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V B Fiedler

Publications and source records attributed to V B Fiedler.

At least 19 recordsLinked to original sources
PubMed1992

Afterload dependent prolongation of left ventricular relaxation: importance of asynchrony.

OBJECTIVE: Acute increases in afterload and in left ventricular asynchrony both independently prolong left ventricular isovolumetric relaxation. The aim of the study was to investigate whether an increased left ventricular afterload augments left ventricular asynchrony, which in turn could mediate the afterload dependent prolongation of left ventricular isovolumetric relaxation. METHODS: Seven chloralose anaesthetised open chest dogs were instrumented with a left ventricular pressure gauge and two pairs of ultrasonic wall thickness crystals in the antero-apical and postero-basal left ventricular wall. At a constant heart rate of 149(SEM 7) beats.min-1, left ventricular pressure was acutely increased by brief manual clamping of the descending (AOCD) and ascending AOCA) thoracic aorta. Left ventricular asynchrony was quantified by the phase difference of the first Fourier harmonic between postero-basal and antero-apical wall motion. Global left ventricular relaxation was measured as the time constant of isovolumetric pressure fall, tau. Regional myocardial relaxation was assessed as the mean rate to half end diastolic thinning. RESULTS: AOCD increased left ventricular peak systolic pressure from 141.9(6.9) mm Hg to a maximum of 182.0(5.1) mm Hg and tau from 34.3(2.4) ms to 48.0(5.0) ms (p less than 0.05). Simultaneously, phase difference increased markedly during AOCD, from 12.7(3.5) degrees to 24.4(2.2) degrees (p less than 0.05). At matched left ventricular peak systolic pressures, AOCA increased tau from 33.4(2.5) ms to only 42.5(4.3) ms (p less than 0.05 v control and AOCD). Concomitantly, the increase in phase difference was smaller and statistically non-significant, at 13.7(2.9) degrees v 17.1(2.5) degrees. During 13 out of the 14 aortic clampings (7 AOCD, 6 AOCA), tau correlated linearly with phase difference [mean r = 0.74(0.03)]. In contrast to their effects on global left ventricular relaxation and asynchrony, neither AOCD nor AOCA influenced the rate to half end diastolic thinning. CONCLUSIONS: (1) left ventricular asynchrony may increase during an acute augmentation of left ventricular afterload; (2) this increased left ventricular asynchrony possibly contributes to the afterload dependent prolongation of left ventricular isovolumetric relaxation rate.

Animals↗
PubMed1992

Monoclonal antibody to tumor necrosis factor--alpha prevents lethal endotoxin sepsis in adult rhesus monkeys.

In a rhesus monkey endotoxin sepsis model established by intravenous administration of 300 mg/kg D-galactosamine and 0.1 microgram/kg lipopolysaccharide from Salmonella abortus equi, hemodynamic, respiratory, metabolic and hematologic variables; levels of blood gases; monkey leukocyte elastase levels, and blood plasma concentrations of tumor necrosis factor--alpha (TNF) were monitored for 6 hours after administration, and again after 24 hours. Thirty minutes after administration of lipopolysaccharide, either 15 mg/kg anti-TNF monoclonal antibody (MoAB; n = 6) or vehicle placebo (saline solution; n = 4) were given intravenously. During this short-term experiment the organ functions were not different between the treatment groups. However, anti-TNF MoAb afforded morphologic protection from heart, lung, liver, and kidney damage after lipopolysaccharide challenge. Coagulation responses (platelet count and levels of fibrinogen, antithrombin III, and thrombin-antithrombin III complex) were smaller in anti-TNF MoAB-treated monkeys. Plasma TNF levels (WEHI cell cytotoxicity assay) reached a peak (350 pg/ml) 60 minutes after lipopolysaccharide administration in vehicle control subjects but no TNF was detected in the anti-TNF MoAB-treated monkeys. All control animals died 67 +/- 30 hours after lipopolysaccharide administration from multiorgan failure. On the contrary, all anti-TNF MoAB-treated animals survived 14 days (p > 0.005 vs placebo group mortality). Thus in short-term monkey experiments our study indicates protection against lipopolysaccharide-induced endotoxin sepsis by anti-TNF MoAB, which may have clinical relevance for the treatment of human septicemia.

Acid-Base Imbalance↗
PubMed1991

Improved coronary thrombolysis by tissue-type plasminogen activator in the presence of BAY U 3405.

The effect of BAY U 3405 (3 mg/kg i.v.) was tested on recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis of an experimentally induced coronary thrombosis in anaesthetized dogs. BAY U 3405, given immediately before an rt-PA infusion, reduced time to reperfusion by more than 50% compared with vehicle-treated controls (P less than 0.01). After cessation of the rt-PA infusion, BAY U 3405 reduced the reocclusion rate compared to controls (P less than 0.05). These results show that BAY U 3405 improves rt-PA-induced coronary thrombolysis in a canine model.

Animals↗
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↗
PubMed1988

Role of arachidonic acid metabolites in cardiac ischemia and reperfusion injury.

Myocardial reperfusion after prolonged periods of ischemia may result in the acceleration and exacerbation of ventricular injury. This is associated with intramitochondrial calcium overload and gross alterations in ultrastructure. Prostaglandins (PGs) (e.g., PGE2, PGE2 alpha, thromboxane A2, PGl2) are synthesized by the heart during myocardial infarction, and cardiotoxic influences of arachidonate on contractile recovery with enhanced efflux of enzymes occur after reperfusion. Accumulation of arachidonic acid in early ischemia indicates degradation of phospholipids as structural components of myocyte membranes. One major cause for reperfusion-induced exacerbation of ischemic damage is a free radical-induced peroxidation of lipids with cellular disruption. On reperfusion, both vasoconstrictive and dilator PGs are released from platelets, myocytes, and endothelium, and flushed downstream. This may cause additional vasoconstriction in the microcirculation of normally and/or hypoperfused cardiac regions. Locally released vasodilating PGs can improve cardiac perfusion and prevent plugging of blood elements, thereby antagonizing cell destruction during flow restoration. Several drugs are available that modify blood cell and myocyte arachidonate metabolism, and may favor synthesis of dilating and antiaggregatory PGs.

Animals↗
PubMed1987

Effects of intracoronary leukotriene D4 infusion on the coronary circulation, hemodynamics, and prostanoid release in porcine experiments.

The effects of leukotriene (LT) D4 (0.5 microgram/min) infusion into the left anterior descending coronary artery (LAD) of anesthetized pigs were studied in the absence or presence of indomethacin (5 mg/kg i.v.). In some pigs, arteriocoronary venous (A-V) blood plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured by RIA technique during LTD4 actions. LTD4 changed LAD blood flow at 5 and 30 s, 2, 4 and 5 min by -46% (p less than 0.01), -93% (p less than 0.001), -45% (p less than 0.01), -28% (p less than 0.05) and 16%, respectively. Thus, the coronary constriction disappeared despite sustained LTD4 infusion and was followed by reactive hyperemia. Indomethacin did not affect the coronary flow or hemodynamic responses to LTD4 infusion. The A-V difference in prostanoids did not change during LTD4 administration. Cyclooxygenase products of arachidonic acid may not be responsible for early constriction and later escape phases of LTD4 effects on the coronary circulation. However, intracoronary bolus injection of LTD4 stimulated prostacyclin release from the vasculature in a dose-dependent manner causing significant reactive hyperemia after temporary blood flow cessation. Release of a LTD4-induced vasodilating factor from the coronary vessels unrelated to prostanoids may cause escape from vasoconstriction during LTD4 infusion.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Enhancement of canine coronary collateral flow by nafazatrom.

The ability of oral nafazatrom treatment (10 mg/kg) 2 h preceding occlusion of the left anterior descending coronary artery for 6 h to limit expansion of myocardial injury was studied in anaesthetized canine hearts. Collateral blood flow was obtained with a load line analysis, employing aortic pressure, post-stenotic coronary pressure, and retrograde coronary flow from the occluded vessel. Contractile changes in the subendocardial ischemic perfused muscles were measured with ultrasonic techniques. Infarct size was determined post-mortem by a biochemical staining method and excision of necrosis. Post-stenotic coronary pressure was slightly below aortic pressure in both groups before coronary occlusion, and fell to 29 and 27% of aortic pressure in vehicle- and drug-treated hearts, respectively, after the insult. Retrograde flow was 2.4 +/- 0.6 vs. 4.1 +/- 0.7 ml/min in tylose- or nafazatrom-treated hearts. Collateral flow amounted to 1.5 +/- 0.06 vs. 2.5 +/- 0.04 ml/min in controls and drug-protected hearts. Contractility (dP/dtmax) and the %-segment shortening were greater in the ischaemic myocardium after nafazatrom treatment. Infarct size was 38 +/- 5.2 vs. 17 +/- 3.4 g/100 g left ventricle in the vehicle controls and nafazatrom group, respectively. Nafazatrom reduced infarct size by 46%. Besides other mechanisms, this was due to improved %-segment shortening and increased periinfarction collateral blood supply to jeopardized but viable myocardium. The drug may be of value in ischaemic heart disease as shown by the enhanced regional myocardial perfusion and improved contractility.

Animals↗
PubMed1986

Protective actions of carbocromene against amitriptyline-induced cardiotoxicity in anesthetized rats.

This study was designed to analyze the effects of carbocromene on circulatory and electrophysiologic failure in rats anesthetized with urethane. Amitriptyline was infused at 0.4 mg/kg/min (n = 12) until death of the animals at 30 +/- 6.7 min due to vascular collapse. Following initial heart rate increase and QRS prolongation, this was characterized by progressive hypotension, bradycardia, intraventricular conduction delay, S-T segment elevation and A-V block. In the initial 31 rats, carbocromene was administered i.v. with 4 mg/kg followed in two groups by 40 (n = 13) and 80 micrograms/kg/min (n = 18) i.v., respectively. The drug was effective in protecting the animals against the acute cardiovascular failure induced by amitriptyline. The preservation was associated with a diminution of the hypotension, negative chronotropic actions, S-T segment elevation and the incidence of A-V block produced by amitriptyline. Survival time of the rats increased to 46 +/- 5.3 min (p less than 0.05 vs. amitriptyline controls) and 63 +/- 6.5 min (p less than 0.01) with infusion of 40 and 80 micrograms/kg/min carbocromene, respectively. These results suggest that carbocromene is an effective treatment of amitriptyline-induced cardiotoxicity by massive overdose with beneficial effects largely due to hemodynamic and metabolic oxygen-sparing impact on the heart. Membrane stabilizing antiarrhythmic carbocromene effects may be contributory factors in its protective value in the treatment of acute amitriptyline poisoning.

Amitriptyline↗
PubMed1985

Failure of nafazatrom to reduce infarct size and arrhythmias in a porcine model of acute coronary occlusion.

The effects of nafazatrom (10 mg/kg, b.i.d., orally for 2 days preoperatively; 10 mg/kg, intraduodenally, 30 min before coronary occlusion) on hemodynamics and arrhythmias were assessed in a group of drug-treated anesthetized pigs and compared with the effects in animals that received the drug vehicle and were treated identically. Infarct size (triphenyl-tetrazolium method) of the left anterior descending coronary artery was 24.4 +/- 2.4% of the left ventricle in nafazatrom-treated hearts after 2 h of occlusion and 26.2 +/- 3.2% in control hearts. Blood pressure, heart rate, left ventricular systolic and end-diastolic pressure, cardiac output and stroke volume were not different between the groups during cardiac insult. There were no differences in the number of premature ventricular contractions, arrhythmia and tachycardia, and ventricular fibrillation. It is concluded that short-term administration of the 5-lipoxygenase inhibitor nafazatrom had no effect on infarction, hemodynamics or arrhythmias in the acutely ischemic porcine myocardium.

Animals↗