Release of plasminogen activator by pentoxifylline and its major metabolite.
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Animals↗
Biomedical subjects
F Markwardt
Publications and source records attributed to F Markwardt.
Effects of calcium channel blockers on the contractile response to dihydroergotamine in isolated human femoral veins.
Contractions induced in spirally cut human postmortem femoral veins by dihydroergotamine, noradrenaline, or 5-hydroxytryptamine (5-HT) were measured isometrically. The influence of calcium channel blockers (verapamil, diltiazem and nifedipine), lanthanum chloride and withdrawal of external calcium on the contractile response of veins to dihydroergotamine was investigated. The agonists noradrenaline and 5-HT were studied in comparison. Verapamil and nifedipine up to a concentration of 1 mumol/l caused a shift to the right of the cumulative concentration-response curves for noradrenaline and 5-HT with a reduction of the maximum contraction. Diltiazem affected the contractile response to 5-HT slightly. The venocontractions induced by dihydroergotamine at a concentration of 0.03 mumol/l were inhibited by the calcium channel blockers in a concentration-dependent manner. Verapamil was most effective, followed by nifedipine and diltiazem. In dihydroergotamine-precontracted veins nifedipine produced a more pronounced relaxation than verapamil. Lanthanum chloride (5 mmol/l) inhibited the dihydroergotamine-induced contraction by about 90%. Exposure of veins to a calcium-free medium for 30 min resulted in an inhibition of the dihydroergotamine-induced venocontraction by more than 90%. The addition of calcium ions to the medium caused an increase in the contraction with a maximum which closely resembled that of the control. The present studies demonstrate that the contractile response of human femoral veins to dihydroergotamine depends to a great extent on extracellular calcium. However, the calcium channel blockers verapamil, diltiazem and nifedipine, inhibit the agonist-induced venocontractions in part only.
Adult↗
Two types of transient outward currents in cardiac ventricular cells of mice.
Ventricular cells of adult mice were prepared by an enzyme digestion procedure. Single channel currents were recorded by a conventional patch clamp technique from cell attached patches. Voltage steps from the holding potential of -80 mV to test potentials between -35 and +50 mV caused openings of two types of outward currents through single channels with the conductances of 27 and 12 pS, respectively. The averaged currents reveal transient time courses for both channel types. The current-voltage relations of both single channel currents were linear over the tested voltage range and intersected the voltage axis at -70 mV. This indicates that both single channel currents are mainly carried by potassium ions. All open and closed times were found to be voltage independent. The 27 pS channel had a mean open time of 3.9 +/- 1.0 ms (n = 8). The closed time consisted of two components with tau 1 = 2.1 +/- 0.2 ms and tau 2 = 50 +/- 19 ms (n = 8). The 12 pS channel had a mean open time of 34.0 +/- 5.2 ms (n = 3) and the two components of the mean closed time have been calculated as tau 1 = 8.3 +/- 2.1 ms and tau 2 = 120 +/- 50 ms (n = 3; all mean +/- SD).
Action Potentials↗
Effects of lidocaine on single cardiac sodium channels.
Lidocaine block of single cardiac sodium channels was studied in cell free inside-out patches of ventricular cells isolated from guinea-pig hearts. When applied to the inner surface of the membrane lidocaine depressed Na channel currents by decreasing the probability P of the channels to open measured from the peaks of the averaged currents. In parallel to the decrease in P the relative number of empty sweeps (nulls) was increased. Half maximum block of the activity of single Na channels was observed at 2.9 microM. Lidocaine affected the gating behaviour of Na channels by shortening of the mean open time tau 0 from 0.44 +/- 0.17 (control) to 0.19 +/- 0.13 (5 microM lidocaine, holding potential-120 mV, test potential -60 mV). Five micromolar lidocaine completely suppressed burst-like openings of Na channels and abolished the slow decaying phase of the averaged currents. A shift from - 120 towards - 160 mV exerted relief from the effect of both P and tau 0.
Animals↗
Release of plasminogen activator by batroxobin.
In the isolated perfused pig ear, batroxobin caused a dose-dependent increase in the release of plasminogen activator. The activator-releasing effect required the presence of the active enzyme. The activator released was of the tissue-type.
Animals↗
Effect of heparin, hirudin, and a synthetic thrombin inhibitor on antithrombin III in thrombin-induced disseminated intravascular coagulation in rats.
The effect of heparin, hirudin, and a synthetic thrombin inhibitor on antithrombin III, fibrinogen and platelets was studied in a rat model of disseminated intravascular coagulation (DIC) induced by thrombin infusion. Antithrombin III is consumed during thrombin infusion to a limited degree. Simultaneous administration of exogenous thrombin inhibitors ameliorates the consumption of fibrinogen and platelets. At high thrombin doses, tolerated only during additional administration of thrombin inhibitors, heparin leads to increased consumption of antithrombin III, whereas hirudin and the synthetic inhibitor do not. In every case, the thrombin effect on fibrinogen and platelets is inhibited.
Animals↗
Modulation of single cardiac sodium channels by DPI 201-106.
Single sodium channel currents were analysed in cell attached patches from single ventricular cells of guinea pig hearts in the presence of a novel cardiotonic compound DPI 201-106. The mean single channel conductance of DPI-treated Na channels was not changed by DPI (20.8 +/- 4 pS, control, 3 patches; 21.3 +/- 1 pS with DPI, 5 mumol/1,3 patches). DPI voltage-dependently prolongs the cardiac sodium channel openings by removal of inactivation at potentials positive to -40 mV. At potentials negative to -40 mV a clustering of short openings at the very beginning of the depolarizing voltage steps can be observed causing a transient time course of the averaged currents. Long openings induced an extremely slow inactivation. Short openings, long openings and nulls appeared in groups referring to a modal gating behaviour of DPI-treated sodium channels. DPI-modified Na channels showed a monotonously prolonged mean open time with increased depolarizing voltage steps, e.g. the open state probability within a sweep was increased. However, the number of non-empty sweeps was decreased with the magnitude of the depolarizing steps, e.g. the probability of the channel being open as calculated from the averaged currents was voltage-dependently decreased by DPI (50% decrease at -50.7 +/- 9 9 mV, 3 patches). Short and long openings of DPI-modified channels could be separated by variation of the holding potential. The occurrence of long Na channel openings was much more suppressed by reducing the holding potential (half maximum inactivation at -112 +/- 8 mV, 4 patches) than that of short openings (half maximum inactivation at -88 +/- 8 mV, 4 patches). Otherwise, short living openings completely disappeared at potentials positive to -40 mV where the occurrence of long openings was favoured. The differential voltage dependence of blocking and activating effects of DPI on cardiac Na channels as well as the differential voltage dependence of the appearance of short and long openings refers to a modal gating behaviour of cardiac Na channels.
Action Potentials↗
Pharmacokinetic studies with 3H-pentosan polysulphate in rabbits.
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Animals↗
[Synthetic inhibitors of serine proteinases. 32. Inhibition of trypsin, plasmin and thrombin by amides of N-alpha-substituted 4-amidinophenylalanine. Effect of various amino acids and blocking groups of the n-alpha residue on inhibitory activity].
Cyclic amides of N alpha-arylsulfonylated 4-amidinophenylalanine are specific, highly potent inhibitors of thrombin. Introduction of amino acids between the arylsulfonyl blocking group and amino nitrogen influence particularly the antithrombin activity. By the use of glycine as spacer the compounds become tight binding thrombin inhibitors, while introduction of other omega-amino acids, Gly-Gly, L-Pro, Gly-L-Pro or L-Pro-Gly, reduces the specificity and potency of thrombin inhibition. Substitution of the arylsulfonyl blocking group for a heteroarylsulfonyl residue or an aryl residue causes a decrease in antithrombin activity, while substitution for a benzoyloxycarbonyl blocking group has only slight influence. It is concluded that the N alpha-moiety is of decisive importance for the antithrombin activity of derivatives of 4-amidinophenylalanine.
Amidines↗
[Release of plasminogen activator by SIN-1].
SIN-1--a pharmacologically active metabolite of the vasodilating agent molsidomine--caused an increase in plasminogen activator release of about 50 per cent at a final concentration of 10(-7) mol/l on perfusion of isolated pig ears. An increase in SIN-1 concentration did not produce a further increase in activator release. The released activator is of the tissue-type. After repeated perfusion of the isolated pig ear with SIN-1 no further significant increase in plasminogen activator release occurred.
Animals↗
[The pharmacodynamics of synthetic thrombin inhibitors of the basic type substituted n-alpha arylsulfonylated phenylalanine amide].
Nonspecific pharmacodynamic effects of synthetic thrombin inhibitors, basically substituted N alpha-arylsulfonylated phenylalanine amides, were studied in animal experiments. Upon intravenous bolus injection they exert a rapid fall in blood pressure, which limitates the tolerance. In contrast to the antithrombin activity, toxicity and side effects of the amidino compounds are not dependent on the position of the amidino group within the molecule. On the other hand, compounds with other basic groups, i.e. the amino, aminomethyl, and guanidinomethyl analogues are less toxic and less hypotensively active. The nonspecific pharmacodynamic effects of synthetic thrombin inhibitors of the benzamidine type must be caused by the highly basic amidino group (the benzamidine moiety) of the compounds.
Amidines↗
Studies on the pharmacokinetics of hirudin.
Absorption, distribution and elimination of the naturally occurring thrombin inhibitor hirudin were studied in dogs after intravenous and subcutaneous injection or intraduodenal application using an assay which detects the inhibitor in blood and urine by its antithrombin activity. The plasma concentration time curve after intravenous injection of the pure polypeptide could be best described by an open two-compartment model with first-order kinetics. Dependent on the dose, long-term infusion or subcutaneous injection produced anticoagulantly effective blood levels for a prolonged period of time. The enteral absorption is very low and does not suffice to produce adequate blood levels. Hirudin is distributed into the extracellular space and eliminated through the kidneys by glomerular filtration in active form with a half-time of about 1 h.
Administration, Oral↗
Release of plasminogen activator by molsidomine and its active metabolite SIN-1.
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Animals↗
Biliary excretion of synthetic benzamidine-type thrombin inhibitors in rabbits and rats.
In rabbits and rats the excretion via the bile of the highly effective and selective synthetic thrombin inhibitor N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide was studied after various routes of administration and varying doses. The concentration in the bile was determined using a biological method, the reliability of which was checked by HPLC-determinations. The compound was excreted in the bile in biologically active unchanged form. Cumulative biliary excretion of the synthetic thrombin inhibitor in rabbits amounted to a high percentage of the administered dose after low doses given either systemically or intraportally. In rats the excretion rates during and after intravenous infusion reached a maximum indicating saturation kinetics. Hepatic uptake and biliary excretion of the highly basic benzamidine derivative essentially contribute to its short plasma half-life.
Amidines↗
Antithrombotic and haemorrhagic effects of synthetic and naturally occurring thrombin inhibitors.
The effects of the synthetic thrombin inhibitor N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide (beta Nas-Gly-(pAm)Phe-Pip) and the naturally occurring inhibitors hirudin and heparin on the bleeding time were studied in mice and rats by the method of transection of the tail tip and of standardized incision of the tail. With both methods the thrombin inhibitors prolonged the bleeding time in dependence on the dose and the plasma concentration obtained. The transection bleeding time was influenced by the inhibitors in a similar manner, whereas in the case of incision of the tail heparin caused a more pronounced effect than hirudin and beta Nas-Gly-(pAm)Phe-Pip. Comparison of the antithrombotic actions of the inhibitors with their effects on the bleeding time showed that, in contrast to the selective thrombin inhibitors hirudin and beta Nas-Gly-(pAm) Phe-Pip, antithrombotically effective doses of heparin induced a clear prolongation of bleeding time.
Animals↗
Experimental studies on the antithrombotic action of a highly effective synthetic thrombin inhibitor.
The antithrombotic action of the highly effective synthetic thrombin inhibitor N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide was studied in various models of experimental thrombosis in rats. Intravenous infusion of the thrombin inhibitor caused a dose-dependent inhibition or prevention of stasis-induced venous thrombosis, of arterial thrombosis after electrically-induced damage of the vessel wall and of thrombotic occlusion of an extracorporeal arterio-venous shunt.
Animals↗
Release of plasminogen activator by pentosan polysulphate.
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Animals↗
Modified gating behaviour of aconitine treated single sodium channels from adult cardiac myocytes.
Currents through single Na channels of ventricular cells from adult mouse and guinea pig hearts were studied using the patch clamp technique. Under control conditions the majority of openings is brief and a clustering at the beginning of the depolarizing pulse can be observed. Only between 1 and 8% of the sweeps show long lasting bursts. The bursting may account for a second slow phase of decay of macroscopic currents. In the presence of aconitine in the pipette up to 80% of the sweeps showed bursts underlying the slow inactivation of aconitine modified macroscopic currents. The mean open times are unchanged but the number of openings per sweep is dramatically increased due to aconitine. It is discussed that Na channels may function in different "modes". One mode is characterized by a fast transition into an absorbing state the other one by frequent reopenings ("bursts"). aconitine favours the "bursting" mode.
Aconitine↗