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EFFECT OF 6-HYDROXYDOPAMINE ON CARDIOTOXICITY OF OUABAIN IN GUINEA PIGS
Japan.
J. Pharntacol.
24, 923 (1974)
SHORT
EFFECT
OF
6-HYDROXYDOPAMINE OF
Hideya
SAITO,
Toru
OUABAIN OTANI,
IN Isami
ON GUINEA SHUDO
COMMUNICATIONS
CARDIOTOXICITY PIGS
and Tsuneyoshi
TANABE
Dcparhncnt of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan Accepted September 12, 1974
Digitalized animals are highly susceptible to the arrhythmic effect of exogenous cate cholamines (1, 2). Large doses of these catecholamines produced an increase in the cate cholamine content in heart muscles and the catecholamine-saturated heart showed an increased responsivenessto the toxic effectof cardiac glycosidesin dogs and guinea pigs (3). Boyajy et al. also reported that ouabain toxicity was decreased in dogs which was pre treated with reserpine (4). However, nothing has been documented concerning the pos sible involvement of brain catecholamines in digitalis toxicity. The present experiments were designed to observe the role of central and peripheral catecholamines in the car diotoxicity of ouabain. Male and female guinea pigs weighing 400 to 600 g were pretreated with 6-hydro xydopamine in the following manner: One group of animals was administered 6-hydro xydopamine, 30 mg/kg i.p., twice a day and one week later 50 mg/kg i.p. twice a day (1st group). The other group of guinea pigs anesthetized with ether was subjected to injec tion of 6-hydroxydopamineinto the right lateral ventricle at a dose of 250 /tg/animal (2nd group). Experiments were then performed on catecholamine-reduced guinea pigs an esthetized with urethane. An external jugular vein was cannulated and continuous infu sion was performed at a rate of 3.2 Pg/min. ECG (lead 11)was recorded. The toxic dose of ouabain was expressed as the minimal dose which produced ventricular arrhythmias. The lethal dose (LD) of ouabain was considered that which produced cardiac art-est. The determination of catecholamine content in the brain cortex, brain stem, heart and adre nal glands was performed in another two groups of guinea pigs pretreated with 6-hydro xydopamine as aforementioned (5). As shown in Table 1, a marked increase in the toxic dose and lethal dose of ouabain was seen in the 1st group of guinea pigs. However, in the second group neither the toxic dose nor the lethal dose of ouabain revealed any change. It has already been shown that systemic administration of 6-hydroxydopamine in duced a selectivereduction of catecholamines in the peripheral tissues without any signifi cant alteration of the catecholamine content in the brain (6, 7, 8). Under these same ex perinmentalconditions, we also determined the catecholamine content of brain cortex,
SHORT TABLE 1. Changes
COMMUNICATIONS
in toxicity
xydopamine
of ouabain
Japan. J. Pharmacol. 24, 924 (1974)
induced
by
pretreatment
with
6-hydro
(6-OHDA)
TABLE2. Changes in the catecholamine content in the brain, heart and adrenal glands following administration of 6-hydroxydopamine (6-OHDA)(1)
brain
stem,
heart
pigs,
a marked
cant
reduction
and reduction
to the
2nd
served
in the
brain
heart
and
From appears not
the to
appear
glands.
group
of
cortex
and
glands
results
obtained
that
brain
was
guinea
adrenal
be closely
As shown
of norepinephrine
of catecholamines
regard
the
adrenal
associated
were
not
herein, with
catecholamines
was
observed
pigs,
brain
in Table seen
in the
heart.
in the
brain
and
a marked
stem,
2, in the
but
reduction significant
1st group
of guinea
However, adrenal
no
of norepinephrine changes
signifi
glands.
With was
in catecholamines
ob in
demonstrated. the reduction a decrease are
related
of catecholamine in ouabain to
the
content
toxicity.
toxicity
in the heart
However,
of ouabain.
it does
SHORT
COMMUNICATIONS
Japan. J. Pharmacol. 24, 925 (1974)
REFERENCES 1) TANABE,T., SAITO,H., OHARA, T., KANNO, M. AND IIDA, S.: Abstracts of the 3rd Interna tional Pharmacological Congress p. 501, S. Paulo, Brazil (1966); 2) SAITO, H., OTANI, T., SHUDO,I., MONMA,Y. AND TANABE,T.: Japan. J. Pharmacol. 23, Suppl. 7 (1973); 3) SAITO, H., OHARA, T., ISHIZAKI,T. AND TANABE,T.: Hokkaido Med. J. 46, 365 (1971) (in Japanese); 4) BOYAJY,L.D. AND NASH, C.B.: J. Pharmacol. exp. Ther. 148, 193 (1965); 5) SAITO, H., WORONKOW,S. AND MYERS, B.: Japan. Circ. J. 33, 620 (1969); 6) BRUS, R.: Archs int. Pharmacodyn. Ther. 201, 71 (1973); 7) HAEUSLER,G., GEROLD, M. AND THOENEN,H.: Arch. Pharmacol. 274, 211 (1972); 8) GAUTHIER,P., NADEAU,R. ANDCHAMPLAIN,J. DE.: Circulation Res. 31, 207 (1972)
J. Pharntacol.
24, 923 (1974)
SHORT
EFFECT
OF
6-HYDROXYDOPAMINE OF
Hideya
SAITO,
Toru
OUABAIN OTANI,
IN Isami
ON GUINEA SHUDO
COMMUNICATIONS
CARDIOTOXICITY PIGS
and Tsuneyoshi
TANABE
Dcparhncnt of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan Accepted September 12, 1974
Digitalized animals are highly susceptible to the arrhythmic effect of exogenous cate cholamines (1, 2). Large doses of these catecholamines produced an increase in the cate cholamine content in heart muscles and the catecholamine-saturated heart showed an increased responsivenessto the toxic effectof cardiac glycosidesin dogs and guinea pigs (3). Boyajy et al. also reported that ouabain toxicity was decreased in dogs which was pre treated with reserpine (4). However, nothing has been documented concerning the pos sible involvement of brain catecholamines in digitalis toxicity. The present experiments were designed to observe the role of central and peripheral catecholamines in the car diotoxicity of ouabain. Male and female guinea pigs weighing 400 to 600 g were pretreated with 6-hydro xydopamine in the following manner: One group of animals was administered 6-hydro xydopamine, 30 mg/kg i.p., twice a day and one week later 50 mg/kg i.p. twice a day (1st group). The other group of guinea pigs anesthetized with ether was subjected to injec tion of 6-hydroxydopamineinto the right lateral ventricle at a dose of 250 /tg/animal (2nd group). Experiments were then performed on catecholamine-reduced guinea pigs an esthetized with urethane. An external jugular vein was cannulated and continuous infu sion was performed at a rate of 3.2 Pg/min. ECG (lead 11)was recorded. The toxic dose of ouabain was expressed as the minimal dose which produced ventricular arrhythmias. The lethal dose (LD) of ouabain was considered that which produced cardiac art-est. The determination of catecholamine content in the brain cortex, brain stem, heart and adre nal glands was performed in another two groups of guinea pigs pretreated with 6-hydro xydopamine as aforementioned (5). As shown in Table 1, a marked increase in the toxic dose and lethal dose of ouabain was seen in the 1st group of guinea pigs. However, in the second group neither the toxic dose nor the lethal dose of ouabain revealed any change. It has already been shown that systemic administration of 6-hydroxydopamine in duced a selectivereduction of catecholamines in the peripheral tissues without any signifi cant alteration of the catecholamine content in the brain (6, 7, 8). Under these same ex perinmentalconditions, we also determined the catecholamine content of brain cortex,
SHORT TABLE 1. Changes
COMMUNICATIONS
in toxicity
xydopamine
of ouabain
Japan. J. Pharmacol. 24, 924 (1974)
induced
by
pretreatment
with
6-hydro
(6-OHDA)
TABLE2. Changes in the catecholamine content in the brain, heart and adrenal glands following administration of 6-hydroxydopamine (6-OHDA)(1)
brain
stem,
heart
pigs,
a marked
cant
reduction
and reduction
to the
2nd
served
in the
brain
heart
and
From appears not
the to
appear
glands.
group
of
cortex
and
glands
results
obtained
that
brain
was
guinea
adrenal
be closely
As shown
of norepinephrine
of catecholamines
regard
the
adrenal
associated
were
not
herein, with
catecholamines
was
observed
pigs,
brain
in Table seen
in the
heart.
in the
brain
and
a marked
stem,
2, in the
but
reduction significant
1st group
of guinea
However, adrenal
no
of norepinephrine changes
signifi
glands.
With was
in catecholamines
ob in
demonstrated. the reduction a decrease are
related
of catecholamine in ouabain to
the
content
toxicity.
toxicity
in the heart
However,
of ouabain.
it does
SHORT
COMMUNICATIONS
Japan. J. Pharmacol. 24, 925 (1974)
REFERENCES 1) TANABE,T., SAITO,H., OHARA, T., KANNO, M. AND IIDA, S.: Abstracts of the 3rd Interna tional Pharmacological Congress p. 501, S. Paulo, Brazil (1966); 2) SAITO, H., OTANI, T., SHUDO,I., MONMA,Y. AND TANABE,T.: Japan. J. Pharmacol. 23, Suppl. 7 (1973); 3) SAITO, H., OHARA, T., ISHIZAKI,T. AND TANABE,T.: Hokkaido Med. J. 46, 365 (1971) (in Japanese); 4) BOYAJY,L.D. AND NASH, C.B.: J. Pharmacol. exp. Ther. 148, 193 (1965); 5) SAITO, H., WORONKOW,S. AND MYERS, B.: Japan. Circ. J. 33, 620 (1969); 6) BRUS, R.: Archs int. Pharmacodyn. Ther. 201, 71 (1973); 7) HAEUSLER,G., GEROLD, M. AND THOENEN,H.: Arch. Pharmacol. 274, 211 (1972); 8) GAUTHIER,P., NADEAU,R. ANDCHAMPLAIN,J. DE.: Circulation Res. 31, 207 (1972)