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E Perzborn

Publications and source records attributed to E Perzborn.

17 recordsLinked to original sources
PubMed1992

Binding characteristics of the new thromboxane A2/prostaglandin H2 receptor antagonist [3H]BAY U 3405 to washed human platelets and platelet membranes.

The new thromboxane A2 antagonist [3H]BAY U 3405 was characterized for its binding to washed human platelets and platelet membranes. In washed platelets the specific binding was reversible, selective and stereospecific, but not saturable. The dissociation constant (Kd) was 6 +/- 2.5 nM, the number of specific binding sites 1177 +/- 306 per platelet. Three structurally different thromboxane A2 (TXA2)/prostaglandin H2 (prostaglandin endoperoxide) (PGH2) receptor ligands completely inhibited the specific binding of [3H]BAY U 3405 in a concentration-dependent manner, indicating that the observed high affinity binding site is the TXA2/PGH2 receptor. In platelet membranes, however, specific [3H]BAY U 3405 binding showed saturability in addition to reversibility, selectivity, and stereospecifity. The Kd of the binding was 9.6 +/- 2.3 nM in kinetic studies and 8.7 +/- 3.7 nM in saturation studies, the inhibition constant (Ki) was 10 +/- 1.1 nM in displacement studies. The TXA2/PGH2 receptor agonists U 46619 and CTA2, and the antagonists Daltroban (BM 13505), I-PTA-OH and SQ 29548 all completely inhibited the specific binding of [3H]BAY U 3405 thus defining the observed binding site as the TXA2/PGH2 receptor. In conclusion, the data suggest that the previously reported TXA2 antagonism of BAY U 3405 is mediated by binding to a specific high affinity binding site of human platelets and platelet membranes that represents the TXA2/PGH2 receptor.

Blood Platelets↗
PubMed1992

pH dependency of the binding of [3H]BAY U 3405 and various non-labelled ligands to the thromboxane A2/prostaglandin H2 receptor of human platelet membranes.

[3H]BAY U 3405 was used to characterize the effect of acidic and alkaline pH values on the binding of the thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor of human platelet membranes. The specific binding of [3H]BAY U 3405 largely increased upon acidification up to pH 5.8. Saturation binding studies revealed an increase in binding affinity without change in the number of binding sites. At pH 7.4 the Kd was 8.7 +/- 3.7 nM (Bmax = 6.6 +/- 0.6 pmol/mg protein) compared to 1.2 +/- 0.2 nM (Bmax = 6.1 +/- 0.6 pmol/mg protein) at pH 5.8. A more than 10-fold higher rate of association was observed at pH 5.8 compared to pH 7.4, while the rate of dissociation showed only minor changes. The kinetically derived dissociation constant was 1 nM (pH 5.8) and 9.6 nM (pH 7.4). The pH dependency of the binding of structurally different non-labelled ligands to the TXA2/PGH2 receptor was evaluated by inhibition studies at pH 5.8 and pH 7.4. BAY U 3405, daltroban, CTA2, and U 46619 showed significantly higher affinities at pH 5.8. In contrast, I-PTA-OH and GR 32191 had a higher affinity at pH 7.4. No significant difference was seen with SQ 29548 at the observed pH values. A second protonable group within the molecules I-PTA-OH, GR 32191, and SQ 29548 might be responsible for the observed differences.

Blood Platelets↗
PubMed1992

pH-dependent binding of the TXA2/PGH2-receptor of human platelet membranes to various ligands.

[3H]-BAY U 3405 was used to characterize the pH-dependency of the binding of various ligands to the TXA2/PGH2-receptor of human platelet membranes. Maximum binding of [3H]-BAY U 3405 is achieved at pH 5.8. In inhibition studies the ligands Daltroban, CTA2, and U 46619 also show a higher affinity at pH 5.8 compared to pH 7.4. In contrast, the ligands I-PTA-OH and GR 32191 have a higher affinity at pH 7.4. No difference is seen with SQ 29548. The ligands I-PTA-OH, GR 32191, and SQ 29548 have a second protonable group in common, which is thought to be the reason for the different pH-dependent binding.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effect of BAY U 3405, a new thromboxane antagonist, on arachidonic acid induced thromboembolism.

The model of AA-induced sudden death employed in these investigations seems to be appropriate for studying the efficacy of TXA2-antagonists. The actions of TXA2 on platelets, respiratory and vascular tissue are considered as key events resulting in the death of the animals. The results obtained in this study, using BAY U 3405 as a selective TXA2 receptor antagonist, clearly show that TXA2 mediated processes are effectively abolished by this type of drug. Since TXA2 is implicated in the pathophysiology of many diseases, potent TXA2 antagonists appear to be useful for treatment of these disorders. BAY U 3405 seems to fulfil these requirements. The threshold dose is 1 to 3 mg/kg p.o. In addition, there is a rapid onset and long duration of action at 10 mg/kg p.o. under the experimental conditions used.

Animals↗
PubMed1991

Protective effect of a novel thromboxane antagonist, BAY-U3405, on canine myocardial damage after coronary artery occlusion and reperfusion.

The effects of a novel thromboxane antagonist, (3R)-3-(4-fluorophenylsulfonmido)-1,2,3,4-tetrahydro-9-carbazol epropanoic acid (BAY-U3405), on myocardial damage due to ischemia and reperfusion (added to accelerate the initiated injury) were studied in anesthetized dogs. The left anterior descending (LAD) coronary artery was occluded for 6 hours and reperfused for 30 minutes. BAY-U3405, 1 mg/kg, was injected intravenously 15 minutes after LAD occlusion, followed by continuous infusion of 10 mg/kg/hour starting at 30 minutes after occlusion. The drug had no hemodynamic effects. During the experiments 6 of 14 animals died of ventricular fibrillation (VF) in the placebo-vehicle controls (3 during occlusion and 3 during reperfusion); in the drug-treated group 5 of 13 dogs died of VF (all during occlusion none during reperfusion). This difference in total mortality and cause was not statistically significant. Reperfusion arrhythmias were largely suppressed by BAY-U3405: 201 +/- 43 versus 689 +/- 98 irregular beats during 30 minutes (p less than 0.001) in the experimental and control groups, respectively. Coronary collateral flow, obtained from a load-line analysis by measurement of retrograde coronary flow, and collateral index were similar in both groups. Therefore, BAY-U3405 did not alter collateral blood supply to the ischemic myocardium. Infarct size, determined with tetrazolium staining, was reduced by 65% (p less than 0.01) after its administration. These results suggest that thromboxane antagonism by BAY-U3405 may delay infarct expansion and reduce the frequency of ventricular arrhythmias during reperfusion of previously ischemic myocardium.

Animals↗
PubMed1990

Characterization of Bay U 3405, a novel thromboxane A2/endoperoxide receptor antagonist.

The thromboxane A2-receptor antagonistic properties of Bay U 3405 [(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbaz o-lepropanoic acid] have been evaluated in various pharmacologic models. Bay U 3405 specifically inhibits platelet aggregation induced by U 46619, collagen, platelet-activating factor, and the second wave of ADP (IC50 0.5, 0.07, 0.3, 0.19 microM) in human plasma. The plasma phase of ADP-induced aggregation is not affected. U 46619-induced platelet aggregation is competitively antagonized (pA2 = 6.3). In humans, ex vivo platelet aggregation is inhibited after oral application of 2 or 50 mg Bay U 3405. Bay U 3405 also specifically and competitively antagonizes U 46619-induced contractions of rabbit aortic rings (pA2 = 7.4). In vivo, Bay U 3405 protects rabbits dose dependently from arachidonic acid or collagen-induced thromboembolism (ED50 1-3 mg/kg p.o). Chronic administration of Bay U 3405 to stroke-prone spontaneously hypertensive rats reduces stroke-related mortality and diminishes the occurrence of cerebral hemorrhages. From these results, we conclude that Bay U 3405 is an orally active, selective, and competitive thromboxane A2-receptor antagonist that may be beneficial in the treatment of cardiovascular or cerebrovascular diseases.

Adenosine Diphosphate↗
PubMed1990

Effect of Bay U 3405, a new thromboxane antagonist, on collagen-induced thromboembolism in rabbits.

Bay U 3405 [(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid] potently inhibits platelet aggregation, thromboxane A2-induced contraction of smooth muscles, and coronary artery thrombosis. We have previously demonstrated inhibition of arachidonic acid-induced sudden death by Bay U 3405. The purpose of this study was to investigate the effects of Bay U 3405 on thromboembolism provoked by collagen. Collagen fibrils dissolved in an isotonic glucose solution were injected into a marginal ear vein of anesthetized rabbits. Sudden death occurred within a few minutes due to elevated thromboxane A2 levels causing intravascular platelet aggregation and myocardial ischemia. In the vehicle-treated group, 100% of the animals died. One of the most prominent parameters was the massive fall in blood pressure. All animals pretreated with 10 mg/kg orally Bay U 3405 survived, showing only a transient hypotensive effect. Tracings of the electrocardiogram and heart rate were unchanged. Bay U 3405 will therefore be useful to elucidate the role of thromboxane A2 in various cardiovascular and respiratory diseases.

Animals↗
PubMed1990

Effects of the novel thromboxane antagonist Bay U 3405 on experimental coronary artery disease.

Bay U 3405 is a novel thromboxane receptor blocker. The present investigations describe its effects on experimental canine and porcine cardiac damage. In anesthetized dogs, a coronary artery was occluded for 6 hours and reperfused for 30 minutes. Bay U 3405 was administered intravenously 15 minutes after occlusion (1 mg/kg) followed by infusion of 10 mg/kg/hr from 30 minutes after ligature. In a second study, the effects of Bay U 3405 on endoperoxide analogue U-46619-induced coronary constriction were studied in anesthetized, open-chest pigs. Bay U 3405 reduced myocardial infarct expansion by 65% (p less than 0.01) assessed with biochemical staining. Hemodynamics and collateral blood flow were unaffected. However, reperfusion arrhythmias were suppressed. In porcine experiments, 1 mg/kg Bay U 3405, given intravenously or intraduodenally, antagonized U-46619-induced coronary vasoconstriction over 5 hours. The studies demonstrate anti-ischemic and antivasoconstrictor properties of Bay U 3405 probably due to binding to platelet and smooth muscle thromboxane receptors. This may have clinical relevance in angina pectoris and myocardial infarction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Synthesis and absolute configuration of the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid and comparison with its enantiomer.

The synthesis of (3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid (Bay u 3405), a new, enantiomerically pure antagonist of thromboxane A2, is described. The determination of the absolute configuration of Bay u 3405 was performed by an X-ray analysis of compound 7 ([3((2S)-acetylamido)-3-phenylpropionamido]-1,2,3,4- tetrahydro-carbazol). Bay u 3405 is in vitro 1 to 2 orders of magnitude more active than its (-)-enantiomer Bay u 3406.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Action of the novel selective thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid on vascular smooth muscle preparations.

The action of the thromboxane A2-receptor-antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) on vascular smooth muscle preparations was investigated in vitro. In rabbit aortic rings Bay u 3405 is a potent inhibitor of vasoconstriction produced by thromboxane A2 (TXA2)/PG endoperoxides generated by stimulated human platelets (EC50 1.3 x 10(-6) mol/l), (+/-)-cTA2 (Carbocyclic thromboxane A2 [2 beta(Z),3 alpha-(1E,3R*)-3- (3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid]) (EC50 3.3 x 10(-7) mol/l) and U 46619 (EC50 3.8 x 10(-7) mol/l). In pig circumflex coronary arteries Bay u 3405 was 150 times more potent (EC50 2.6 x 10(-9) mol/l) than in rabbit aorta. In rabbit and rat aorta the concentration-response curves for U 46619 were shifted to the right in a parallel manner and the maximum responses were not suppressed. The Schild-plot yielded a straight line with a slope of 1.14 (rabbit) or 1.29 (rat) and pA2 values of 7.43 and 8.59, respectively. The vasoconstrictive action of other agonists such as KCl, serotonin, histamine, epinephrine, norepinephrine, acetylcholine and angiotensin were not affected. In human platelets inhibition of the TXA2-synthase was seen only at concentrations of Bay u 3405 of 2.4 x 10(-5) mol/l and above. From these findings it is concluded that Bay u 3405 is a potent, competitive TXA2/endoperoxide receptor antagonist in vascular smooth muscle.

Animals↗
PubMed1989

Inhibition of platelet aggregation in vitro and ex vivo by the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid.

(3R)-3-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was tested for inhibition of platelet aggregation in vitro (human platelet rich plasma) and ex vivo (rat). Aggregation induced by collagen, arachidonic acid, thrombin, adenosine diphosphate (ADP, biphasic response), epinephrine and U 46619 was inhibited at minimum effective concentrations of 0.01 to 0.1 micrograms/ml in vitro. Following oral administration to rats the ED50 for the dose-dependent inhibition was 36 micrograms/kg. At a dose of 100 micrograms/kg p.o. significant inhibition was obtained up to 16 h. Bay u 3405 is considered a potential drug for treatment of some cardiovascular disorders.

Animals↗
PubMed1989

Reduction of in vivo coronary artery thrombosis by the novel thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid.

The effects of thromboxane (Tx)A2 antagonism were examined in a canine model of platelet-dependent coronary occlusion. The novel TxA2 antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was studied to ensure that antithrombotic effects seen in vivo were platelet-mediated and did not reflect unspecific compound effects. Bay u 3405 (1, 3, 10 and 30 mg/kg i.v.) inhibited in vivo platelet aggregation and increased the time to thrombotic vascular occlusion by 2.8 h (p less than 0.05) after 30 mg/kg were given. A dose-dependent reduction of intravascular occlusive thrombus growth occurred: thrombus wet weight decreased from 66 +/- 6 mg in vehicle controls to 42 +/- 6 mg, 25 +/- 5 mg, 18 +/- 3 mg and 6 +/- 2 mg after administration of 1, 3, 10 and 30 mg Bay u 3405 i.v., respectively. Electrocardiographic signs for developing myocardial ischemia were largely prevented by the compound. Collagen-induced platelet aggregation ex vivo was inhibited by over 60% in drug-treated animals. The observed delay of thrombotic coronary occlusion reflected an inhibition of platelet aggregation and protection from coronary vasoconstriction at the site of thrombus formation, most likely mediated through blockade of TxA2 receptors.

Animals↗
PubMed1985

The effects of nafazatrom in an acute occlusion-reperfusion model of canine myocardial injury.

The effects of lipoxygenase enzyme inhibitor nafazatrom on infarct size, haemodynamics, and prostanoid release was studied in a canine occlusion-reperfusion model of ischaemic myocardial injury. Treatment was with 10 mg/kg nafazatrom i.d., starting before coronary occlusion, 2 h and 6 h thereafter, and was repeated in 6 h intervals. The left anterior descending (LAD) coronary artery was occluded for 6 h and reperfused for 42 h. Infarct size and anatomic area dependent on the occluded LAD were determined post mortem by the tetrazolium staining technique. Nafazatrom significantly reduced the extent of irreversible myocardial ischaemic damage whether it was expressed as g/100 g left ventricle (24 +/- 4 vs. 46 +/- 6 in controls; p less than 0.01; mean +/- SEM) or as percentage of LAD risk region for infarcting (38 +/- 8 vs. 65 +/- 7% in controls; p less than 0.05). Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure and dP/dtmax decreased while filling pressure, heart rate, and the S-T segments of the ECG increased. The incidence of ventricular fibrillation was 8% during drug treatment and coronary ligature vs. 25% in controls (n.s.). During reperfusion, nafazatrom reduced the incidence of ventricular premature contractions and tachycardia. Ex vivo platelet aggregation in response to collagen was not inhibited by nafazatrom. Prostanoid release (thromboxane B2 and 6-keto-prostaglandin F1 alpha as breakdown products of thromboxane A2 and prostacyclin, respectively) remained unaltered in vehicle controls but nafazatrom treatment elevated prostacyclin release significantly at 4 and 5 h during LAD occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Relaxation of carbocyclic thromboxane A2-induced contractions of isolated coronary arteries by nifedipine.

+/- Carbocyclic thromboxane A2 (2.9 x 10(-7) mol/l) contracted isolated rings of cat coronary artery. These contractions could be partly inhibited by low concentrations of nifedipine (50% inhibitory concentration - IC50 = 6.8 x 10(-8) mol/l) and completely relaxed by papaverine. Relaxation of thromboxane-induced coronary spasm may contribute to the effectiveness of calcium antagonists in variant angina, which may be caused or exacerbated by thromboxane A2 release from platelets.

Animals↗
PubMed1981

Nimodipine inhibits carbocyclic thromboxane-induced contractions of cerebral arteries.

Carbocyclic thromboxane A2 (CTA2) constricted rabbit basilar and saphenous arteries. The contractions of the basilar artery, but not those of the saphenous artery, were potently inhibited by the calcium antagonist nimodipine. Selective inhibition of thromboxane-induced vasoconstriction of cerebral vessels may contribute to the beneficial actions of calcium antagonists in models of cerebral ischaemia or vasospasm.

Animals↗
PubMedDate not supplied

Effect of BAY U 3405, a new thromboxane antagonist, on sudden death in rabbits.

We studied the effects of BAY U 3405 in experimental models of arachidonic acid- and collagen-induced sudden death. BAY U 3405 was effective in dose-dependently inhibiting death from both arachidonic acid and collagen at doses of 1, 3 and 10 mg/kg orally. The survival rate, usually amounting to less than 10% in vehicle-treated animals, was dramatically increased to 100% at the highest dose. The data obtained emphasize the role of thromboxane A2 as a mediator in this model, and the potential usefulness of BAY U 3405 for thromboembolic disorders.

Animals↗