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Interaction of prostaglandin E1 with oxytocin on mammary gland of the lactating rabbit
EUROPEAN JOURNAL OF PHARMACOLOGY 8 (1969) 377-379. NORTH-HOLLANDPUBLISHINGCOMP., AMSTERDAM
I N T E R A C T I O N OF P R O S T A G L A N D I N E 1 WITH OXYTOCIN ON MAMMARY GLAND OF THE LACTATING RABBIT R.K. T(JRKER and B.K. KIRAN Department of Pharmacology, University of Ankara, Faculty o f Medicine, Ankara, Turkey
Accepted 6 November 1969
Received 2 October 1969
R.K. T~IRKERand B.K. KIRAN,Interaction of prostaglandin E ~ with oxytocin on mammary gland of the lactating rabbit, European J. Phaxmacol. 8 (1969) 377-379. Prostaglandin El, when given by close arterial or intravenous injection did not produce any change in the milk-ejection pressure of the lactating rabbit but it decreased the milk-ejection activity of oxytocin. Adrenergic blockade did not influence this inhibition. It is concluded that the inhibitory action of prostaglandin E~ on oxytocin-inducedmilk-ejection activity of the lactating rabbit is a consequence of a direct action of the lipid on myoepithelial ceils. Milk-ejection activity
Oxytocin effect
1. INTRODUCTION Prostaglandin E ~ (PGE ~) usually contracts isolated smooth muscle (Bergstr~Sm, Carlson and Weeks, 1968), but it relaxes rat isolated duodenum (Khairallah, Page and Tiirker, 1967) and tracheal muscle (Horton and Main, 1965; Tiirker and Khairallah, 1969). On the other hand, PGEI enhances the contractile effects of angiotensin, serotonin and vasopressin on vascular smooth muscle, the relaxing effects of bradykinin and norepinephrine on the rat isolated duodenum (Khairallah, Page and TiJrker, 1967) and the contractile effects of vasopressin, oxytocin and histamine on guinea-pig uterus (Clegg, Hall and Pickles, 1966). The effect of PGE~ on mammary gland has not been reported previously. In the present investigation the action of PGE1 and its interaction with oxytocin on milk-ejection activity of the lactating rabbit were studied.
2. MATERIAL AND METHODS White lactating rabbits 2 to 4 wk postpartum and
Lactatingrabbit
ProstaglandinE ~effect
weighing 2.5 - 4 . 5 kg were used. The animals were anaesthetized by i.v. injection of sodium pentobarbital (35 mg/kg). The trachea was cannulated and in some experiments artificial respiration was applied. Intravenous injections were made into the marginal veins of the ears. For retrograde intraarterial injections and for recording milk-ejection pressure from lower inguinal teat, the method of Bisset et al. (1967) was used. The duct was cannulated by a polyethylene catheter and connected to a pressure transducer (Statham P23AA). Recordings were made on a Beckman Dynograph type-RB. The volume of the retrograde intraarterial injected material was 0.2 ml and was washed in 0.2 ml saline within 2 sec.
3. RESULTS Single retrograde i.a. injections of PGE1 did not produce any change in milk-ejection pressure of the lactating rabbit. Oxytocin, however, increased the milk-ejection pressure within 2 to 3 sec when given by the same route. The minimal dose of oxytocin was around 1 to 3 ~U. and the response was dose-dependent. No tachyphylaxis to oxytocin occurred when the
378
R.K.TURKER and B,K.KIRAN J~able 1 Dose of oxytocin (~U.) retrograde i.a.
.~oL I i
,~
0,I~~<~ ~ I
!
0 /,
0
0
0
6
12
I
2/,
I
~u
~u
I,u
pu
Fig. ]. Effect o f various doses o f o × y t o c i n on m~[k-eicction
pressure. Upper tracing: Control doses of oxytocin (O). Middle and lower tracings: The effect of two different infusions of prostaglandin El(P), on the same doses of oxytocin. Time 1 min. interval between doses was 3 m i n (fig. 1). The response to oxytocin decreased significantly when it was given after a single dose of PGE1 (0.1 to 1/~gi.a.). The inhibitory effect of PGE~ usually persisted 3 to 5 rain following single retrograde i.a. injection. Pretreatment of animals with dihydroergotamine (2 mg/kg i.v.) and propranolol (I mg/kgi.v.) did not produce any change in the inhibitory effect of PGEl. Intravenous continuous infusion of PGEI (0.1 t~g/kg/min and 1 ~tg/kg/min) decreased the response to single i.a. injections of oxytocin (fig. 1). The results are tabulated in table 1. Single doses of PGE1 given by retrograde i.a. injection produced a significant and long-lasting inhibition of milk-ejection pressure when the tonus of the mammary gland was increased by a continuous i.v. drip o f oxytocin, 0.1/~U./kg/min (fig. 2). The minimal dose range of PGEI which produced an inhibition of milk-ejection pressure was 0.1 to 1 ~g i.a.
~o
-~ z:~ I4 ~ 14#-/=t~r-H4 ! ~t ~ . t _ t - t ~ :: ~ '
~ ~ ~.~. o~
~
Fig. 2. The depressant effect of prostaglandin El(P) on oxytocin (O) induced increase of milk-ejection pressure. Time 1 min.
Milk-ejectionpressure (ram H20) ......................... During i.v. drip of PGE 1 Control 0.1 ~g/kg/min 1 ug/kg/min
3
28 + 3.2 a (20--40) b
2 _+0.6 (0-5)
0.5 (0 -2)
6
54+_6 (47-60)
17 +_1.4 (13- 22)
1.5 (0-3)
12
95.3 + 4.5 (82-1 I0)
69.5 + 4.8 (62-80)
49 _+3.5 (40-60)
24
131 + 6 (115-150)
124 +_4.4 (110-140)
88 +__4 (72-100)
a Mean values of six experiments + S.E. of the mean. b Range. 4. DISCUSSION The results of the present investigation show that PGEx inhibits the milk-ejection response to oxytocin in lactating rabbits. Interference of the lipid with the absorption of oxytocin by myoepithelial cells could possibly account for this interaction. However, it is unlikely, since small doses of PGE1 which do not produce any systemic effects when given retrograde i.a. can cause inhibition. Recently Kayaalp and TiJrker (1968) showed that PGEI causes a sustained release of catecholamines from the adrenal glands of dogs. On the other hand, the milk-ejection activity of oxytocin is inhibited by catecholamines (Chan, 1965 ; Bisset, Clark and Lewis, 1967). Chan ( 1 9 6 5 ) h a s shown that the inhibitory effect of catecholamines on milk-ejection activity on the lactating rabbit cannot be blocked by alpha- and beta-adrenergic blockers, indicating that the inhibitory effects are not the result of their vasoconstrictor activity preventing oxytocin from reaching the mammary gland. Bisset, Clark and Lewis (1967) however, have observed that beta-adrenergic blockers can abolish the inhibitory effect o f epinephrine on oxytocin-induced milkejection of the lactating rat and guinea-pig. It is possible that PGE1, when given by the systemic route, causes a release of catecholamines from adrenal glands which then inhibit oxytocin induced milkejection. In the above experiments, alpha-and betaadrenergic blockers did not abolish the inhibitory
MAMMARY GLAND AND PGEl effect of PGE1. Thus it was concluded that, the mechanism of the inhibitory effect of PGEI on milk-ejection activity of oxytocin is an intrinsic phen o m e n o n and is most likely due to a direct effect on myoepithelial cells.
ACKNOWLEDGEMENTS The authors are grateful to J.R. Weeks, Upjohn Co., Kalamazoo, Mich., U.S.A. for the supply of prostaglandin E 1, and to Mr. M. Kaba~am for his excellent technical assistance. REFERENCES Bergstr6m, S., L.A. Carlson and J.R.Weeks, 1968, The prostaglandins: A family of biologically active lipids, Pharmacol. Rev. 20, 1. Bisset, G.W., B.J. Clark, J. Haldar, M.C. Harris, G.P. Lewis
379
and M. Roche E. Silva, 1967, The assay of milk-ejection activity in the lactating rat, Brit. J. Pharmacol. 31,537. Bisset, G.W., B.J. Clark and G.P. Lewis, 1967, The mechanism of the inhibitory action of adrenaline on the mammary gland, Brit. J. Pharmacol. 31,550. Chart, W.Y., 1965, Mechanism of epinephrine inhibition of the milk-ejection response to oxytocin, J. Pharmacol. Exptl. Therap. 147, 48. Clegg, P.C., W.J. Hall and U.R. Pickles, 1966, The action of ketonic prostaglandins on the guinea-pig myometrium, J. Physiol. (London) 183, 123. Horton, E.W. and 1.H.M. Main, 1965, A comparison of the actions of prostaglandins F2a and E 1 on smooth muscle, Brit. J. PharmacoL 24,470. Kayaalp, S.O. and R.K. Tiirker, 1968, Release of catecholamines from the adrenal medulla by prostaglandin El, European J. Pharmacol., 2, 175. Khairallah, P.A., I.H. Page and R.K. Tiirker, 1967, Some properties of prostaglandin El action on muscle, Arch. Intern. Pharrnacodyn. 169, 328. Turker, R.K. and P.A. Khakallah, 1969, Prostaglandin E 1 action on canin isolated tracheal muscle, J. Pharm. Pharmacol. 21,498.
I N T E R A C T I O N OF P R O S T A G L A N D I N E 1 WITH OXYTOCIN ON MAMMARY GLAND OF THE LACTATING RABBIT R.K. T(JRKER and B.K. KIRAN Department of Pharmacology, University of Ankara, Faculty o f Medicine, Ankara, Turkey
Accepted 6 November 1969
Received 2 October 1969
R.K. T~IRKERand B.K. KIRAN,Interaction of prostaglandin E ~ with oxytocin on mammary gland of the lactating rabbit, European J. Phaxmacol. 8 (1969) 377-379. Prostaglandin El, when given by close arterial or intravenous injection did not produce any change in the milk-ejection pressure of the lactating rabbit but it decreased the milk-ejection activity of oxytocin. Adrenergic blockade did not influence this inhibition. It is concluded that the inhibitory action of prostaglandin E~ on oxytocin-inducedmilk-ejection activity of the lactating rabbit is a consequence of a direct action of the lipid on myoepithelial ceils. Milk-ejection activity
Oxytocin effect
1. INTRODUCTION Prostaglandin E ~ (PGE ~) usually contracts isolated smooth muscle (Bergstr~Sm, Carlson and Weeks, 1968), but it relaxes rat isolated duodenum (Khairallah, Page and Tiirker, 1967) and tracheal muscle (Horton and Main, 1965; Tiirker and Khairallah, 1969). On the other hand, PGEI enhances the contractile effects of angiotensin, serotonin and vasopressin on vascular smooth muscle, the relaxing effects of bradykinin and norepinephrine on the rat isolated duodenum (Khairallah, Page and TiJrker, 1967) and the contractile effects of vasopressin, oxytocin and histamine on guinea-pig uterus (Clegg, Hall and Pickles, 1966). The effect of PGE~ on mammary gland has not been reported previously. In the present investigation the action of PGE1 and its interaction with oxytocin on milk-ejection activity of the lactating rabbit were studied.
2. MATERIAL AND METHODS White lactating rabbits 2 to 4 wk postpartum and
Lactatingrabbit
ProstaglandinE ~effect
weighing 2.5 - 4 . 5 kg were used. The animals were anaesthetized by i.v. injection of sodium pentobarbital (35 mg/kg). The trachea was cannulated and in some experiments artificial respiration was applied. Intravenous injections were made into the marginal veins of the ears. For retrograde intraarterial injections and for recording milk-ejection pressure from lower inguinal teat, the method of Bisset et al. (1967) was used. The duct was cannulated by a polyethylene catheter and connected to a pressure transducer (Statham P23AA). Recordings were made on a Beckman Dynograph type-RB. The volume of the retrograde intraarterial injected material was 0.2 ml and was washed in 0.2 ml saline within 2 sec.
3. RESULTS Single retrograde i.a. injections of PGE1 did not produce any change in milk-ejection pressure of the lactating rabbit. Oxytocin, however, increased the milk-ejection pressure within 2 to 3 sec when given by the same route. The minimal dose of oxytocin was around 1 to 3 ~U. and the response was dose-dependent. No tachyphylaxis to oxytocin occurred when the
378
R.K.TURKER and B,K.KIRAN J~able 1 Dose of oxytocin (~U.) retrograde i.a.
.~oL I i
,~
0,I~~<~ ~ I
!
0 /,
0
0
0
6
12
I
2/,
I
~u
~u
I,u
pu
Fig. ]. Effect o f various doses o f o × y t o c i n on m~[k-eicction
pressure. Upper tracing: Control doses of oxytocin (O). Middle and lower tracings: The effect of two different infusions of prostaglandin El(P), on the same doses of oxytocin. Time 1 min. interval between doses was 3 m i n (fig. 1). The response to oxytocin decreased significantly when it was given after a single dose of PGE1 (0.1 to 1/~gi.a.). The inhibitory effect of PGE~ usually persisted 3 to 5 rain following single retrograde i.a. injection. Pretreatment of animals with dihydroergotamine (2 mg/kg i.v.) and propranolol (I mg/kgi.v.) did not produce any change in the inhibitory effect of PGEl. Intravenous continuous infusion of PGEI (0.1 t~g/kg/min and 1 ~tg/kg/min) decreased the response to single i.a. injections of oxytocin (fig. 1). The results are tabulated in table 1. Single doses of PGE1 given by retrograde i.a. injection produced a significant and long-lasting inhibition of milk-ejection pressure when the tonus of the mammary gland was increased by a continuous i.v. drip o f oxytocin, 0.1/~U./kg/min (fig. 2). The minimal dose range of PGEI which produced an inhibition of milk-ejection pressure was 0.1 to 1 ~g i.a.
~o
-~ z:~ I4 ~ 14#-/=t~r-H4 ! ~t ~ . t _ t - t ~ :: ~ '
~ ~ ~.~. o~
~
Fig. 2. The depressant effect of prostaglandin El(P) on oxytocin (O) induced increase of milk-ejection pressure. Time 1 min.
Milk-ejectionpressure (ram H20) ......................... During i.v. drip of PGE 1 Control 0.1 ~g/kg/min 1 ug/kg/min
3
28 + 3.2 a (20--40) b
2 _+0.6 (0-5)
0.5 (0 -2)
6
54+_6 (47-60)
17 +_1.4 (13- 22)
1.5 (0-3)
12
95.3 + 4.5 (82-1 I0)
69.5 + 4.8 (62-80)
49 _+3.5 (40-60)
24
131 + 6 (115-150)
124 +_4.4 (110-140)
88 +__4 (72-100)
a Mean values of six experiments + S.E. of the mean. b Range. 4. DISCUSSION The results of the present investigation show that PGEx inhibits the milk-ejection response to oxytocin in lactating rabbits. Interference of the lipid with the absorption of oxytocin by myoepithelial cells could possibly account for this interaction. However, it is unlikely, since small doses of PGE1 which do not produce any systemic effects when given retrograde i.a. can cause inhibition. Recently Kayaalp and TiJrker (1968) showed that PGEI causes a sustained release of catecholamines from the adrenal glands of dogs. On the other hand, the milk-ejection activity of oxytocin is inhibited by catecholamines (Chan, 1965 ; Bisset, Clark and Lewis, 1967). Chan ( 1 9 6 5 ) h a s shown that the inhibitory effect of catecholamines on milk-ejection activity on the lactating rabbit cannot be blocked by alpha- and beta-adrenergic blockers, indicating that the inhibitory effects are not the result of their vasoconstrictor activity preventing oxytocin from reaching the mammary gland. Bisset, Clark and Lewis (1967) however, have observed that beta-adrenergic blockers can abolish the inhibitory effect o f epinephrine on oxytocin-induced milkejection of the lactating rat and guinea-pig. It is possible that PGE1, when given by the systemic route, causes a release of catecholamines from adrenal glands which then inhibit oxytocin induced milkejection. In the above experiments, alpha-and betaadrenergic blockers did not abolish the inhibitory
MAMMARY GLAND AND PGEl effect of PGE1. Thus it was concluded that, the mechanism of the inhibitory effect of PGEI on milk-ejection activity of oxytocin is an intrinsic phen o m e n o n and is most likely due to a direct effect on myoepithelial cells.
ACKNOWLEDGEMENTS The authors are grateful to J.R. Weeks, Upjohn Co., Kalamazoo, Mich., U.S.A. for the supply of prostaglandin E 1, and to Mr. M. Kaba~am for his excellent technical assistance. REFERENCES Bergstr6m, S., L.A. Carlson and J.R.Weeks, 1968, The prostaglandins: A family of biologically active lipids, Pharmacol. Rev. 20, 1. Bisset, G.W., B.J. Clark, J. Haldar, M.C. Harris, G.P. Lewis
379
and M. Roche E. Silva, 1967, The assay of milk-ejection activity in the lactating rat, Brit. J. Pharmacol. 31,537. Bisset, G.W., B.J. Clark and G.P. Lewis, 1967, The mechanism of the inhibitory action of adrenaline on the mammary gland, Brit. J. Pharmacol. 31,550. Chart, W.Y., 1965, Mechanism of epinephrine inhibition of the milk-ejection response to oxytocin, J. Pharmacol. Exptl. Therap. 147, 48. Clegg, P.C., W.J. Hall and U.R. Pickles, 1966, The action of ketonic prostaglandins on the guinea-pig myometrium, J. Physiol. (London) 183, 123. Horton, E.W. and 1.H.M. Main, 1965, A comparison of the actions of prostaglandins F2a and E 1 on smooth muscle, Brit. J. PharmacoL 24,470. Kayaalp, S.O. and R.K. Tiirker, 1968, Release of catecholamines from the adrenal medulla by prostaglandin El, European J. Pharmacol., 2, 175. Khairallah, P.A., I.H. Page and R.K. Tiirker, 1967, Some properties of prostaglandin El action on muscle, Arch. Intern. Pharrnacodyn. 169, 328. Turker, R.K. and P.A. Khakallah, 1969, Prostaglandin E 1 action on canin isolated tracheal muscle, J. Pharm. Pharmacol. 21,498.