JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2006, 57, 4, 627636
www.jpp.krakow.pl
1 1 2 S. LIPIÑSKA , A. ¯EBROWSKA-BADALLA, J. LIPIÑSKA
OXYTOCIN RELEASE AFTER BLEEDING IN RAT:
THE ROLE OF SYMPATHETIC AND RENIN-ANGIOTENSIN SYSTEM
1 Chair of Experimental and Clinical Physiology, Department of Clinical Physiology,
2 Medical University of Lodz II Chair of Pediatrics, Clinic of Pediatric Cardiology
Medical University of Lodz
The aim of this experiment was to compare the role of renin-angiotensin and
sympathetic nervous system in post-haemorrhagic mechanism of oxytocin release.
Oxytocin content in venous dialysates was determined by radioimmunoassay. In
control rats the release of oxytocin into dialysates did not change during whole
experiment. The injection of captopril induced 2-fold higher oxytocin release, but
caused no change in oxytocin release after bleeding. Superior cervical
ganglionectomy (SCGx) 20 days before, caused 5-fold higher increase in oxytocin
release than in control group. Injection of captopril in rats after SCGx, did not
decrease the high level of oxytocin in dialysate. However, bleeding increased
oxytocin release and 1 hour after bleeding the highest - 14-fold increase, took place.
In the contrary to 14-fold increase in oxytocin release in animals with superior
cervical ganglia (SCG), bleeding after SCGx caused only 2-fold higher oxytocin
release. When SCGx, bleeding and injection of captopril were done simultaneously,
oxytocin release remained on the control concentration level. We assumed that
blockade of renin angiotensin system and sympathetic dennervation prevent the
increase in oxytocin release after bleeding. On basis of our present experiments, it can
be assumed that, in posthaemorrhagic oxytocin release into the blood, sympathetic
innervation derived from SCGx, as well as, renin-angiotensin system are involved.
Key words: oxytocin, bleeding, superior cervical ganglion, renin-angiotensin system
INTRODUCTION
Oxytocin is a neurohormone synthesised not only in the magnocellular nuclei of the hypothalamus: paraventricular and supraoptic nuclei, but also in the microcellular neurons of the paraventricular nucleus innervates many structures of 628
the central nervous system, where regulation centers of the cardiovascular system are located. It is suggested, that oxytocin acts in regulation cardiovascular homeostasis
(5-12). Oxytocin increases the hart rate during stress (6-9). It also strengthen baroreceptor reflex and decreases blood pressure by alpha-2-adrenergic system
(10). Antagonist of oxytocin produces a mild pressor response (11).
Not only vasopressin but also oxytocin stimultaneous release after bleeding is still discussed. Experiments on the rats showed that, oxytocin content in neurohypophysis after bleeding was decreased (12-14) and its release into the blood increased rapidly (15).
Our previous studies showed, that in posthaemorrhagic mechanism of vasopressin release peripheral noradrenergic (sympathetic) projection to the hypothalamic-pituitary axis, derived from the SCG, as well as, renin-angiotensin system, were involved (16). We showed also, that after SCGx oxytocin content in posterior pituitary lobe was lower (12).
The aim of the present study was to investigate what was the role of the renin- angiotensin and sympathetic system in post-haemorrhagic oxytocin release.
MATERIAL AND METHODS
Animals
The experiments were performed on male rats, weighing 300-320 g, 5-9 months old F1 generation cross-strains of male August and female Wistar, from the Institute of Oncology in
Warsaw. The animals in surgical experiments were anaesthetised by an i.p. injection of a solution containing 6 mg of chloralose (Roth) and 60 mg of urethane (Flucka Ah, CH-9470 Bucks) per 100 g b.w. In chronic experiments the animals were anaesthetized by i.p. injection by hexobarbitane 80 mg/kg b.w. All procedures were carried out according to EU directives and reviwed by local Ethical
Committee.
Experimental groups:
1. control (n = 10);
2. injection of captopril i.v. half hour before dialysis (5mg/100g b.w.), (n = 8);
3. injection of captopril and bleeding (1% b.w.), (n = 8);
4. 20 days after superior cervical ganglionectomy, injection of captopril (n = 10);
5. after superior cervical ganglionectomy, injection of captopril and bleeding (n= 10);
6. 20 days after superior cervical ganglionectomy (n = 10);
7. 20 days after superior cervical ganglionectomy and bleeding (n = 10);
8. bleeding (1% b.w.), (n = 10).
Exposure and superior cervical ganglionectomy
The salivary glands were exposed through a ventral incision in the neck. After that, they were retracted, to expose the strap muscles. Each SCG was identified at the bifurcation of the common carotid artery. The ganglia were totally removed from both sides. Care was taken to administer and attain a surgical stage of anaesthesia and to allow a rapid recovery of the animal. 629
Blood withdrawal from the inferior vena cava
The inguinal region was infiltrated with 2% polocaine hydrochloride. The femoral vein was exposed and a thin polyethylene catheter filled with isotonic saline was introduced toward the vena cava. Heparin (100 UJ/mL in 0.2 mL) was injected through the catheter and blood volume, which was equivalent to 1% b.w. was withdrawn during 1-2 min.
Dialysate blood sampling
In order to obtain blood dialysate, one polyethylene cannula was inserted into the heart end of the internal maxillary vein, and the second into the maxillary vein in the vicinity of cavernous sinus of the sella turcica. Blood was drawn from the region of sella turcica through the polyethylene cannula to the minidialysator with the use of the peristaltic pump. After that blood was returned to the circulation through the cannula inserted into the heart end of the maxillary vein. At the beginning of the experiment 2 mL of Locks solution with heparin (400UJ/mL) was injected into the internal maxillary vein. The whole amount of dialysing fluid was exchanged every 30 min for 3 hrs, by draining it directly into a test tube. Six 1 mL samples of dialysate were obteined in that way. Before refilling the minidialysator with dialysing fluid, it was rinsed with Mc
Ilwain-Rodnight solution. At the end of each experiment 1% solution of trypan blue was injected through the cannula inserted into the internal maxillary vein. Then the brain was removed from the skull and the dye in the posterior pituitary lobes was verified under a stereomicroscope. Into the results were included only, these dialysate samples, that are collected from animals, which showed the staining of the posterior pituitary lobe. Staining of the posterior pituitary lobe has proved proper insertion of the cannula into the vicinity of cavernous sinus of the sella turcica, and proper blood collection (17).
Minidialysator characteristics
Minidialysators have two tips for Louers needles, one to connect with cannula in vein and the other with a peristaltic pump. There are two other tips for Louers needles for exchange of the dialysing fluid.
Minidialysators were tested in in vitro experiments. 60% of oxytocin amount was recovered to the dialysing fluid (18).
Radioimmunoassay of oxytocin
The oxytocin content in dialysates was assayed by radioimmunoassay and expressed in pg/mL/30 min.
Statistical analysis
Statistical analysis of the results was performed with a two-way factorial analysis of variance
(ANOVA) followed by Duncans test.
RESULTS
The release of oxytocin into the dialysis fluid in control rats was stable during
180 min of the experiment and maintain at the mean level 16.7± 3.9 pg/mL/30 min (group 1; sample I-VI). The injection of captopril (group 2) caused 2-fold higher oxy release, but caused no increase in oxytocin release after bleeding 630
(group 3). SCGx 20 days earlier (group 6), caused a significant increase in oxytocin release, 5-fold higher than in control group. Injectjon of captopril in rats after SCGx (group 4), did not decrease the high level of oxytocin in dialysate.
Bleeding (group 8) also increased oxytocin release. The highest, 14-fold increase, took place 1 hour after bleeding. Bleeding after SCGx (group 7) caused only 2- fold higher oxytocin release in the contrary to 14-fold increase of oxytocin release in animals with SCG. After SCG, the injection of captopril and bleeding (group
5) done together oxytocin release was abolished to the control concentration. The results are summarized on Figure 1 and Table 1
DISCUSSION
Oxytocin release into the dialysate after bleeding
Oxytocin release into the dialysate was stable during 3 hours of our present experiments. The method of blood dialysis applied in the present study allowed us to observe the dynamic changes in neurohormone release in the same animal.
Blood collected from the cavernous sinus of sella turcica region, was that outflowing from the brain, as well as, from pituitary gland. That was the reason there were much more hormones than in peripheral blood (19). Grzegorzewski and co-authors postulated the possibility of oxytocin transfer from the cavernous sinus to arterial blood suppling the brain and hypophysis (20).
Fig. 1. Oxytocin realese into the dialisate (pg/mL/30 min) 631
Table 1. Oxytocin release into the dialysate, pg/mL/30 min (means ±SE).
sample No I II III IV V VI group
1 control 13.8 ± 4.0 19.7 ± 4.8 13.2 ± 3.3 16.9 ± 3.7 19.7± 3.8 17.1 ± 3.9
2 captopril 20.9 ± 1.8 22.3 ± 1.7 21.7 ± 1.6* 38.7 ± 6.6* 42.3 ± 8.2* 47.5 ± 9.2*
3 captopril 28.0 ± 3.7* 38.4 ± 8.6* 39.2 ± 6.1* 43.2 ±12.6* 55.5 ± 9.4* 33.5 ± 5.8* + bleeding
4 SCGx + 73.9 ± 12.8* 53.8 ± 6.8* 43.3 ±12.3* 80.8 ± 14.2* 87.2 ± 17.8* 83.0 ± 13.0* captopril
5 SCGx +
captopril 9.7 ± 2.3 18.0 ± 2.0 13.5 ± 1.7 11.0 ±1.2 14.3 ± 2.4 15.0 ± 2.1
+ bleeding
6 SCGx 60.2 ± 9.3* 82.2 ±10.2* 79.0 ± 13.1* 94.8 ± 15.3* 98.5 ± 15.2* 107.0 ± 16.8*
7 SCGx + 65.0 ± 5.3* 68.7 ± 5.3* 80.0 ± 8.8* 110.1 ± 12.8* 130.0 ± 15.6* 115.0 ± 18.3* bleeding
8 bleeding 18.4 ± 2.6 23.0 ± 2.2 60.5 ± 8.8* 109.0 ±13.8* 234.0 ± 28.0* 120.0 ± 13.8*
*statistically significant: group 1, 5 vs. group 2, sample III-VI; (p < 0.001) group 1, 5 vs. group 3, 4, 6,7; (p < 0.001) group 1, 5 vs. group 8, sample III-VI;VI; (p < 0.001) group 7 sample I, II vs. group 8, sample I,II; (p < 0.001) group 7 sample V vs. group 8, sample V; (p < 0.001)
Oxytocin concentraction in blood dialysates from cavernous sinus of the sella turcica, obteined in the present experiment, might result from the release of this neurohormone into blood and its uptake in the area of the rete mirabile. In the present experiment we noted an increase in oxytocin release following haemorrhage. The fact that haemorrhage stimulates the release of vasopressin and oxytocin from the neurohypophysis has been known for many years.
Mechanisms responsible for cardiovascular adaptation to hypotensive hypovolemia are still not well understood. Integrated neural, humoral and local mechanisms, which become activated in haemorrhagic shock conditions, lead to the centralisation of the circulation. The redistribution of circulating blood is mainly due to increased activity of sympathetic nervous system, activation of renin-angiotensin system, secretion of vasopressin and oxytocin (21).
Oxytocinergic connections between the paraventricular nucleus and the brain stem are thought to be important in the control of autonomic function.
Oxytocinergic neurons send projections to the dorsal vagal complex and the nucleus of the solitary tract. Injection of oxytocin into these regions affects neural activity and heart rate (3,4). Electrical stimulation of the PVN has been reported to either increase (7,8) or decrease (9) heart rate and injection of oxytocin antagonist is thought to abolish these effects (10) 632
Oxytocin release after superior cervical ganglionectomy
In present study we observed, that 20 days after SCGx, oxytocin release into the dialysate increased. The increase in oxytocin release 20 days after SCGx was more probably connected with sympathetic denervation than with the effect of postoperative stress.
Other authors and our previous studies, demonstrated that SCGx in rats decreased oxytocin content in the neurohypophysis. (22, 23). Studies of Fendler demonstrated that, in rats with removed SCG the miniature neurohypophysis at the proximal end of the cut pituitary stalk was not formed, while there was a degeneration of neurosecretory neurones in the hypothalamus (23). In other
3 studies performed in SCGx rats, a significant decrease in basal hypothalamic H-
NA uptake was found (24) and decrease of NA content in median eminence and in neurohypophysis was observed (25-27).
After a complete denervation of structures innervated by SCG (28), 20 days after SCGx, the content of oxytocin in dialysates was higher than in control rats, which probably resulted from the lack of neurohormone release inhibition.
On the basis of previous and present studies, we proposed that oxytocin release from neurohypophysis was probably continually inhibited by impulsation from SCG. SCGx however, neutralised this inhibition. In the consequence, there was an increased neurohormone release into the blood, and its decreased content in posterior pituitary, demonstrated earlier (12).
The effect of SCG on the oxytocin release could take place, both, directly or via the pineal gland, as the dependence between the pineal body and the release of the posterior pituitary neurohormones has been demonstrated (29,30).
Influence of renin-angiotensin system on the oxytocin release
In the present study we indicated, that inactivation of renin-angiotensin system
(injection of captopril) administrated in our study, increased basal oxytocin release into dialysate. These observations indicated, that probably in physiological conditions, angiotensin II (AII), by inhibition of oxytocinergic neurons, decreased oxytocin release into the blood. The injection of captopril, caused significant decrease in post-haemorrhagic oxytocin release. In the condition of activated oxytocinergic neurons after bleeding, AII could stimulate oxytocin release.
Other authors showed, that AII could have stimulating or inhibiting effects on central oxytocinergic neurons. Dawson et al. demonstrated, that in conscious rats intravenous AII injection led to the activation of paraventricular nucleus (31).
Successive studies indicated, that increase in oxytocin release evoked by central infusion of AII, was abolished by AT1 receptor blockade and inhibited by AT2 receptor antagonist (32,33).
Central AII receptor blockade did not alter the increase in circulating oxytocin during sucking. These data indicated, that central angiotensin system did not have a direct role in stimulating of oxytocin release during sucking (33). Furthermore, 633
the stimulating or inhibiting effect of AII on oxytocin secretion depends on its concentration. Roesch et al. showed, that intraventricular injection of 5 ng of AII attenuated, and 10 ng induced oxytocin secretion (34).
Influence of AII on oxytocin release is thought to be modified by neurotransmitters and hormones. Oxytocin release in response to intracerebroventricular injection of AII was significantly diminished by central phentolamine (alpha-2 adrenergic blocker) injection (33). Roesch hypothesised, that mineralocorticoids might attenuate AII-induced activation of inhibitory oxytocinergic neurons (34). Central administration of ornithine vasotocin (oxytocin antagonist) before AII injection inhibited the activity of oxytocinergic neurons (11).
The oxytocin response to exogenously administered prostaglandins (PGD-2), can be negatively modulated by mechanism dependent upon AII AT1 receptors (35).
Ozaki and co authors suggested that angiotensin II potentiates the excitatory synaptic inputs into supraoptic nucleus neurones, via the AT1 receptors.
AII is known to increase blood pressure by causing vasoconstriction of peripheral arterioles and by stimulating the secretion of aldosterone. AII induces also the release of posterior pituitary lobe neurohormones as described above. In recent years various different AII activities were discovered. It is known that AII contributes in endothelial dysfunction through oxidative stress (36), inhibiting
NO synthesis (37), enhancing leukocytes infiltration and adhesion to vascular wall (38). Furthermore, few observations indicated that AII could activate the coagulation cascade by increasing tissue factor expression and could also evoke antithrombotic effect as described recently (39-42). Moreover, AII inhibits fibrynolysis by increasing plasminogen activator inhibitor type 1 (PAI-1) expression (43). Captopril, plasma angiotensin-converting enzyme inhibitor, used in our researches seems to abolish all the AII actions.
On the basis of our experiments, it can be assumed that, in posthaemorrhagic oxytocin release into the blood, sympathetic innervation derived from SCG, as well as, renin angiotensin system were involved. Mechanism of this interaction is still not well known and requires further studies.
Acknowledgements: I would like to express may gratitude to Mrs Beata Bia³a, for her technical assistance during the experiments, Monika Or³owska-Majdak, Ph.D., for supplying the anti oxytocin antiserum and Jadwiga Kaczorowska-Skóra, M. Sc. for performing oxytocin radioimmunoassay
The study was supported by a grant No 502-16-23 and 53 0079-1 for Medical University of Lodz.
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Received: January 24, 2006
Accepted: October 27, 2006
Authors address: Stanis³awa Lipiñska, Chair of Experimental and Clinical Physiology,
Department of Clinical Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz,
Poland; tel./fax 042 678 26 61; e-mail: [email protected]