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H Darius

Publications and source records attributed to H Darius.

At least 109 records · Page 6Linked to original sources
PubMed1986

[Organic nitrates and prostaglandins in the cardiovascular system].

The beneficial effect of organic nitrates in acute myocardial ischemia is commonly explained by their hemodynamic actions, especially the dilatation of venous capacitance vessels. Recent studies have shown an inhibition of platelet function by organic nitrates ex vivo but not in vitro. Antiplatelet activities of organic nitrates might represent an additional mechanism, independent of vascular actions which might eventually involve stimulation of prostacyclin formation by the vessel wall. In vitro experiments on isolated coronary artery preparations have demonstrated stimulation of PGI2 as well as inhibition of platelet thromboxane synthesis by a number of organic nitrates. Optimal stimulation requires the presence of a free nitro group in the molecule at a particular steric position and can be suppressed by a number of inhibitors, including corticosteroids, indomethacin and methylene blue. Administration of the organic nitrate teopranitol to healthy volunteers is associated with depressed platelet secretion ex vivo which is not seen with the compound in vitro. It is concluded that further clinical elucidation of the PGI2-related mechanism in the action of organic nitrates in patients appears to be both necessary and useful.

Adenosine Triphosphate↗
PubMed1986

Cardioprotective actions of a new calcium channel blocker in acute myocardial ischemia.

The ability of anipamil, a calcium channel blocker, to protect ischemic myocardial tissue was investigated in pentobarbital anesthetized cats. Two bolus injections of anipamil (1.0 mg/kg i.v.) or their vehicle (i.e., 95% ethanol) were given 30 and 150 min post-ligation of the left anterior descending coronary artery. Anipamil significantly reduced the elevated S-T segment elevation and T wave amplitude suggesting a moderating influence on cellular ischemia. The drug also significantly blunted the loss in myocardial creatine kinase activity and amino-nitrogen concentrations from ischemic myocardial tissue, compared to cats receiving only the vehicle. These changes are suggestive of a cardioprotective effect of this calcium channel blocker. Since no significant change in the pressure rate index was seen with anipamil, a decrease in myocardial oxygen demand does not appear to be the major mechanism of the cardioprotective action of the agent. Therefore, anipamil protected the heart from ischemic damage, possibly by a direct cytoprotective action.

Animals↗
PubMed1986

In vivo anti-platelet properties of anipamil, a calcium channel blocker, in the rabbit.

The anti-platelet actions of anipamil, a new calcium channel blocker were studied in anesthetized rabbits using continuous on-line techniques to measure platelet count and platelet secretion by ATP release. Anipamil, at a dose of 0.5 mg/kg twice daily for three days, prior to challenge with collagen (100 micrograms/kg) or arachidonic acid (1.1 mg/kg), was without effect. However, 2 and 5 mg/kg of anipamil significantly retarded the decline in platelet count to both platelet activators, although anipamil failed to significantly diminish the hypotensive effect of these platelet activators, or significantly increase survival to arachidonic acid. Moreover, anipamil was without effect on the platelet effects of platelet activating factor (PAF). Thus, anipamil has the ability to partially inhibit the activation of platelets in vivo.

Adenosine Triphosphate↗
PubMed1985

Antiaggregatory effects of thromboxane receptor antagonists in vivo.

The antiaggregatory and antisecretory effects of two newly developed thromboxane receptor antagonists, BM-13,177 and SQ-29,548, were studied in an in vivo model of platelet activation. Arterial platelet count and whole blood ATP concentrations were measured continuously on-line in the arterial blood of anesthetized rabbits. Injections of collagen decreased peripheral platelet count by 25% of initial value. ATP concentrations increased 50 to 100 nM during collagen challenge. SQ-29,548 and BM-13,177 dose-dependently reduced platelet loss to about 50% of that observed in vehicle treated animals. Injection of arachidonic acid (AA) or 9,11-methanoepoxy-PGH2 resulted in sudden death of the animals associated with a 67 to 69% decrease in platelet count and a marked release of ATP. Pretreatment with SQ-29,548 or BM-13,177 increased survival rates from 0 to 100%, and reduced or totally inhibited ATP secretion and decreases in platelet count. In contrast, the thromboxane synthetase inhibitor, dazoxiben, was effective in inhibiting AA induced sudden death, but was without any effect when 9,11-methanoepoxy-PGH2 was used as the challenging agent. We conclude that SQ-29,548 and BM-13,177 are effective in antagonizing the effects of subsequent conversion to thromboxane A2. BM-13,177 and SQ-29,548 are generally considered as specific antagonists of endoperoxide/thromboxane receptors on platelets and smooth muscles in vitro. Preliminary clinical studies with BM-13,177 showed a marked inhibition of ex vivo platelet aggregation in human volunteers and patients (18, 19). These reports encourage further study of thromboxane receptor antagonists as effective anti-thrombotic drugs in the experimental and clinical setting.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Inhibition of thromboxane and 12-HPETE formation by dazoxiben and its two thiophenic acid-substituted derivatives.

LG 82-4-00 (5-(2-(1-imidazolyl)-ethoxy)-thiophene-2-carboxylate) and LG 82-4-01 (4-chloro-thiophenic-substituted derivative) were examined for specific inhibition of thromboxane (TX) synthetase. Thromboxane formation was measured by a radioimmunoassay specific for TXB2. In thrombin (0.6 IU/ml)-stimulated, washed human platelet suspensions (WPS) the IC50 (microM) for inhibition of TX formation were 1.1 (LG 82-4-00), 1.3 (LG 82-4-01) and 0.7 (dazoxiben). LG 82-4-00, LG 82-4-01 and dazoxiben also inhibited collagen (0.6-2.5 micrograms/ml)-induced TXB2 formation and platelet aggregation in human platelet-rich plasma. Neither LG 82-4-00 nor LG 82-4-01 had vasoconstrictor, proaggregatory or TX antagonistic activity or affected primary wave ADP aggregation. There was less than 10% inhibition of PGI2 formation from bovine coronary artery slices with concentrations up to 100 microM. At 100 microM, dazoxiben inhibited thrombin-induced 12-HPETE formation in WPS by 81 +/- 10% whereas LG 82-4-00 and LG 82-4-01 were much less active. These data indicate that LG 82-4-00 and LG 82-4-01 are specific inhibitors of thromboxane synthetase in human platelets.

Animals↗
PubMed1985

[Inhibition of platelet aggregation and thromboxane formation by the calcium antagonist nisoldipine following a single oral dose of 10 mg. A double-blind study in healthy probands].

The influence of the calcium antagonist nisoldipine on collagen-induced platelet aggregation and platelet thromboxane formation was studied ex vivo in healthy male volunteers in a double-blind, placebo-controlled crossover design. Measurements of general haemodynamics, immunoreactive 6-oxo-prostaglandin F1 alpha and thromboxane B2 ex vivo and collagen-induced (0.6 and 2.5 micrograms/ml) platelet aggregation were performed immediately before (time 0), 0.5 h, 1 h and 2 h after ingestion of 10 mg nisoldipine or an identical placebo tablet. Compared with the control response at time 0, administration of nisoldipine resulted in a significant inhibition of both low-collagen-induced platelet aggregation and formation of immunoreactive thromboxane B2 at time 0.5 h. There were no changes in heart rate or systolic blood pressure but a significant decrease in diastolic blood pressure by nisoldipine at 1 h. No such change was obtained with placebo and there were also no alterations with nisoldipine in platelet aggregation and thromboxane formation after stimulation by high-dose collagen at this or any other time of the study. The data demonstrate a platelet-inhibitory potential of nisoldipine in healthy men which is probably related to an increased resistance of the platelet membrane against foreign stimuli.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Anti-ischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats.

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction, and has a direct cytolytic effect, thromboxane receptor antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.5 hours. ST segment elevation declined significantly (p less than 0.02) after BM-13,177 treatment, suggesting a reduction in cellular ischemia. The loss in myocardial creatine kinase (CK) activity and in free amino-nitrogen concentration in the ischemic area was also significantly reduced (p less than 0.01). No significant changes in blood pressure or heart rate were seen with BM-13,177 during myocardial ischemia or in nonischemic control cats. Blood levels of BM-13,177 were sufficient to inhibit ex vivo platelet aggregation induced by the prostaglandin endoperoxide analog, U-46,619. Data from isolated cat coronary arteries suggest that BM-13, 177 antagonizes the thromboxane/endoperoxide receptor in coronary vascular smooth muscle. These experiments indicate that TxA2 plays a significant role in propagating the extension of ischemic damage, and that thromboxane receptor antagonism is an effective means of reducing the damage provoked by TxA2 in acute myocardial ischemia.

Animals↗
PubMed1985

In vivo interaction of prostacyclin with an inhibitor of cyclic nucleotide phosphodiesterase, HL 725.

Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. The interaction of synthetic PGI2 and the potent phosphodiesterase inhibitor HL 725 was studied in a model of systemic platelet activation by intravenous injection of collagen. Platelet aggregate formation was evaluated by continuous on-line measurement of the circulating platelet count. Collagen injection in rabbits receiving vehicle caused a 30 +/- 3% decrease in the circulating platelet count. Infusion of PGI2 (0.05, 0.1 and 0.75 micrograms kg-1 min-1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 micrograms kg-1 min-1) caused a slight but significant effect. Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 micrograms kg-1 min-1 inhibited platelet aggregate formation to a greater extent than when either substance was used alone and produced a comparable inhibition to PGI2 at 0.75 micrograms kg-1 min-1. Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. The infusion of a combination of PGI2 and HL 725 before collagen produced a decrease in the MABP which was greater than when either compound was used on its own. Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1985

Blockade of thromboxane and the prevention of eicosanoid-induced sudden death in mice.

We studied the effects of thromboxane-receptor antagonism and thromboxane synthetase inhibition in a thrombotic model of sudden death in mice. Intravenous injection of arachidonic acid (AA; 80 mg/kg) or the prostaglandin-endoperoxide analog U-46,619 (2.3 mg/kg) results in sudden death in approximately 90% of the animals. Pretreatment with the thromboxane receptor antagonist SQ-29,548 (0.3-10 mg/kg) protects dose-dependently against AA and U-46,619-induced sudden death. In contrast, CGS-13,080, a thromboxane synthetase inhibitor, shows a dose-dependent beneficial effect in AA-induced sudden death only. Although PTA2 has partial thromboxane agonistic properties in the rabbit, it protected the mice against AA-induced sudden death, thus demonstrating TxA2 antagonistic properties in this species. These data emphasize the importance of thromboxane A2 as a major mediator of arachidonic acid-induced sudden death and the effectiveness of thromboxane-receptor antagonists in endoperoxide-induced sudden death.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Beneficial effects of a new potent and specific thromboxane receptor antagonist (SQ-29,548) in vitro and in vivo.

SQ-29,548, a newly synthetized thromboxane receptor antagonist, was investigated for its effects on platelet and vascular thromboxane receptors in vivo and in vitro. Arachidonic acid (AA)-induced sudden death in rabbits was dose-dependently inhibited by SQ-29,548 at doses ranging from 0.2 to 2 mg/kg. Sudden death was accompanied by a 46 +/- 6% decrease in continuously measured circulating platelet count, which was also dose-dependently inhibited by SQ-29,548. The AA-induced increase in continuously recorded whole blood ATP content was 1.2 +/- 0.4 microM and was significantly diminished by all SQ-29,548 doses used. Platelet aggregation induced by AA, the endoperoxide analog U-46,619 or collagen in platelet-rich plasma was dose-dependently inhibited by SQ-29,548 which exerted an IC50 of 0.8, 0.3 or 2.9 microM, respectively. In contrast, ADP and platelet-activating factor acether-induced platelet aggregation were unaffected at concentrations of SQ-29,548 up to 260 microM. Thromboxane B2 formation was not significantly altered by SQ-29,548 (1-100 microM) in platelet-rich plasma stimulated with AA or in spontaneously clotting whole blood. Thromboxane synthetase, cyclooxygenase and lipoxygenase product formation were unaffected by SQ-29,548 when washed rabbit platelets were stimulated with radiolabeled AA and the products were measured after separation by thin-layer chromatography. U-46,619 (500 nM), carbocyclic thromboxane A2 (15 nM) and prostaglandin F2 alpha (3 microM)-induced contractions of rabbit pulmonary artery were antagonized by SQ-29,548 exerting a IC50 value between 120 and 40 nM, whereas norepinephrine-induced contractions were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1985

The action of flupirtine on prostaglandin formation and platelet aggregation in vitro.

The action of ethyl-N-(2-amino-6-(4-fluorophenylmethylamino) pyridin - 3 - yl) carbamate (flupirtine, D 9998), a recently synthesized analgesic, on prostaglandin formation and platelet aggregation was studied in vitro. Flupirtine was found to significantly inhibit the basal prostaglandin I2 formation in preparations of the rat aorta as well as the arachidonic acid-stimulated prostaglandin release form the Langendorff-perfused guinea pig heart. The IC50 amounted to 5-50 mumol/l in these systems and was more than one order of magnitude higher than indometacin (0.5-1 mumol/l). Flupirtine was found to inhibit dose-dependently the collagen - but not the primary adenosine diphosphate-induced aggregation of human platelets, being again 1 order of magnitude less potent than indometacin (IC50: 4.0 vs. 0.6 mumol/l). Interestingly there was no inhibition of arachidonic acid-induced thromboxane formation of human platelets by flupirtine in concentrations up to 23 mumol/l. These data suggest a weak inhibition of prostaglandin formation by flupirtine. There may also exist a weak local anaesthetic activity of the agent, demonstrated here on the rabbit cornea, that aids the observed decrease in sensitivity of smooth muscle preparations and might help to explain the inhibition of collagen-induced platelet aggregation in absence of diminished thromboxane formation. It is concluded that these modifications of prostaglandin formation by flupirtine are probably of minor importance for an analgesic action of the compound in vivo.

Adenosine Diphosphate↗
PubMed1985

Arterial wall regeneration in small-caliber vascular grafts in rats. Neoendothelial healing and prostacyclin production.

Clinically available synthetic graft materials frequently fail when used as a small-caliber arterial substitute. Therefore, we developed a new type of graft material, prepared from a mixture of polyurethane and poly-L-lactic acid, to be used as a scaffold for the regeneration of the arterial wall. In this study microporous, compliant, biodegradable polyurethane/poly-L-lactic acid grafts (n = 16) and polytetrafluoroethylene grafts (n = 16) were implanted in the rat abdominal aorta and evaluated 3, 6, and 12 weeks after implantation. First, we evaluated the extent of neoendothelial healing (n = 8) by means of light microscopy and scanning electron microscopy. Next, we studied the ability of the neoendothelial cells to produce prostacyclin (n = 8) by means of bioassay for prostacyclin and radioimmunoassay for its stable hydrolysis product, 6-oxo-prostaglandin F1 alpha. There were no significant differences between the two graft types in the amount of prostacyclin production per unit graft area covered with neoendothelium, and this amount was the same as for normal endothelium. However, the polytetrafluoroethylene grafts showed incomplete neoendothelial healing, even after 12 weeks of implantation, in contrast to the polyurethane/poly-L-lactic acid grafts. The better healing characteristics of the polyurethane/poly-L-lactic acid grafts ensured the fast development of a complete neoarterial wall, possessing strength, compliance, and thromboresistance equivalent to normal arterial wall tissue. These results demonstrate that arterial wall tissue regeneration in polyurethane/poly-L-lactic acid grafts may open new perspectives in the field of arterial reconstructive surgery.

Animals↗
PubMed1984

Stereospecific stimulation of coronary vascular PGI2 by organic nitrates--studies with the new compound teopranitol (KC-046).

PGI2 release of bovine coronary arteries (BCA) was studied in vitro (bioassay) under control conditions and in presence of the new isoidide-nitrate teopranitol (2-(gamma-theophylline-7-ylpropylamino)-2-desoxy-L-isoidide- 5-nitrate- bifumarate) (KC-046). Teopranitol dose-dependently stimulated (2-200 nmoles/1) PGI2 release 2-3-fold. This action was inhibited by both methylene blue (150 mumoles/1) and indomethacin (11 mumoles/1). The 5-[endo] stereoisomere (KC-144) was inactive, although both compounds produced an equally potent relaxation of isolated BCA strips. Similar stereospecificity was found for isosorbide nitrates. It is suggested that stimulation of coronary vascular PGI2 by organic nitrates is critically determined by the steric position of the free nitrate group(s), whereas the vasodilation is a more general property.

Animals↗
PubMed1982

The release of prostacyclin (PGI2) by pentoxifylline from human vascular tissue.

The influence of pentoxifylline (Trental) on prostacyclin (PGI2) formation was studied in vitro, using preparations of human umbilical arteries and veins. In addition, the thromboxane formation in human platelets was investigated. Pentoxifylline at 11 mumol/l concentration stimulated PGI2-release from umbilical veins from 14 +/- 8 to 28 +/- 4 pmol/100 mm2 (P less than 0.05). Similarly, pentoxifylline stimulated PGI2-formation in umbilical arteries at 36 and 110 mumol/l concentration from 12 +/- 2 to 23 +/- 10 and 25 +/- 4 pmol/100 mm2, respectively (P less than 0.05). These amounts of pentoxifylline also produced dose-dependent relaxation of venous and arterial vessel strips but did not change the ADP- or collagen-induced platelet aggregation in platelet-rich plasma in vitro. There was no influence by pentoxifylline on the arachidonic acid-induced thromboxane formation of human platelets. These data demonstrate for the first time stimulation of PGI2-formation in human blood vessels by pentoxifylline in vitro. It is suggested, that the antiplatelet effects of pentoxifylline in vivo may be mediated by primary vascular mechanisms.

Arachidonic Acid↗
PubMed1981

Beneficial effects of a new carbacyclin derivative, ZK 36 374, in acute myocardial ischemia.

The potential therapeutic value of the chemically stable carbacyclin analog ZK 36 374 was studied in acute myocardial ischemia (MI). In anesthetized cats, the left anterior descending coronary artery was ligated and 30 min later an i.v. infusion of ZK 36 374 (0.18 microgram/kg X min) on vehicle was initiated and continued for 4.5 hr. ZK 36 374 reduced the ST-segment elevation at 2 to 5 hr (P less than .01) when compared to vehicle-treated MI cats. ZK 36 374 completely prevented the loss of CK specific activities and the decrease in percentage of bound cathepsin D in the infarcted area of the myocardium (P less than .01), but had no influences on any of these parameters in shamoperated animals. In addition, ZK 36 374 reversed the MI-induced decrease in circulating platelet count toward the preinfarction levels, probably by dispersion of circulating platelet aggregates. ZK 36 374 prevented the ischemia-induced loss of myocardial catecholamines from adrenergic nerve terminals. ZK 36 374, at 0.18 microgram/kg X min, exerted a maximum antiplatelet effect, whereas a significant decrease in arterial blood pressure was seen at 1.79 microgram/kg X min (-30-40%). This indicates a considerable dissociation between antiplatelet and blood pressure-lowering activities of ZK 36 374 in this model. The data demonstrate a significant protective effect of ZK 36 374 in acute MI that might be associated with its platelet-stabilizing, antiadrenergic and myocardial cytoprotective activities.

Animals↗