and the prostanoid TP receptor agonists, U46619 and I-BOP, constricted the human umbilical artery with pEC50 values of 7.3+/-0. 2, 6.7+/-0.1, and 7.3+/-0.2, respectively. The selective TP receptor antagonist, GR32191 (0.1 microM), shifted the concentration-effect curves to U46619 and I-BOP to the right, but had no effect on the response to 5-HT. 2. The natural prostaglandins, PGF2alpha and PGE2, caused concentration-dependent contraction with pEC50 values of 5.2+/-0.2 and 4.9+/-0.2, respectively. PGD2 was a partial agonist with a pEC50 of 5.24+/-0.03. GR32191 (0.1 microM) inhibited the responses to all of these compounds suggesting that they produce contraction by acting at TP receptors. 3. Sulprostone failed to elicit contraction in the human umbilical artery at concentrations up to 4.4 microM suggesting the absence of EP1 and EP3 receptors. Despite this, 17-phenyltrinor PGE2 and GR63799 both induced contraction at concentrations above 1 microM, but the effects were sensitive to GR32191 (0.1 microM). 4. Fluprostenol had no effect on the human umbilical artery at concentrations up to 17 microM suggesting the absence of FP receptors. Cloprostenol was ineffective in two tissues, but caused contraction in one tissue at the highest concentration tested (1.7 microM). However, this response was abolished in the presence of GR32191 (0.1 microM). 5. The effects of four TP receptor antagonists were assessed by global non-linear regression analysis. GR32191, SQ29548, SQ30741, and ICI192605 competitively inhibited responses to U46619 with pKb values of 8.0+/-0.1, 7.6+/-0.1, 7.0+/-0. 2 and 8.1+/-0.1, respectively. 6 These results suggest that the human umbilical artery functionally expresses TP receptors, but not EP1, EP2 or FP receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Dinoprostone; Fatty Acids, Unsaturated; Female; Heptanoic Acids; Humans; In Vitro Techniques; Isometric Contraction; Pregnancy; Prostaglandin Antagonists; Receptors, Prostaglandin; Serotonin; Umbilical Arteries; Vasoconstriction; Vasoconstrictor Agents

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

F2-isoprostanes are prostaglandin (PG) isomers produced in vivo through free radical-catalyzed peroxidation of arachidonic acid, which may affect platelet function. The current study investigated the effects of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) on critical events of platelet activation. A dose-dependent increase in platelet adhesion to fibrinogen- and plasma-coated microwells by 8-epi-PGF2alpha (1 to 1000 nmol/L) was observed when resting platelets (plasma from 1.3+/-0.2% to 5.5+/-0.2%, EC50 of 48 nmol/L; fibrinogen from 3.3+/-0.3% to 6.4+/-0.2%, EC50 of 35 nmol/L; mean+/-SEM, n=8, P<0.001) and thrombin-stimulated human platelets were used. The expression of the adhesion molecule glycoprotein IIb/IIIa was increased by 10 to 1000 nmol/L 8-epi-PGF2alpha in resting platelets (from 64.8+/-2.1% to 83.9+/-1.3%; n=5, P<0.01) and in stimulated platelets. The secretion of the glycoprotein GMP-140 increased only in the presence of both thrombin and 10 to 1000 nmol/L 8-epi-PGF2alpha (from 48.5+/-3.1% to 63.1+/-2.0%, P<0.05). The antiaggregatory effects of both the NO donor NOR-3 (basal, 21.4+/-4.6%; with 8-epi-PGF2alpha, 30.8+/-6.9%; n=14, P<0.05) and endothelial cells that release NO (basal, 18.5+/-4.6%; with 8-epi-PGF2alpha, 30.7+/-5.3%; n=15, P<0.001) were also reduced. All of these effects were prevented by the thromboxane receptor antagonist GR32191 but not affected by acetylsalicylic acid. An increase in free intracellular calcium concentration, measured with the use of fura 2, was observed with 8-epi-PGF2alpha. In conclusion, F2-isoprostanes may participate in oxidative injury by inducing platelet activation and by reducing the antiplatelet activity of NO: increased platelet adhesiveness and expression of the fibrinogen receptor are induced by nanomolar amounts of 8-epi-PG-F2alpha. Platelet secretion and aggregation can also be induced in the presence of platelet agonists.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Biphenyl Compounds; Blood Platelets; Calcium; Cells, Cultured; Dinoprost; Dose-Response Relationship, Drug; Drug Interactions; Endothelium, Vascular; F2-Isoprostanes; Heptanoic Acids; Humans; Nitric Oxide; P-Selectin; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Thromboxane; Vasoconstrictor Agents

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

Arterial grafts have been demonstrated to be very effective for coronary artery bypass surgery. Thromboxane A2 (TXA2) is a potent vasoconstrictor for arterial grafts. To determine whether the specific TXA2 (TP) receptor antagonist GR32191B is effective in inhibition of prostanoid or nonprostanoid receptors, we studied the effect of GR32191B in human internal mammary artery (IMA) segments, taken from coronary bypass patients, in organ chambers. In IMA precontracted with U46619 (10 nM, n = 7), prostaglandin F2 alpha (PGF2 alpha 1 microM, n = 7), or potassium chloride (K+ 25 microM, n = 6). GR32191B induced 100.0 +/- 0, 97.86 +/- 2.14, or 45.87 +/- 7.63% relaxation. In other experiments, one IMA ring taken from each patient was used as a control and others from the same patient were allocated to other groups treated with different concentrations of GR32191B [3-300 nM for U46619, 30 nM-3 microM for PGF2 alpha, 300 nM-100 microM for K+, 3 microM norepinephrine (NE), and 3 microM for 5-hydroxytryptamine (5-HT)] for 1 h before concentration-contraction curves to these vasoconstrictors (expressed as percentage of K(+)-induced contraction force) were established. Treatment with GR32191B (300 nM) significantly decreased the contraction induced by U46619 (from 306.4 +/- 22.1 to 61.9 +/- 24.9%, p < 0.01) and that induced by PGF2 alpha (from 208.2 +/- 13.5 to 1.4 +/- 1.4%, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Biphenyl Compounds; Coronary Artery Bypass; Dinoprost; Dose-Response Relationship, Drug; Female; Heptanoic Acids; Humans; In Vitro Techniques; Male; Mammary Arteries; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Prostaglandin Antagonists; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin; Serotonin Receptor Agonists; Thromboxane A2; Vasoconstrictor Agents

1. Cumulative administrations of U46619, a thromboxane A2 analogue, and prostaglandin (PG) F2 alpha produced concentration-dependent contractions of isolated dog renal arterial preparations, which were significantly and concentration-dependently inhibited by vapiprost. 2. A bolus administration of U46619 or PGF2 alpha produced sustained contracture of these preparations, which was concentration-dependently relaxed by cumulative vapiprost. 3. Results indicate that vapiprost inhibits U46619- and PGF2 alpha-induced dog renal arterial contractions through antagonism for so-called TP receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Dinoprost; Dogs; Dose-Response Relationship, Drug; Female; Heptanoic Acids; In Vitro Techniques; Male; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Renal Artery; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Effects of the new thromboxane A2 antagonist vapiprost (SN-309, GR-32191B, CAS 85505-64-2) on isolated canine blood vessels were investigated. U46619 ((15S)-hydroxy-11a, 9a-(epoxymethano) prosta-5Z, 13E-dienoic acid) 10(-10)-10(-6) mol/l, a thromboxane A2 analogue, produced concentration-dependent contractions of oblong or ring preparations isolated from basilar, coronary, mesenteric and femoral arteries. Vapiprost 10(-8) and 10(-7) mol/l significantly and concentration-dependently shifted the concentration-contraction curves for U46619 of these arteries to the right. The pA2 values were 8.80 +/- 0.09 in basilar arteries, 8.67 +/- 0.12 in coronary arteries, 8.86 +/- 0.05 in mesenteric arteries and 9.01 +/- 0.07 in femoral arteries. On the other hand, oblong or ring preparations of basilar, coronary, mesenteric and femoral arteries showed sustained contractile responses to KCl 3 x 10(-2) mol/l, U46619 10(-7) mol/l or prostaglandin (PG) F2 alpha 10(-5) mol/l. Norepinephrine (NE) 3 x 10(-5) mol/l also produced sustained contractions in mesenteric and femoral arterial preparations, but not in basilar and coronary arterial preparations. Vapiprost 10(-10)-3 x 10(-6) mol/l relaxed these four arterial preparations constricted with U46619 10(-7) mol/l and PGF 2 alpha 10(-5) mol/l in a concentration-dependent fashion, but hardly affected them constricted with KCl 3 x 10(-2) mol/l. NE 3 x 10(-5) mol/l-induced contractures of mesenteric and femoral arterial preparations were not influenced by any concentrations of vapiprost. Results indicate that vapiprost has an antagonistic action on a so-called TP-receptor and/or a vasoconstrictive prostaglandin(s)-receptor and thus produces vasorelaxation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Dinoprost; Dogs; Female; Heptanoic Acids; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Thromboxane A2; Vasoconstrictor Agents

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

Electrical field stimulation of dog isolated basilar artery produced neurogenically mediated contractions which were unaffected by phentolamine (1 microM), atropine (1 microM), ketanserin (1 microM) or methiothepin (0.1 microM). Responses were abolished by GR32191 (1-10 nM), BM 13.177 (0.1-10 microM) or flurbiprofen (0.5 microM) and markedly attenuated by dazoxiben (1-10 microM). Removal of the endothelium by Triton X-100-perfusion did not modify the magnitude of contractions to electrical stimulation and GR32191 still abolished the responses. GR32191 (1-10 nM) did not modify neurogenically mediated contraction of rabbit ear artery or potassium chloride-induced contraction of dog basilar artery. The results suggest that electrical field stimulation of dog basilar artery causes contractions which are mediated via a cyclo-oxygenase product with characteristics similar to thromboxane. This thromboxane-like substance is not endothelial in origin, nor released by contraction of the cerebrovascular smooth muscle per se and is therefore derived from a subendothelial, possibly neuronal, source.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Basilar Artery; Biphenyl Compounds; Dinoprost; Dogs; Electric Stimulation; Endothelium, Vascular; Female; Heptanoic Acids; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Neurons; Phentolamine; Prostaglandin Endoperoxides, Synthetic; Rabbits; Substance P; Thromboxanes

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

In human bronchial rings the thromboxane A2 (TxA2) mimetic, U46619, produced cumulative concentration-related contractions up to a maximum of 141 +/- 23% of the response induced by carbachol or acetylcholine. The geometric mean EC50 value was 3.2 X 10(-8) M (95% confidence interval: 1.2, 8.9 X 10(-8) M) (n = 5). Contractions to U46619 were unaffected by atropine (10(-6) M) or verapamil (10(-5) M), but were competitively antagonized by the TxA2 antagonist GR32191 with a pA2 value of 8.40 +/- 0.41. The maximum contractile response to prostaglandin (PG) F2 alpha was smaller (90 +/- 9%, n = 13) and the potency was less (EC50 = 2 X 10(-6) M) than that of U46619. Contractions to PGF2 alpha were also competitively antagonized by GR32191 with a pA2 value of 8.18 +/- 0.08. Concentration-response curves to PGE2 were biphasic, relaxation at concentrations from 10(-9) to 10(-6) M and contraction from 10(-6) to 3 X 10(-5) M. GR32191 10(-7) M inhibited the contractile portion of the response curve in 8 of 11 tissues. Based on these results we conclude that U46619, PGF2 alpha and PGE2 all contract human airways by stimulation of the TxA2 (TP) receptor.

Topics: Atropine; Biphenyl Compounds; Bronchi; Carbachol; Dinoprost; Dinoprostone; Heptanoic Acids; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Thromboxane A2; Verapamil