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Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines XXVII Inhibition of Leucocyte Adherence to Endothelium by the Oligoamine RE 1492C and the NO-Donor RE 2047.

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Inhibition of Leucocyte Adherence
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XXVII
Inhibition of Leucocyte Adherence to Endothelium by the Oligoamine
RE 1492C and the NO-Donor RE 2047
Klaus Rehse”, Thomas Ciborski and Bemd Muller**
* Institut fur Pharmazie der Freien Universitiit Berlin, Konigin-Luise-Str. 2+4, D-14195 Berlin, Germany
and
**
Institute of Pharmacology, Research Laboratories of Schering AG Berlin and Ber3amen
Received June 20, 1994
Antiaggregatorische und anticoagulante Eigenschaften von Oligoaminen, 27. Mitt.:
Hemmung der Leukocytenadharenz an Endothelien durch das Oligoamin RE 1492C und den NO-Donor RE 2047
Das Oligoamin RE 1492C (N,iV’,N”-4-Phenylbutyl-1,3,5-benzol-triThe oligoamine RE 1492C (NJV’JV’’-4-phenylbutyl-1,3,5-benzene-trime-methanamin-N,” jV”-triethylcarbamat) hemmte die durch elektrische
thanamine-N,N” ’-triethylcarbamate)inhibited the electrically provoked
Endothelstimulation hervorgerufene Leukocytenadhaenz in Mesenterialleucocyte adhesion to the endothelium of rat mesentenc venoles. An oral
venolen von Ratten. Nach oraler Gabe von 60 mgjkg wurde eine signifidose of 60 m a g gave a significant inhibition of 65-78%. This is comparkante Hemmung von 65-78% erreicht. Dies ist vergleichbar mit der Wirable to effects seen after i.v. administrationof iloprost Or €%El, respectivekung von Iloprost bzw. PGE, nach intravenoser Infusion. Der NO-Donor
ly. In the same dosage the NO-donor RE 2047 (3-methyl-N-nitroso-sydRE 2047 (3-Methyl-N-nitroso-sydnon-5-imin)
zeigte in der gleichen
none-5-imine) produced an inhibition of 21-27%.
Dosierung wie RE 1492Ceine Hemmung von 21-27%.
The oligoamine RE 1492 (N,”’”-4-phenylbutyl-1,3,5-benzene-trimethanamine) does influence a wide variety of cell properties depending on
the cell type investigated. So blood platelets are protected from aggregation regardless which stimulus is used’). In erythrocytes reaggregability is
maintained during storage, and hemolysis is inhibited2).In cultured tumor
cell lines cell proliferation is strongly decreased3).Even the growth of bacteria is inhibited by submicromolar concentrationsof RE 1492. The closer
inspection of the effects on red blood cells showed altered membrane
permeability as well as the alteration of elastomechanicalproperties4).For
oral application and in vivo investigations the N,”JV”-tricarbamate of RE
1492 has been synthesized and named RE 1492C5).In vivo the sum of the
effects stated above gives rise to strong antithrombotic properties. In the
last years the contribution of leucocytes to endothelial cell damage and
hence to atherosclerosis and myocardial infarction has become obvious6).
We, therefore, were prompted to investigate the influence of RE 1492C on
the adherence of leucocytes to damaged or at least altered endothelium.
As we could show that NO donors potentiate the antithrombotic effect of RE 1492’) we included the newly
developed nitrosimine RE 2047 (3-methyl-N-nitrososydnone-5-imine) into our investigations.
RE 2047
I
-6
RE 1492 C
Scheme 1: Chemical structures of RE 3492C and RE 2047
Arch. Pharm. (Weinheim) 328,125-126 (1995)
The system we used to study the leukocyte adherence has been
described9).In short in anaethetized rats a jejunal loop was exteriorized by
a midline incision and fixed on a microscopic stage. The venules (diameter
23-39 pm) are observed by a microscope. The number of roling leucocytes
is counted from a predetermined 200 pm segment by means of resting
video pictures. Now a steel microelectrode is advanced to the venule wall
by a micromanipulator and an impulse train of 1 s duration applied to produce electrical damage to the venules. After 15, 30,45 and 60 min the
video pictures are taken, the marginated leucocytes counted and their nurnber per mm2calculated. Red Blood Cell (RBC) flow velocity is monitored.
Only venules with a constant flow of 2 mm/s are used.
The results obtained with the two title compounds are
summarized in Tab. 1. Time zero was 4 h (RE 1492C) or
2 h (RE 2047) after oral administration. After a dose of 60
m g k g RE 1492C significantly inhibited the leucocyte
adherence 15-45 min after the electrical stimulus. This corresponds to a 65% (30 min) or 78% (45 min) inhibition.
This effect is in the same order of magnitude as with iloprost 0.1 mg/kg/min i.v. (91/91%) or PGEl 2 mg/kg/min.
i.v. (68/87%). The effect of RE 1492C is dose dependent.
With 30 m a g the effect is obvious, but yet not significant
against control, but significant against the 60 mgkg dose
(*) at 30 min and 45 min. The 120 m g k g dose as well
inhibits the leucocyte adherence significantly from 15-45
min against control. The effect, however, is not significantl y different from the 60 m g k g dose. This indicates that
with 60 m a g the maximum effect already is obtained. The
flow velocity at all doses and all times is not altered significantly. Compound RE 2047 in a 60 mg/kg dose only 15
rnin after the electrical stimulus significantly reduces the
0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheirn, 1995
0365-6233/95/0202-0125$5.00 + .25/0
126
Rehse. Ciborski and Muller
Tab. 1: Influence of RE 1492C and RE 2047 on the leucocyte adherence to rat venules. Statistics: Wilcoxon U-test"), s = standard deviation; s, = standard error of the means. Significance against 60 mg/kg
leucocyte adherence. After 30 or 45 min a slight inhibition
of adherence is observed (21/27%), which, however, is not
significant. The values roughly correspond to the 30 m&g
dose of RE 1492C. The blood flow velocity is slightly but
not significantly reduced. The main reason may be the
smooth vasodilating effects observed with this dose of RE
2047'O). We conclude that at least the antithrombotic effects
of RE 1492C partly may be due to its influence on leucocyte adherence. As we recently did find a potentiation of
the antithrombotic effects of RE 1492C by RE 20477) it
might be worth to investigate the combined administration
of these two drugs on the leucocyte adherence.
Experimental Part
Syntheses of RE 1492C and RE 2047 have been reported',*).- The leucocyte adherence experiments were carried
out as described by Mullerg).
References
K. Rehse, Drug Future 1988,13,941-950.
K. Rehse, H. Kaehler, H. Kuberka, Arch. Pharm. (Weinheim) 1990,
323,475-479.
3 K. Rehse, B. Noak, R. Maurer, P. Hilgard, Arch. Pharm. (Weinheim)
1991,324,797-801.
4 C. Woyke, Dissertation FU Berlin, 1994.
5 K. Rehse, A. Kesselhut, V. Schein, M. Kihpfe, B. Rose, E. Unsold,
Arch. Pharm. (Weinheim) 1991,324,301-305.
6 J.M. Harlan, Blood 1985,65,513-525.
7 K. Rehse, T. Ciborski, Arch. Pharm. (Weinheim), submitted, Oligoamines XXVI.
8 K. Rehse, K.-J. Schleifer, T. Ciborski, H. B o b , Arch. Pharm. (Weinheim) 1993,326,791-797.
9 B. Muller, M. Schmidtke, W. Witt, Eicosanoids 1988, I , 13-17.
10 L. Sachs, Angewandte Statistik, Springer-Verlag, Berlin 1984, p. 230.
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[Ph256]
Arch. Pharm. (Weinheim) 328,125-126 (1995)
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xxvii, 2047, oligoamines, inhibition, endothelial, effect, platelet, donor, leucocytes, anticoagulant, 1492c, aggregation, adherence, oligoamide
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