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Sugar derivatives of indolamines, part V : Cardiovascular effects and “anti-stress” activity of desoxyfructose derivative of serotonin and 5-methoxy-tryptamine
THROMBOSIS @ Pergamon
RESEARCH 15;245-253 Printed in Great Britain Press Ltd.1979. oo49-3848/79/0601-045
#02.00/o
SUGARDERIVATIVES OF INDOLAMINES, PARTV : CARDIOVASCULAH EFFECTSAND "ANTI-STRESS" ACTIVITYOF DESOXYFRUCTOSE DERIVATIVE OF SEROTONINAND 5-METHOXY-TRYPTAMINE
L. Mester*,
M. Mester,
K.P. Bhargava, and M. Cheucle
C. Labrid,
G. Dureng
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, 91190, France; King George's Medical College, Department of Pharmacology, Lucknow, India and Centre Europ6en de RecherchesMauvernay, Riom-63201, France (Received 9.1.1979; in revised form 27.2.1979. Accepted by Editor W. H. Seegers) ABSTRACT Desoxyfructo-serotonin oxalate and free base produced a decrease of the blood pressure and heart rate of vagotomized cats (in total doses of 100 mg, i.v.) for 30 and 120 min. respectively, with total blocking of the carotid occlusion pressor response. With desoxyfructo-5-methoxytryptamine the decrease in the blood pressure lasts only 1 minute, followed by a 30 min. moderate increase. With this compound the C.O. pressor response is not blocked. On anaesthetized dogs with opened thorax low doses of the drug (100-200 ug/kg i.v.) produced a similar decrease of the blood pressure and heart rate, however, only for a short time (3 min.). An important increase in the sinusal coronary flow and partial oxygen pressure was also observed. Oral administration of desoxyfructo-serotonin oxalate (50 mg/kg) reduced to 40% the gastric ulcer formation by restraint in rats. With the same compound (100 mg/kg i.p. daily per 4 days) a very significant "anti-stress" activity was observed on mice by increased swimming endurance, Rota-Rod test performance, anti-ulcer effect and by elimination of milk induced leucocytosis.
To whom enquiries
should be addressed. 245
246
SUGAR DERIVATIVES OF INDOLAMINES
Vo1.15,No.1/2
INTRODUCTION Haemostasis and thrombosis are doubtless phenomena located in the crossing of very different knowlege including medicine, biochemistry, polymerization and physical chemistry of layers. A multidisciplinary approach (1) has been proposed to explain the mechanism of these phenomena and also the multiple role of platelets in basic physiological processes (2). A typical example for the multidisciplinary approach was given in 1975, by the annoncement that the first step of the Maillard reaction (3) (the so called Amadori reaction), worldwide investigated in food chemistry since the beginning of this century, can occur in haemostasis (4). Afterwards, but no more thana year later, two independent teams (5,6) reported the discovery of such Amadori type sugar derivatives of haemoglobin in normal and diabetic individuals. Since then the eventuality of the formation of desoxy-sugar derivatives from serotonin in physiological conditions, and the possible role of endogenous or exogenous desoxyfructo-serotonin in haemostasis have met with some interest. A multidisciplinary approach means also studies in a wide.rareaconcerning platelets. Platelet aggregation is still considered as the major factor in thrombotic accidents , however, platelets appear to have some relation to many factors implicated in thrombosis, like hemodynamic factors, vascular permeability and stress (7). On the basis of the above statements it appears desirable to explore also cardiovascular and "anti-stress" effects of drugs with potential anti-thrombic activity. For.this reason, three indolamine sugar derivatives : desoxyfructo-serotonin oxalate (DF-5HT ox.), desoxyfructo-serotonin free base (DF-5HT base) and desoxyfructo-5-methoxytryptamine (DF-5-MT ox.) were investigated to establish their effects in these fields, if any. MATERIAL AND METHODS The following compounds were prepared as earlier reported (8,9) and were tested : 1. Desoxyfructo-serotonin oxalate (DF-5HT ox) m-w. 428. 2. Desoxyfructo-serotonin base (DF-5HT base) m-w. 338. 3. Desoxyfructo-5-methoxy-tryptamine oxalate (DF-5MT ox) m.w. 442. The compounds were dissolved in normal saline. I. CARDIOVASCULAR EFFECTS : using _--_____ the drug _________-__ intravenousA. On bilaterally ___ vaqotomized cats,_____ _________--____-____-_--ly in total doses of 100 mg_per animal _ _______-____________------------* The cardiovascular effects of compounds No. 1,2, and 3 were studied in bilaterally vagotomized cats (10 Cats in each group) anesthetized with pentobarbitone. The drugs were administered in total doses of 100 mg, in 5 ml normal Saline (i.v.),
Vo1.15,No.1/2
SUGAR DERIVATIVES
OF INDOLAMINES
247
Their effect was studied on resting blood pressure, on pressor responses evoked by either carotid occlusion for lo-30 sec. or by l-2 ug/kg of noradrenaline given intravenously. The cardiovascular effects are summarized in TABLE I. using --_-__-_ the drug B. On anaesthetized dogs-_______ with opened thorax ___________________ ___________L_____ intravenously _____---_________ in doses of 100 ~gLhg_asd_200_~gLkgL_EegEectl____________ in 1 ml normal saline (in 1 min 1 vely,________________________________, --_ Lots of 5 anaesthetized dogs of the same race and weighat least 19 kg wereused in these experiments, after tracheoing tomy. The sinusal coronary flow (ml/mn) and the sinusal coronary P$I~ (partial pressure of oxygen in mm Hg) were measured (10). Femoral arterial pressure (11) and cardiac frequency (12) were registered. The results are summarized in TABLE II. II. ANTI-STRESS
STUDIES
:
A. On rats using ________ the drug ______ orally ~--~~~-~~~----_-~ in doses of 50 mg& __,__-_L____The method of Bonfils et al. (13) was used to produce ulrestraint due to immobilization, on Wistar male rats cers by weighing 180+ 20 gr. Before immobilization the "treated" group of animals received by oral probe 50 mg/kg of the drug. After 18 hours the number of animals showing gastric ulcers, was established. B. On mice using ______-_ the drugs_______ intraperitonially in doses of 100 ____________ __-_______ -____-___-__--_&kg in 0.25 ml npzmpl -------_-__--__-_saline (in 1 min.1 ________---for four days-------______1. Effect on swimming endurance test - The mice were divided in 3 groups of ten animals each, one group served as control and each animal of this group received normal saline (0.25 ml) intraperitoneally and other 2 groups were pretreated with test compounds in doses of 100 mg/kg (i.p.) for four days. The animals of each group were forced to swim till exhaution (swimming time) in separate porcelain tanks filled with water (3O'C). 2. Anti-ulcerogenic effect - Effect of the compounds was seen on restraintulcers. Restraint ulcers were produced in groups of ten animals each by immobilisation for 18 hours (14). One group served as control and other groups received the compounds in doses of 100 mg/kg (i.p.) one hour before the start of the experiment. 3. Milk induced leucocytosis - Albino mice weighing between 20-25 gm were divided into groups of 10 animals each. Leucocyte count was done an the blood samples collected from the tail vein of each mouse . The effect of test compounds was seen after 100 mg/kg dose given i.p. once daily for four days) on milk induced leucocytosis (15). 4. Rota-rod performance in mice was followed Kinnard and Carr (16). 5. Pentobarbitone
narcosis
was done
in mice.
by the method
of'
248
SUGAR DERIVATIVES OF INDOLAMINES
v01.15,N0.1/2
RESULTS AND DISCUSSIOW The cardiovascular effects of the compounds were studied on blood pressure, on heart rate and on pressor response evoked by carotid occlusion (C.O.). As shown on TABLE I., both serotonin sugar derivatives produced on vagotomized cats first a slow increase (5 to 10 %) of the basal blood pressure for 2 to 5 min., followed by an important decrease (30 to 40 %). The duration of this effect was 30 minutes with the oxalic salt, followed by a moderate increase (2~ %), while in the case of the free base, the decrease was constant up to 120 min. The heart rate decreased with both compounds by about 2O %.Recovery to normal did not occur for 120 min. Both, desoxyfructo-serotonin oxalate and free base, blocked completely the pressor effect evoked by carotid occlusion or by norepinephrine, showing that the effect of the serotonin sugar derivatives is a central one. While the two sugar derivatives of serotonin show nearly the same cardiovascular effects, the behaviour of desoxyfructo-5methoxy-tryptamine oxalate is clearly different. After a very short decrease of the blood pressure (1 min.), this compound produced a moderate increase of the blood pressure for 30 min., with a weak decrease (6 %) of the heart rate. The Carotid occlusion (C.O.) pressor response in this case was not blocked. The maximal deviations from normal values, observed on anaesthetized dogs with opened thorax, using the drug intravenously in low doses as 100 ug/kg and 200 ug/kg, respectively, are similar to those observed on vagotomized cats using the drugs intravenously in about 100 times higher doses. However, the duration of the effects with low doses is very short, about 3 min. A very significant increase of sinusal coronary flow and observed at the same time. partial oxygen pressure (PV02) was Results are shown on TABLE II. The "anti-stress" activity of the compounds was investigated looking at swimming endurance, Rota-Rod test performance, anti-ulcer effect and milk induced leucocytosis. In all these tests desoxyfructoserotonin shows a highly significant activity with 30 % increase in swimming endurance, 150 % increase in RotaRod test, 80 % anti-ulcer effect and with total elimination of milk induced leucocytosis. Desoxyfructo-5-methoxy-tryptamine showed no effect (TABLE III). One oral dose (50 mg/kg) of desoxyfructo-serotonine oxalate reduced to 40 % in rats the gastric ulcerization by restraint.
+
114
3.
Each
one
1. DF-5-NT
+ 20 - 50
180
2.
:
1 5 30 2 10
2 10 60
180
1 30
150
Acu230 redup t0 120
Not
2 30 105
TABLE
I.
-10
+50 - 20
+ 30 - 20
-__-_-
1
2 45
3:
1
5 60
5 60 to
120 5
redup
to
30 Not occu-
120
rdup
25 Not occu-
Onset Peak Duration (min) (mid bin)
_-_
HEART RATE (Beats/min) ___--
30
14
22
- 16
Blocked
ked
Bloc-
CO
----
1
2
1
1
5
1
15
90
105
onsetPeakl%ration (mid (mirl bin)
RESPONSE (in mm)
OF SEROTONIN
BasZZZZkge
OF SOME NEW SUGAR DERIVATIVES AND OF 5-METHOXYTRYPTAMINE
Duration IZFFECT (min) BasalChange
EFFECTS
Oxalate; 2. DF-5-TH Base; 3. DF-5-methoxytryptamine oxalate was given in 100 mg doses in 5 ml normal saline (i.v.)
-40 imci.imTKL + 18 1 5
+4 - 32 + 16
Onset Peak
-_--_-_-'--_-T--------
BLOOD PRESSURE (in mm Hg)
82
z 3 g
1.
*
CARDIOVASCULAR
SUGAR DERIVATIVES
250
Variation
%
+
Vo1.15,No.1/2
OF INDOLAMINES
? D? F-5HT:200 ? D?F-5HT:
100
pg/kg 100
0
P < 0,05
A
p <
a02
=
p <
041
0
p < 0,001
jtg /kg
+ 50
0 __
Sinusal coronary flow
;it
P” 0,
:
:: .. . :..:
Sinusal
1:.
r
p
-5c I, TABLE EFFECTS
II.
OF DESOXYFRUCTO-SEROTONIN
FLOW AND PvOz,
ON SINUSAL
ON HEART RATE AND BLOOD
CORONARY
PRESSURE
Vo1.15,No.l/2
SUGAR DERIVATIVES
OF INDOLAMINES
251
252
SUGAR DERIVATIVES OF INDOLAMINES
Vo1.15,No.l/2
CONCLUSION The observed moderate decrease of blood pressure and heart rate, together with the total blocking of the C.O. pressor respon__ se and the simultaneous increase of sinusal coronary flow and partial oxygen pressure (PvO~), should favourably complete the earlier reported effects of desoxyfructo-serotonin on platelets (17-20). The observed "anti-stress" activity may also contribute to eliminate or to diminish some of the factors, which seem to be involved directly or indirectly in thrombotic accidents. ACKNOWLEDGEMENT This research was realized within the framework of the Indo-French Scientific and Technical Cooperation Program. The authors are grateful to the Fondation pour la Recherche Medicale Frangaise for a grant. REFERENCES 1.
COPLEY, A.L., Platelet and Physiological Defense Mechanisms in "Platelets : a Multidisciplinary Approach", Ed. G. de Gaetano and S. Garattini, Raven Press, New York, 1978.
2.
COPLEY, A.L. and WITTE, S., Physiological Microthromboembolization as the Primary Platelet Function : Elimination of Invaded Particles from the Circulation and its Pathogenic Significance. Thromb.Res., 8, 251, 1976.
3.
MAILLARD, L.C.,Action des acides amines sur les sucres. Formation des melanoidines par voie m6thodologique. C.R. Acad. sci., 260, 3208, 1912.
4.
MESTER, L., KRASKA, B., CRIBA, J. and MESTER, M., Sugar-Amine Interactions in the Blood Clotting System and their Effects on Haemostasis. Proc. 5th Congr. Intern. Thrombosis and Haemostasis, Paris, p.233, 1975.
5.
FLUCKIGER, R. and WINTERHALTER, X.H., In vitro Synthesis of Hemoglobin Al,=. FEBS Letters, 71, 356, 1976.
6.
KOENIG, R.J., BLOBSTEIN, S.H. and CERAMI, A., Structure of Carbohydrate of Hemoglobin Ale. J. Biol. Chem., 252, 2992, 1977.
7.
HAUST, M.D., Platelets, Thrombosis and Atherosclerosis. - in "Platelets, Drugs and Thrombosis" Ed.J. Hirsh, J.F. Cade, A.S. Gallus and E. SchBnbaum. S. KRAGER, Basel, p. 94, 1975.
8.
MESTER, L., and MESTER, M., 1-Desoxy-1-(5-hydroxy-tryptamino)D-fructose : A new reducing sugar derivative of serotonin. J. Carbohydr.Nucleos. Nucleot., 2, 141, 1975.
Vo1.15,No.1/2
9.
SUGAR DERIVATIVES
OF INDOLAMINES
253
L., and MESTER, M. "FructosBrotonine : Nouveaux derives de la sdrotonine". ANVAR, French patent No 75 22577, 1975.
MESTER,
10.
GARATTINI, s., and VALZELLI, L. Serotonin and cardiovascular system, Chapter 9 in "Serotonin", Elsevier Publ.Co.Amsterdam 1965.
11.
COHEN, Y. and BLANCHARD, P. Influence de la chelation du calcium sur les effets tensionnels de la sdrotonine chez le chien. J. Physiol., 52, 569, 1960.
12.
BRAUNWALD, E. Control of myocardial oxygen consumption : Physiologic and clinical considerations. Am. J. Cardiol., -27 (41, 416, 1971.
13.
BONFILS, S., LIEFOOGHE, G., ROSSI, G. and LAMBLING, A. L'ulcbre de contrainte du Rat blanc. Modifications de la frequence lesionnelle par differents procedds op&atoires et pharmacodynamiques. C.R. Sot. Biol., 151, 1149, 1957.
14.
BONFILS, S., ROSSI, G., LIEFOOGHE, G. and LAMBLING, A., Ulcere experimental de contrainte, I. : Methodes, frequence des lesions, modifications par certains procedes techniques et pharmacologiques. Rev. frang. Etudes clin. biol., 4, 146, 1959.
15.
BREKHMAN, 1.1. and DARDYMOV, I.V. Substances of plant origin which increase non specific resistance. Annu. Rev. Pharmacol. 2, 419, 1969.
16.
KINNARD, Wm. J. jr. and CARR, C.J. A preliminary procedure for evaluation of central-nervous-system depressants. J. Pharmacol. Exptl. Therap., 121, 354, 1957.
17.
MESTER, L., MESTER, M., RENDU, F., LABRID, C. and DURENG, G. Sugar Derivatives of Indolamines, Part I. : Aggregation induced by Desoxyfructo-serotonin and its Active Transport Through the Platelet Membrane. Thromb. Res. 12, 783, 1978.
18.
BHARGAVA, K.P., GUJRATI, V.R., BASHEE ALI, MESTER, M., and MFSTER, L. Sugar Derivatives of Indolamines, Part II. : Difference in the Oxidation of Serotonin and its Desoxyfructose Derivative by Rat Brain Monoamine Oxidase. Thromb.Res. -12 791, 1978.
19.
LAUNAY, J.-M., and MESTER, L. Sugar Derivatives of Indolamines Part III. : Effect of Desoxyfructo-serotonin on the Uptake and Release of Serotonin by Human Platelets. Thromb. Res. in press.
20.
MESTER, L., LAUNAY, J.-M., and MESTER, M. Sugar Derivatives of Indolamines, Part IV. : Dissociation between the Affinity of Desoxyribulo-serotonin towards D and M Type Tryptaminergic Receptors and Study of its Effect on-Platelet Functions. Thromb.Res., in press.
RESEARCH 15;245-253 Printed in Great Britain Press Ltd.1979. oo49-3848/79/0601-045
#02.00/o
SUGARDERIVATIVES OF INDOLAMINES, PARTV : CARDIOVASCULAH EFFECTSAND "ANTI-STRESS" ACTIVITYOF DESOXYFRUCTOSE DERIVATIVE OF SEROTONINAND 5-METHOXY-TRYPTAMINE
L. Mester*,
M. Mester,
K.P. Bhargava, and M. Cheucle
C. Labrid,
G. Dureng
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, 91190, France; King George's Medical College, Department of Pharmacology, Lucknow, India and Centre Europ6en de RecherchesMauvernay, Riom-63201, France (Received 9.1.1979; in revised form 27.2.1979. Accepted by Editor W. H. Seegers) ABSTRACT Desoxyfructo-serotonin oxalate and free base produced a decrease of the blood pressure and heart rate of vagotomized cats (in total doses of 100 mg, i.v.) for 30 and 120 min. respectively, with total blocking of the carotid occlusion pressor response. With desoxyfructo-5-methoxytryptamine the decrease in the blood pressure lasts only 1 minute, followed by a 30 min. moderate increase. With this compound the C.O. pressor response is not blocked. On anaesthetized dogs with opened thorax low doses of the drug (100-200 ug/kg i.v.) produced a similar decrease of the blood pressure and heart rate, however, only for a short time (3 min.). An important increase in the sinusal coronary flow and partial oxygen pressure was also observed. Oral administration of desoxyfructo-serotonin oxalate (50 mg/kg) reduced to 40% the gastric ulcer formation by restraint in rats. With the same compound (100 mg/kg i.p. daily per 4 days) a very significant "anti-stress" activity was observed on mice by increased swimming endurance, Rota-Rod test performance, anti-ulcer effect and by elimination of milk induced leucocytosis.
To whom enquiries
should be addressed. 245
246
SUGAR DERIVATIVES OF INDOLAMINES
Vo1.15,No.1/2
INTRODUCTION Haemostasis and thrombosis are doubtless phenomena located in the crossing of very different knowlege including medicine, biochemistry, polymerization and physical chemistry of layers. A multidisciplinary approach (1) has been proposed to explain the mechanism of these phenomena and also the multiple role of platelets in basic physiological processes (2). A typical example for the multidisciplinary approach was given in 1975, by the annoncement that the first step of the Maillard reaction (3) (the so called Amadori reaction), worldwide investigated in food chemistry since the beginning of this century, can occur in haemostasis (4). Afterwards, but no more thana year later, two independent teams (5,6) reported the discovery of such Amadori type sugar derivatives of haemoglobin in normal and diabetic individuals. Since then the eventuality of the formation of desoxy-sugar derivatives from serotonin in physiological conditions, and the possible role of endogenous or exogenous desoxyfructo-serotonin in haemostasis have met with some interest. A multidisciplinary approach means also studies in a wide.rareaconcerning platelets. Platelet aggregation is still considered as the major factor in thrombotic accidents , however, platelets appear to have some relation to many factors implicated in thrombosis, like hemodynamic factors, vascular permeability and stress (7). On the basis of the above statements it appears desirable to explore also cardiovascular and "anti-stress" effects of drugs with potential anti-thrombic activity. For.this reason, three indolamine sugar derivatives : desoxyfructo-serotonin oxalate (DF-5HT ox.), desoxyfructo-serotonin free base (DF-5HT base) and desoxyfructo-5-methoxytryptamine (DF-5-MT ox.) were investigated to establish their effects in these fields, if any. MATERIAL AND METHODS The following compounds were prepared as earlier reported (8,9) and were tested : 1. Desoxyfructo-serotonin oxalate (DF-5HT ox) m-w. 428. 2. Desoxyfructo-serotonin base (DF-5HT base) m-w. 338. 3. Desoxyfructo-5-methoxy-tryptamine oxalate (DF-5MT ox) m.w. 442. The compounds were dissolved in normal saline. I. CARDIOVASCULAR EFFECTS : using _--_____ the drug _________-__ intravenousA. On bilaterally ___ vaqotomized cats,_____ _________--____-____-_--ly in total doses of 100 mg_per animal _ _______-____________------------* The cardiovascular effects of compounds No. 1,2, and 3 were studied in bilaterally vagotomized cats (10 Cats in each group) anesthetized with pentobarbitone. The drugs were administered in total doses of 100 mg, in 5 ml normal Saline (i.v.),
Vo1.15,No.1/2
SUGAR DERIVATIVES
OF INDOLAMINES
247
Their effect was studied on resting blood pressure, on pressor responses evoked by either carotid occlusion for lo-30 sec. or by l-2 ug/kg of noradrenaline given intravenously. The cardiovascular effects are summarized in TABLE I. using --_-__-_ the drug B. On anaesthetized dogs-_______ with opened thorax ___________________ ___________L_____ intravenously _____---_________ in doses of 100 ~gLhg_asd_200_~gLkgL_EegEectl____________ in 1 ml normal saline (in 1 min 1 vely,________________________________, --_ Lots of 5 anaesthetized dogs of the same race and weighat least 19 kg wereused in these experiments, after tracheoing tomy. The sinusal coronary flow (ml/mn) and the sinusal coronary P$I~ (partial pressure of oxygen in mm Hg) were measured (10). Femoral arterial pressure (11) and cardiac frequency (12) were registered. The results are summarized in TABLE II. II. ANTI-STRESS
STUDIES
:
A. On rats using ________ the drug ______ orally ~--~~~-~~~----_-~ in doses of 50 mg& __,__-_L____The method of Bonfils et al. (13) was used to produce ulrestraint due to immobilization, on Wistar male rats cers by weighing 180+ 20 gr. Before immobilization the "treated" group of animals received by oral probe 50 mg/kg of the drug. After 18 hours the number of animals showing gastric ulcers, was established. B. On mice using ______-_ the drugs_______ intraperitonially in doses of 100 ____________ __-_______ -____-___-__--_&kg in 0.25 ml npzmpl -------_-__--__-_saline (in 1 min.1 ________---for four days-------______1. Effect on swimming endurance test - The mice were divided in 3 groups of ten animals each, one group served as control and each animal of this group received normal saline (0.25 ml) intraperitoneally and other 2 groups were pretreated with test compounds in doses of 100 mg/kg (i.p.) for four days. The animals of each group were forced to swim till exhaution (swimming time) in separate porcelain tanks filled with water (3O'C). 2. Anti-ulcerogenic effect - Effect of the compounds was seen on restraintulcers. Restraint ulcers were produced in groups of ten animals each by immobilisation for 18 hours (14). One group served as control and other groups received the compounds in doses of 100 mg/kg (i.p.) one hour before the start of the experiment. 3. Milk induced leucocytosis - Albino mice weighing between 20-25 gm were divided into groups of 10 animals each. Leucocyte count was done an the blood samples collected from the tail vein of each mouse . The effect of test compounds was seen after 100 mg/kg dose given i.p. once daily for four days) on milk induced leucocytosis (15). 4. Rota-rod performance in mice was followed Kinnard and Carr (16). 5. Pentobarbitone
narcosis
was done
in mice.
by the method
of'
248
SUGAR DERIVATIVES OF INDOLAMINES
v01.15,N0.1/2
RESULTS AND DISCUSSIOW The cardiovascular effects of the compounds were studied on blood pressure, on heart rate and on pressor response evoked by carotid occlusion (C.O.). As shown on TABLE I., both serotonin sugar derivatives produced on vagotomized cats first a slow increase (5 to 10 %) of the basal blood pressure for 2 to 5 min., followed by an important decrease (30 to 40 %). The duration of this effect was 30 minutes with the oxalic salt, followed by a moderate increase (2~ %), while in the case of the free base, the decrease was constant up to 120 min. The heart rate decreased with both compounds by about 2O %.Recovery to normal did not occur for 120 min. Both, desoxyfructo-serotonin oxalate and free base, blocked completely the pressor effect evoked by carotid occlusion or by norepinephrine, showing that the effect of the serotonin sugar derivatives is a central one. While the two sugar derivatives of serotonin show nearly the same cardiovascular effects, the behaviour of desoxyfructo-5methoxy-tryptamine oxalate is clearly different. After a very short decrease of the blood pressure (1 min.), this compound produced a moderate increase of the blood pressure for 30 min., with a weak decrease (6 %) of the heart rate. The Carotid occlusion (C.O.) pressor response in this case was not blocked. The maximal deviations from normal values, observed on anaesthetized dogs with opened thorax, using the drug intravenously in low doses as 100 ug/kg and 200 ug/kg, respectively, are similar to those observed on vagotomized cats using the drugs intravenously in about 100 times higher doses. However, the duration of the effects with low doses is very short, about 3 min. A very significant increase of sinusal coronary flow and observed at the same time. partial oxygen pressure (PV02) was Results are shown on TABLE II. The "anti-stress" activity of the compounds was investigated looking at swimming endurance, Rota-Rod test performance, anti-ulcer effect and milk induced leucocytosis. In all these tests desoxyfructoserotonin shows a highly significant activity with 30 % increase in swimming endurance, 150 % increase in RotaRod test, 80 % anti-ulcer effect and with total elimination of milk induced leucocytosis. Desoxyfructo-5-methoxy-tryptamine showed no effect (TABLE III). One oral dose (50 mg/kg) of desoxyfructo-serotonine oxalate reduced to 40 % in rats the gastric ulcerization by restraint.
+
114
3.
Each
one
1. DF-5-NT
+ 20 - 50
180
2.
:
1 5 30 2 10
2 10 60
180
1 30
150
Acu230 redup t0 120
Not
2 30 105
TABLE
I.
-10
+50 - 20
+ 30 - 20
-__-_-
1
2 45
3:
1
5 60
5 60 to
120 5
redup
to
30 Not occu-
120
rdup
25 Not occu-
Onset Peak Duration (min) (mid bin)
_-_
HEART RATE (Beats/min) ___--
30
14
22
- 16
Blocked
ked
Bloc-
CO
----
1
2
1
1
5
1
15
90
105
onsetPeakl%ration (mid (mirl bin)
RESPONSE (in mm)
OF SEROTONIN
BasZZZZkge
OF SOME NEW SUGAR DERIVATIVES AND OF 5-METHOXYTRYPTAMINE
Duration IZFFECT (min) BasalChange
EFFECTS
Oxalate; 2. DF-5-TH Base; 3. DF-5-methoxytryptamine oxalate was given in 100 mg doses in 5 ml normal saline (i.v.)
-40 imci.imTKL + 18 1 5
+4 - 32 + 16
Onset Peak
-_--_-_-'--_-T--------
BLOOD PRESSURE (in mm Hg)
82
z 3 g
1.
*
CARDIOVASCULAR
SUGAR DERIVATIVES
250
Variation
%
+
Vo1.15,No.1/2
OF INDOLAMINES
? D? F-5HT:200 ? D?F-5HT:
100
pg/kg 100
0
P < 0,05
A
p <
a02
=
p <
041
0
p < 0,001
jtg /kg
+ 50
0 __
Sinusal coronary flow
;it
P” 0,
:
:: .. . :..:
Sinusal
1:.
r
p
-5c I, TABLE EFFECTS
II.
OF DESOXYFRUCTO-SEROTONIN
FLOW AND PvOz,
ON SINUSAL
ON HEART RATE AND BLOOD
CORONARY
PRESSURE
Vo1.15,No.l/2
SUGAR DERIVATIVES
OF INDOLAMINES
251
252
SUGAR DERIVATIVES OF INDOLAMINES
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CONCLUSION The observed moderate decrease of blood pressure and heart rate, together with the total blocking of the C.O. pressor respon__ se and the simultaneous increase of sinusal coronary flow and partial oxygen pressure (PvO~), should favourably complete the earlier reported effects of desoxyfructo-serotonin on platelets (17-20). The observed "anti-stress" activity may also contribute to eliminate or to diminish some of the factors, which seem to be involved directly or indirectly in thrombotic accidents. ACKNOWLEDGEMENT This research was realized within the framework of the Indo-French Scientific and Technical Cooperation Program. The authors are grateful to the Fondation pour la Recherche Medicale Frangaise for a grant. REFERENCES 1.
COPLEY, A.L., Platelet and Physiological Defense Mechanisms in "Platelets : a Multidisciplinary Approach", Ed. G. de Gaetano and S. Garattini, Raven Press, New York, 1978.
2.
COPLEY, A.L. and WITTE, S., Physiological Microthromboembolization as the Primary Platelet Function : Elimination of Invaded Particles from the Circulation and its Pathogenic Significance. Thromb.Res., 8, 251, 1976.
3.
MAILLARD, L.C.,Action des acides amines sur les sucres. Formation des melanoidines par voie m6thodologique. C.R. Acad. sci., 260, 3208, 1912.
4.
MESTER, L., KRASKA, B., CRIBA, J. and MESTER, M., Sugar-Amine Interactions in the Blood Clotting System and their Effects on Haemostasis. Proc. 5th Congr. Intern. Thrombosis and Haemostasis, Paris, p.233, 1975.
5.
FLUCKIGER, R. and WINTERHALTER, X.H., In vitro Synthesis of Hemoglobin Al,=. FEBS Letters, 71, 356, 1976.
6.
KOENIG, R.J., BLOBSTEIN, S.H. and CERAMI, A., Structure of Carbohydrate of Hemoglobin Ale. J. Biol. Chem., 252, 2992, 1977.
7.
HAUST, M.D., Platelets, Thrombosis and Atherosclerosis. - in "Platelets, Drugs and Thrombosis" Ed.J. Hirsh, J.F. Cade, A.S. Gallus and E. SchBnbaum. S. KRAGER, Basel, p. 94, 1975.
8.
MESTER, L., and MESTER, M., 1-Desoxy-1-(5-hydroxy-tryptamino)D-fructose : A new reducing sugar derivative of serotonin. J. Carbohydr.Nucleos. Nucleot., 2, 141, 1975.
Vo1.15,No.1/2
9.
SUGAR DERIVATIVES
OF INDOLAMINES
253
L., and MESTER, M. "FructosBrotonine : Nouveaux derives de la sdrotonine". ANVAR, French patent No 75 22577, 1975.
MESTER,
10.
GARATTINI, s., and VALZELLI, L. Serotonin and cardiovascular system, Chapter 9 in "Serotonin", Elsevier Publ.Co.Amsterdam 1965.
11.
COHEN, Y. and BLANCHARD, P. Influence de la chelation du calcium sur les effets tensionnels de la sdrotonine chez le chien. J. Physiol., 52, 569, 1960.
12.
BRAUNWALD, E. Control of myocardial oxygen consumption : Physiologic and clinical considerations. Am. J. Cardiol., -27 (41, 416, 1971.
13.
BONFILS, S., LIEFOOGHE, G., ROSSI, G. and LAMBLING, A. L'ulcbre de contrainte du Rat blanc. Modifications de la frequence lesionnelle par differents procedds op&atoires et pharmacodynamiques. C.R. Sot. Biol., 151, 1149, 1957.
14.
BONFILS, S., ROSSI, G., LIEFOOGHE, G. and LAMBLING, A., Ulcere experimental de contrainte, I. : Methodes, frequence des lesions, modifications par certains procedes techniques et pharmacologiques. Rev. frang. Etudes clin. biol., 4, 146, 1959.
15.
BREKHMAN, 1.1. and DARDYMOV, I.V. Substances of plant origin which increase non specific resistance. Annu. Rev. Pharmacol. 2, 419, 1969.
16.
KINNARD, Wm. J. jr. and CARR, C.J. A preliminary procedure for evaluation of central-nervous-system depressants. J. Pharmacol. Exptl. Therap., 121, 354, 1957.
17.
MESTER, L., MESTER, M., RENDU, F., LABRID, C. and DURENG, G. Sugar Derivatives of Indolamines, Part I. : Aggregation induced by Desoxyfructo-serotonin and its Active Transport Through the Platelet Membrane. Thromb. Res. 12, 783, 1978.
18.
BHARGAVA, K.P., GUJRATI, V.R., BASHEE ALI, MESTER, M., and MFSTER, L. Sugar Derivatives of Indolamines, Part II. : Difference in the Oxidation of Serotonin and its Desoxyfructose Derivative by Rat Brain Monoamine Oxidase. Thromb.Res. -12 791, 1978.
19.
LAUNAY, J.-M., and MESTER, L. Sugar Derivatives of Indolamines Part III. : Effect of Desoxyfructo-serotonin on the Uptake and Release of Serotonin by Human Platelets. Thromb. Res. in press.
20.
MESTER, L., LAUNAY, J.-M., and MESTER, M. Sugar Derivatives of Indolamines, Part IV. : Dissociation between the Affinity of Desoxyribulo-serotonin towards D and M Type Tryptaminergic Receptors and Study of its Effect on-Platelet Functions. Thromb.Res., in press.