- Email: [email protected]
The effect of desmethylimipramine on reserpine and insulin-induced release of gastric histamine and adrenal catecholamines
Life Sciences Vol. 3, pp. 381-388, 1984. Pergamon Press, Inc. Printed in the United States .
THE EFFECT OF DESNiETIiYLII4IPRAMINE ON RESERPINE AND INS[TLIN-INDIICED RELEASE OF GASTRIC HISTAMINE AND ADRIIZAh CATECHCLAMINFS~ Parkhorst A . Shore and Dorothy Buafield2 Department of Pharmacology IIniveraity of Texas Southwestern Medical School, Dansa, Texas
(Received 12 March 1984) The administration of insulin or reserpi.ne is known to cause gastric acid secretion and lesions in the gastric mucosa (1-4) . It has been demonstrated recently that these same agents induce a lowering of gastric histamine levels in the rat (5) .
The action
of either reaerpine or insulin in promoting gastric acid secretion or in lowering gastric histamine levels can be abolished or largely blocked by vagotomy or by pretreatment with a gsnglionic blocking agent, thus demonstrating that the histamine-lowering effect of both agents is associated with vagal activity (5) . Reserpine and insulin are also known to effect a lowering of the adrenal catecholamine content in various species (6-9) .
The
mechanism is associated with sympathetic activity, as the catecholamine lowering induced by either of these agents can be in}, i bited by ganglionic blockade or surgical interruption of the
sympathetic pathway to the adrenal gland (7,$) . The antidepressant drug, imipramiae, has been shown to possess "anti-reaerpine" properties including antagonism of reserpine-induced CNS depression sad inhibition of peripheral manifestations of reserpine actions such as salivation sad Supported by PHS Research Grant MH-05$31 . 2 Guest Worker from Gleao Laboratories, Middlesex, England .
381
982
EFFECT OF DMI ON AMIIdE RELEASE blepheroapasm (10,11) .
Vol . 9, No. 4
Imipramine has also been shown to inhibit
reserpine-induced gastric lesions and adrenal catecholamine lowering (11,12) . Studies of the metabolic fate of imiprami.n e have revealed that these anti-reaerpine actions of imipramine reside in its metabolic product, de~ethylimipramine ( 10-1 2 ), which has been reported to exert an antidepressant effect in man more rapidly than the parent drug (13) . In the present paper, the action of desmethylimipramine (IMI) on reserpine and insulin induced gastric histamine and adrenal catecholamine lowering has been studied in the rat .
It will be
demonstrated that IIü is capable of inhibiting each of these effects . Methods Fasted fe~ma7.e Holtzman rata (]1t0-180 g) were treated with insulin (5 II/100 g) or reserpine (5 mg/kg) as described in a previous publication (5) .
For assessment of drug-induced effects
on gastric histamine content, rats were killed 5 hours after insulin or reaerpine .
For assessment of effects on catecholemine
content of the adrenals, rats were killed 5 hours after insulin or 16 hours after reaerpiae administration .
Histamine content of
whole washed stomach, and catecholamine content (epinephrine and norepinephrine) of whole left adrenal gland were measured fluorometrically ea described elsewhere (].L,.,15) .
IMI (20 mg/kg) was
administered intraperitoaeally 30 min before insulin or reaerpine . RQaulta Administration of reaerpine or insulin markedlry reduced the gastric histamine content (Fig . 1) and the adrenal catecholamine content (Fig . 2) .
Pretreatment of the animals with IIrII blocked
or greatly inhibited the action of insulin and reserpine oa both
EFFECT OF DMI ON AMII~TE RELEASE
Vol . 3, No. 4
gastric histamine and adrenal catecholamine content (Figs . 1 and
so
s
0
fenfref
OMI
~wpirr
OMI + ~r
Irnufin
DMI + Irwutin
FIG . 1 Effect of desmethylimipramine on reserpine and insulin-induced Experimental details are gastric histamine lowering in the rat . described tinder METHOAS . Vertical columns denote mean histamine concentration t standard error . Figures within coltmlna denote ntmtber of experiments . Effect of DMI on reaerpine or insulin responses is highly significant (P z 0 .001) .
fo
5
O
FIG . 2 Effect of desmethylimipramine on reaerpine end insulin-induced Experimental details adrenal catecholamine lowering in the rat . are described under METHODS . Vertical columns denote mean catecholemine content t standard error per left e.drenal gland . Figures within cohlmna denote number of ezperimenta . Effect of DMI oa reaerpine or insulin responses is highly significant (P ~ 0 .001) .
383
364
EFFECT OF DMI ON AMII~TE RELEASE
Vol . 3, No. 4
l?~acuasion The action of insulin and reaerpine in lowering gastric histamine content and adrenal catecholamine content confirms the earlier work cited above .
The action of II~II in inhibiting
reaerpine-induced catecholamine lowering in the adrenals is also in accord with previous reports .
The present work shows that II~II
is capable of inhibiting yet another action of reaerpine, release of gastric histamine .
Of more significance, however, is the
ability of IMI to antagonize the catecholamine and histamine lowering induced~by insulin .
This finding demonstrates that II~II
is not specifically an anti-reserpine agent insofar as peripheral amine lowering i§ concerned . The actions of imipremine and its active metabolic product, LMI, are complez .
Thus, in low doses, imipremine has been
reported to potentiàte, while higher doses inhibit, the autonomic responses following administration of a ganglionic stimulant (16) . The drug has a similar biphasic action on the carotid occlusion reflex and decreases the response of the cat's nictitating membrane to pre- or poatganglionic electrical stimulation of the cervical sympathetic nerve .
Oaborae end Sigg (16) conclude that
the action of imipramine in "potentiating or decreasing peripheral adrenergic sad cholinergic responses is dus to changes in transmission of impulses along nerve fibers and/or at synapses ." The action of IMI in decreasing the effects of both reaerpine and insulin on gastric histamine and adrenal catecholeminea is perhaps most simply ezplained by this mechanism as similar inhibition of reserpine or insulin effects on tissue amines can be elicited by geaglionic blocking agents or nerve transaction . possibility remains, however, that at least a portion of these
The
effects of IIü might reside in a central action of the drug in
Vol. 3, No. 4
EFFECT OF DMI ON AMIIdE RELEASE
385
decreasing reserpine or insulin -induced central sutonomic outflow . Referencea 1.
W . E . BARRETT, A . J . PLUr4fER, A . E . E9RL and B . ROGIE, J . Phermacol . exn . Ther .
2.
~, 3 (1955) .
B . J . HAVERBACK and D . F . BOGDANSRI, Proc . Soc . e~ml Biol .,
N Y. 9~, 392 (1957) . 3.
73
I . LEVSEN, E . LACROIg and G . DENIE~ESPER, E~merientia ~,
(1959) . 4. .
H . HANKE, Z . ees . e~ . Med .
5.
K . S . KIM and P . A . SHORE, J . Pharmacol . e~m . Ther , ll~,
43, 447 (1934) " 321
(1963) . 6.
A . CARLSSON, E . ROSENGREN, A . BERTLER and J . NILSSON, in S . GARLTTINI and V . GHETTI, Ps~chotropic Ih~uFa
p.
363 .
(1957) .
Elsevier, Amsterdam
7.
M . HOLZBAIIER and M . VOGT, J . Neurochem . 1,
8.
B . B . BRODIE, J . S . OLIN, R . G . KUNTZt~fAPT and P . A . SNORE, i nce ~,
9.
8 (1956) .
1293 (1957) .
A . CARLSSON and N . A . HILLARP, Acta Phssiol . Scaund .
~, 235
(1956) . ~, 454
10 .
B . B . BRODIE, M . H . BICKEL and F . SQLSIIt, Med . Esn .
11 .
S . GARITTINI, A . GIACHETTI, A . JORI, L . PIERI and L . VALZEf1LI, J . Pherm . Pharmacol . 1~1,
509 (1962) .
12 .
G . ZBINDEN, Int . J . Neuronharmacol .
13.
N . S . KLINE, G . SLI+IPSON and B . B . BRODIE, Ist . J . Neuronharmacol . 1,
].L,..
55 (1962) .
P . A . SHORE, A . BDRKHALTER ead V . H . COHN, J . Pharmacol . eam . Ther .
15 .
~, 435 (1962) .
2~7, 182 (1959) .
P . A . SHORE end J . S . OLIN, J . Phermacol : e~ . Ther .
(1958) .
1.2~2, 295
388
EFFECT OF DMI ON AMIIdE RELEASE 16 .
Vol. S, No. 4
M . OSBORNE end E . B . SIGG, Arch . int . pharmacodm . ~, 273
THE EFFECT OF DESNiETIiYLII4IPRAMINE ON RESERPINE AND INS[TLIN-INDIICED RELEASE OF GASTRIC HISTAMINE AND ADRIIZAh CATECHCLAMINFS~ Parkhorst A . Shore and Dorothy Buafield2 Department of Pharmacology IIniveraity of Texas Southwestern Medical School, Dansa, Texas
(Received 12 March 1984) The administration of insulin or reserpi.ne is known to cause gastric acid secretion and lesions in the gastric mucosa (1-4) . It has been demonstrated recently that these same agents induce a lowering of gastric histamine levels in the rat (5) .
The action
of either reaerpine or insulin in promoting gastric acid secretion or in lowering gastric histamine levels can be abolished or largely blocked by vagotomy or by pretreatment with a gsnglionic blocking agent, thus demonstrating that the histamine-lowering effect of both agents is associated with vagal activity (5) . Reserpine and insulin are also known to effect a lowering of the adrenal catecholamine content in various species (6-9) .
The
mechanism is associated with sympathetic activity, as the catecholamine lowering induced by either of these agents can be in}, i bited by ganglionic blockade or surgical interruption of the
sympathetic pathway to the adrenal gland (7,$) . The antidepressant drug, imipramiae, has been shown to possess "anti-reaerpine" properties including antagonism of reserpine-induced CNS depression sad inhibition of peripheral manifestations of reserpine actions such as salivation sad Supported by PHS Research Grant MH-05$31 . 2 Guest Worker from Gleao Laboratories, Middlesex, England .
381
982
EFFECT OF DMI ON AMIIdE RELEASE blepheroapasm (10,11) .
Vol . 9, No. 4
Imipramine has also been shown to inhibit
reserpine-induced gastric lesions and adrenal catecholamine lowering (11,12) . Studies of the metabolic fate of imiprami.n e have revealed that these anti-reaerpine actions of imipramine reside in its metabolic product, de~ethylimipramine ( 10-1 2 ), which has been reported to exert an antidepressant effect in man more rapidly than the parent drug (13) . In the present paper, the action of desmethylimipramine (IMI) on reserpine and insulin induced gastric histamine and adrenal catecholamine lowering has been studied in the rat .
It will be
demonstrated that IIü is capable of inhibiting each of these effects . Methods Fasted fe~ma7.e Holtzman rata (]1t0-180 g) were treated with insulin (5 II/100 g) or reserpine (5 mg/kg) as described in a previous publication (5) .
For assessment of drug-induced effects
on gastric histamine content, rats were killed 5 hours after insulin or reaerpine .
For assessment of effects on catecholemine
content of the adrenals, rats were killed 5 hours after insulin or 16 hours after reaerpiae administration .
Histamine content of
whole washed stomach, and catecholamine content (epinephrine and norepinephrine) of whole left adrenal gland were measured fluorometrically ea described elsewhere (].L,.,15) .
IMI (20 mg/kg) was
administered intraperitoaeally 30 min before insulin or reaerpine . RQaulta Administration of reaerpine or insulin markedlry reduced the gastric histamine content (Fig . 1) and the adrenal catecholamine content (Fig . 2) .
Pretreatment of the animals with IIrII blocked
or greatly inhibited the action of insulin and reserpine oa both
EFFECT OF DMI ON AMII~TE RELEASE
Vol . 3, No. 4
gastric histamine and adrenal catecholamine content (Figs . 1 and
so
s
0
fenfref
OMI
~wpirr
OMI + ~r
Irnufin
DMI + Irwutin
FIG . 1 Effect of desmethylimipramine on reserpine and insulin-induced Experimental details are gastric histamine lowering in the rat . described tinder METHOAS . Vertical columns denote mean histamine concentration t standard error . Figures within coltmlna denote ntmtber of experiments . Effect of DMI on reaerpine or insulin responses is highly significant (P z 0 .001) .
fo
5
O
FIG . 2 Effect of desmethylimipramine on reaerpine end insulin-induced Experimental details adrenal catecholamine lowering in the rat . are described under METHODS . Vertical columns denote mean catecholemine content t standard error per left e.drenal gland . Figures within cohlmna denote number of ezperimenta . Effect of DMI oa reaerpine or insulin responses is highly significant (P ~ 0 .001) .
383
364
EFFECT OF DMI ON AMII~TE RELEASE
Vol . 3, No. 4
l?~acuasion The action of insulin and reaerpine in lowering gastric histamine content and adrenal catecholamine content confirms the earlier work cited above .
The action of II~II in inhibiting
reaerpine-induced catecholamine lowering in the adrenals is also in accord with previous reports .
The present work shows that II~II
is capable of inhibiting yet another action of reaerpine, release of gastric histamine .
Of more significance, however, is the
ability of IMI to antagonize the catecholamine and histamine lowering induced~by insulin .
This finding demonstrates that II~II
is not specifically an anti-reserpine agent insofar as peripheral amine lowering i§ concerned . The actions of imipremine and its active metabolic product, LMI, are complez .
Thus, in low doses, imipremine has been
reported to potentiàte, while higher doses inhibit, the autonomic responses following administration of a ganglionic stimulant (16) . The drug has a similar biphasic action on the carotid occlusion reflex and decreases the response of the cat's nictitating membrane to pre- or poatganglionic electrical stimulation of the cervical sympathetic nerve .
Oaborae end Sigg (16) conclude that
the action of imipramine in "potentiating or decreasing peripheral adrenergic sad cholinergic responses is dus to changes in transmission of impulses along nerve fibers and/or at synapses ." The action of IMI in decreasing the effects of both reaerpine and insulin on gastric histamine and adrenal catecholeminea is perhaps most simply ezplained by this mechanism as similar inhibition of reserpine or insulin effects on tissue amines can be elicited by geaglionic blocking agents or nerve transaction . possibility remains, however, that at least a portion of these
The
effects of IIü might reside in a central action of the drug in
Vol. 3, No. 4
EFFECT OF DMI ON AMIIdE RELEASE
385
decreasing reserpine or insulin -induced central sutonomic outflow . Referencea 1.
W . E . BARRETT, A . J . PLUr4fER, A . E . E9RL and B . ROGIE, J . Phermacol . exn . Ther .
2.
~, 3 (1955) .
B . J . HAVERBACK and D . F . BOGDANSRI, Proc . Soc . e~ml Biol .,
N Y. 9~, 392 (1957) . 3.
73
I . LEVSEN, E . LACROIg and G . DENIE~ESPER, E~merientia ~,
(1959) . 4. .
H . HANKE, Z . ees . e~ . Med .
5.
K . S . KIM and P . A . SHORE, J . Pharmacol . e~m . Ther , ll~,
43, 447 (1934) " 321
(1963) . 6.
A . CARLSSON, E . ROSENGREN, A . BERTLER and J . NILSSON, in S . GARLTTINI and V . GHETTI, Ps~chotropic Ih~uFa
p.
363 .
(1957) .
Elsevier, Amsterdam
7.
M . HOLZBAIIER and M . VOGT, J . Neurochem . 1,
8.
B . B . BRODIE, J . S . OLIN, R . G . KUNTZt~fAPT and P . A . SNORE, i nce ~,
9.
8 (1956) .
1293 (1957) .
A . CARLSSON and N . A . HILLARP, Acta Phssiol . Scaund .
~, 235
(1956) . ~, 454
10 .
B . B . BRODIE, M . H . BICKEL and F . SQLSIIt, Med . Esn .
11 .
S . GARITTINI, A . GIACHETTI, A . JORI, L . PIERI and L . VALZEf1LI, J . Pherm . Pharmacol . 1~1,
509 (1962) .
12 .
G . ZBINDEN, Int . J . Neuronharmacol .
13.
N . S . KLINE, G . SLI+IPSON and B . B . BRODIE, Ist . J . Neuronharmacol . 1,
].L,..
55 (1962) .
P . A . SHORE, A . BDRKHALTER ead V . H . COHN, J . Pharmacol . eam . Ther .
15 .
~, 435 (1962) .
2~7, 182 (1959) .
P . A . SHORE end J . S . OLIN, J . Phermacol : e~ . Ther .
(1958) .
1.2~2, 295
388
EFFECT OF DMI ON AMIIdE RELEASE 16 .
Vol. S, No. 4
M . OSBORNE end E . B . SIGG, Arch . int . pharmacodm . ~, 273