Pharmacological Reports Copyright © 2012 2012, 64, 14421454 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Function of the hypothalamo-neurohypophysial system in rats with myocardial infarction is modified by melatonin
Joanna Ciosek, Jacek Drobnik
Department of Neuropeptides Research, Medical University of Lodz, Narutowicza 60, PL 90-136 £ód, Poland
Correspondence: Ciosek Joanna, e-mail: [email protected]
Abstract: Background: Pineal and melatonin interactions with the hypothalamo-neurohypophysial system are well documented. In addition, vasopressin and oxytocin secretion are known to be part of the neuroendocrine response to chronic heart failure evoked by myocar- dial infarction. The present study was undertaken to evaluate the possible regulatory role of melatonin in the vasopressin and oxyto- cin release in rats with myocardial infarction. Methods: The vasopressin and oxytocin content of the hypothalamus and neurohypophysis, as well as their plasma levels, were radioimmunoassayed in sham-operated or pinealectomized rats with left coronary artery ligation (CAL)-evoked myocardial infarc- tion as well as under melatonin treatment. Results: Infarcted rats demonstrated increased vasopressin and oxytocin plasma levels, but melatonin restricted the release of both neurohormones in these rats. Experimental myocardial infarction in pinealectomized rats caused a distinct inhibition of vasopressin release but intensified oxytocin secretion. In pinealectomized rats substituted with melatonin, pineal indole amine was seen to inhibit oxytocin release and stimulate vasopressin secretion. Conclusions: (i) CAL-induced myocardial infarction is the reason for increased hypothalamo-neurohypophysial system activity in rats; melatonin plays the role of inhibitory neuromodulator of vasopressin and oxytocin release in this state. (ii) Myocardial infarction evoked in pinealectomized rats is characterized by the inversion of the neurohumoral response pattern in respect of inhibited vasopressin release. (iii) Melatonin stimulates vasopressin (but decreases oxytocin) release in pinealectomized rats with myocardial infarction.
Key words: myocardial infarction, melatonin, vasopressin, oxytocin, pinealectomy
Abbreviations: AVP – arginine vasopressin, CAL – coronary physial endings, are modulated by different neuro- artery ligation, CHF – chronic heart failure, MI – myocardial modulators/neuromediators of central or systemic infarction, MLT – melatonin, NH – neurohypophysis, OT – origin. The relationships between the pineal gland and oxytocin, PVN – paraventricular nucleus, PX – pinealectomy, RIA – radioimmunoassay, SCN – suprachiasmatic nucleus, hypothalamo-neurohypophysial system function is SON – supraoptic nucleus, VEH – vehiculum (solvent) well documented. The major product of the pineal gland, melatonin (MLT), has been found to modify the AVP and/or OT release from the neurohypophysis (NH) under in vivo [32, 47, 48] and in vitro [55, 94] Introduction conditions and its action may be inhibitory or stimula- tory depending on the dose applied. According to The processes of hypothalamic biosynthesis of vaso- Forsling and Williams [32], MLT modulates the neu- pressin (AVP) and oxytocin (OT), as well as the re- rohypophysial response to different stimuli, with low lease of both neurohormones from the neurohypo- doses enhancing the response. Pinealectomy (PX) was
1442 Pharmacological Reports, 2012, 64, 14421454 Melatonin and neurohypophysis function in infarcted rats Joanna Ciosek and Jacek Drobnik
shown to decrease the AVP and OT content in the hy- The aim of the present study was to make the first pothalamus and NH followed by an increase their attempt to explain the possible relationships between plasma concentrations [47, 48]. the pineal gland and the function of the hypothala- MLT acts in the central nervous system as a neuro- mo-neurohypohysial system in animals with MI, and modulator of different processes [4, 6, 15, 39]. Nu- to estimate the degree of MLT participation in neuro- merous scientific observations have suggested that hormonal response to MI. MLT exerts significant influence on the cardiovascu- lar system [80]. MLT, after binding with vascular re- ceptors MT1 and MT2, elicits vasoconstriction and vasodilation, respectively [25]. However, the distribu- Material and Methods tion of MT1 and MT2 receptors in the cardiovascular system remains to be explored. Important actions of MLT are the reduction of blood pressure [37, 71, 78] Animals and an anti-adrenergic influence on myocardial con- tractility [1] exerted by its receptors in the heart [69] Male adult rats of the Wistar strain weighing 280 ± 30 g and arteries [64]. MLT decreases blood pressure in (the mean ± SD) were housed at room temperature normal, spontaneously hypertensive as well as pin- and in a controlled light:dark cycle (phase L : phase D) ealectomized rats [9, 42, 58]. On the other hand, PX (phase L on from 06:00 to 18:00). All the animals had has been noted to be the reason of the hypertension in free access to commercial food pellets (LSM, Bacutil, rats [57]. According to Erºahin et al. [28] MLT pro- Poland) as well as tap water ad libitum. There were tects against renovascular hypertension- induced tis- four animals per cage. The study was approved by the sue damage and improves cardiac function. MLT has Local Commission of Ethics of £ódŸ. the cardioprotective properties by its direct free radi- cals scavenging and by its indirect stimulatory action Drugs on the antioxidant enzyme system [23, 45, 48]. Drob- nik et al. [27] have shown that MLT exerts an aug- 1. Melatonin (MLT; N-acetyl-5-methoxytryptamine; mented influence on procollagen gene expression in Sigma Chemical Co., St. Louis, MO, USA) was dis- the infarcted heart scar of pinealectomized rats. MLT solved in solvent (VEH; 2% ethanol in 0.9% sodium has been shown to reverse left ventricular fibrosis in chloride) and injected subcutaneously (sc) in a dose of spontaneously hypertensive rats [84]. 60 µg/100 g b.w. according to earlier experiments Chronic heart failure (CHF) is the state related to with MLT [13]. stimulation of some of the neurohumoral mechanisms 2. Thiopental (Sandoz, lot AR 8028) injected intrape- which maintain normal circulating blood volume, ritoneally (ip). 8 blood pressure as well as organ perfusion. The pre- 3. [Arg ]-Vasopressin and oxytocin, for standard 125 dominant reason for chronic heart failure is myocar- curve preparation as well for iodination with I, dial infarction (MI) [34]. This state is characterized come from Peninsula Laboratories Europe Ltd. by impaired left ventricular systolic function and chamber dilation, as well as congestion of the lung Experimental protocol and low cardiac output. CHF is accompanied by an increase of neurohumoral activity [33]. This activa- During the experiments, two surgical operations were tion may include the sympathetic nervous system, employed: MI and PX. renin-angiotensin-aldosterone system, AVP, and atrial natriuretic peptide [18, 33]. The high level of AVP Pinealectomy and the C-terminal fragment of provasopressin (co- peptin) observed during CHF state may be treated as Thirty-five days before decapitation and 7 days before risk factors for the survival of many heart failure pa- induction of MI, rats were subjected to either a PX or tients [59, 86, 87]. On the other hand, according to sham-PX according to the procedure described by Ondrejcakova et al. [68], OT may exert cardioprotec- Kuszak and Rodin [62]. Under thiopental anesthesia, tive effects on ischemia-reperfusion induced myocar- the head was placed in a stereotactic device. After dial injury. cutting the hair, a skin incision and then a rectangular
Pharmacological Reports, 2012, 64, 14421454 1443 aperture in the skull were made using a dental drill. rats); Group 6: pinealectomized animals with MI The superior sagittal sinus was cut between two liga- (PX/MI rats); Group 7: pinealectomized rats with MI tures. The pineal gland was extracted after grasping it treated with VEH (PX/MI + VEH rats); Group 8: pin- with small curved forceps. The sham PX comprised ealectomized rats with MI injected with MLT (PX/MI the same surgical procedure without removal of the + MLT rats). pineal gland. In accord with the daily rhythm of MLT secretion, all injections were made once daily between 17:30 Left coronary artery ligation and 18:00 h for 28 days of the experiment; a similar scheme of MLT injections has been used by our team Induction of MI was performed according to Seyle in earlier studies [26, 27]. with some modifications [26]. All rats were subjected On the day of the experiment, animals were decapi- to ligation of the left coronary artery. Under thiopental tated between 9:00 and 10:00 a.m. The procedure of anesthesia, rats were ventilated with positive pressure decapitation was carried out very quickly with the use through a tube inserted into the trachea and attached of the guillotine for experimental animals. Each rat to a respirator for small animals. After opening the was decapitated in the laboratory room separately pericardium, the heart was brought outside and the from the other animals. The brain and the pituitary left coronary artery was ligated with nylon suture 6/0. with intact pituitary stalk were carefully removed The ligation was performed at the centre of an imagi- from the skull; the disruption of the cranial bones was nary line between the left margin of the pulmonary begun from the superior area and neurointermediate cone and the closest point of insertion of the left lobe was then separated (the anterior lobe of the pitui- auricular appendage. At the end of the operation, four tary was excised). sutures were applied on the skin wounds. The mortal- Following this, the brain was frozen and a block of ity was 35%. Animals that survived the surgery were tissue containing the hypothalamus was dissected included into the experiment. After 4 weeks, all ani- from the brain as follows: rostral limit – frontal plane mals were euthanized by decapitation. The sham in- situated about 1.0 mm anterior to the anterior margin farction was performed according to the same proce- of the optic chiasm; caudal limit – frontal plane just dure without coronary artery ligation (CAL). The to- behind the mammilary bodies; lateral limits – sagittal tal free wall of the left ventricle was excised and planes passing, on both sides, just through the hypo- divided into the scar and non-infarcted myocardium. thalamic fissures [11, 93]. Such hypothalamic block The circumference of the total free wall of the left contained a suprachiasmatic nucleus (SCN) as well as ventricle and the scar was drown on paper and then the SON and PVN hypothalamic nuclei [8, 11]. The their surface areas were measured by Reissprazsions- depth of the dissection was approximately 2.5–3.0 mm planimeter. The size of the scar measured as the per- from the base of the brain. The total dissection time centage of the surface area of the free wall of the left was about 3 min from the decapitation. ventricle covered by the surface area of the scar The NH or the hypothalamus was homogenized in ranged from 42.86 to 59.71%. Significant differences 1 ml of 0.25% (resp. in 0.5 ml of 0.5%) acetic acid in between the scar area of the infarcted hearts of all the 0.9% NaCl solution. The tissue suspension was trans- rats in the experimental group were not noted (the ferred into a centrifuge tube and the homogenizer was 2 mean was between 96 and 115 mm ). The weight of washed with 1 ml of the same solution in the case of the hearts was not statistically different in all groups. the NH or twice with 0.5 ml in the case of the hypo- thalamus. The pooled sample was heated for 5 min on Plan of the experiments a boiling water bath and centrifuged for 30 min (room temperature, relative centrifugal force ca. 650 G = The experimental animals were divided into eight 6380 m/s). The supernatant was removed and made up groups: Group 1: rats subjected to sham MI (SHAM-MI to a constant volume. The final extracts were frozen rats); Group 2: rats with MI (MI-rats); Group 3: rats and stored at –20°C until assayed for AVP and OT. subjected to MI and injected sc with VEH (100 µl/100 g The trunk blood was collected and its plasma os- b.w.) (MI + VEH rats); Group 4: rats with MI injected molality and hematocrit index were estimated. Plasma sc with MLT (60 µg/100 g b.w.) (MI + MLT rats); osmolality was measured in duplicate by freezing Group 5: rats with sham PX and MI (SHAM-PX/MI point depression using semimicroosmometer (Knauer
1444 Pharmacological Reports, 2012, 64, 14421454 Melatonin and neurohypophysis function in infarcted rats Joanna Ciosek and Jacek Drobnik
& Co., Berlin, Germany). AVP and OT were extracted of the experimental data was performed using from the plasma using C18 Sep-Pak microcolumns “STATISTICA” (Version 6.0) software (StatSoft, (Waters Corp., Milford, Massachusetts, lot No. Kraków, Poland). The results were calculated by use W9224G1). The AVP and OT content of the samples of the Kruskal-Wallis analysis of variance by ranks was determined by radioimmunoassay. (ANOVA) test; if ANOVA revealed significant ef- fects, post-hoc analyses were performed using the Radioimmunoassay (RIA) Mann-Whitney U test (statistical significance of dif- ferences between the means of two groups com- The hypothalamic and neurohypophysial AVP and OT pared); p < 0.05 was used as the minimal level of sig- content as well as plasma neurohormones concentra- nificance. tion were determined by double-antibody specific RIA, as previously described by Ciosek and Stempniak [10]. Anti-AVP and anti-OT antibodies were obtained in the Department of Physiology and Biochemistry, Results Medical University of Lodz. The antibody titer was 1:24,000 for AVP and 1:80,000 for OT (both final di- Results are summarized in Figures 1–8. lutions) and the lower limit of detection for the assay was 1.25 pg AVP/tube and 1.25 pg OT/tube. For stan- MI, PX and MLT treatment and AVP release dard curve preparation as well as iodination with 125I, 8 using the chloramine-T method, AVP ([Arg ] lot The AVP content of the hypothalamus of rats with 802958) and OT (OT synth.; lot 027179) from Penin- surgically-evoked MI distinctly increased in compari- sula Laboratories Europe Ltd. were used. The intra- son to sham-operated ones (Fig. 1. MI vs. SHAM-MI: assay coefficients of variation for the AVP were less p < 0.001). In the same animals, neurohypophysial than 3.5% and less than 5% for OT (all samples AVP storage diminished and plasma AVP level rose within the experiment were tested in the same RIA to (Fig. 2 and 3. MI vs. SHAM-MI: p < 0.001). The avoid inter-assay variability). plasma osmolality value was then distinctly decreased (Fig. 7. MI vs. SHAM- MI: p < 0.001) without any Statistical evaluation of results change of hematocrit index in these animals (Fig. 8. MI vs. SHAM-MI). The final AVP and OT levels were expressed in nano- In infarcted animals with an intact pineal gland, grams (ng) per mg of the hypothalamic tissue, in ng melatonin did not modify the AVP content of the hypo- for whole NH and in picograms (pg) per 1 ml of thalamus and NH (Fig. 1 and 2. MI + MLT vs. MI + plasma. All results were reported as the mean ± stan- VEH) but it did decrease its level in the plasma (Fig. 3. dard error of the mean (SEM). Statistical analysis MI + MLT vs. MI + VEH: p < 0.05). No significant
30 Vasopressin content in the hypothalamus Fig. 1. Vasopressin content in the hy- pothalamus. (MI) myocardial infarc- 25 tion; (SHAM-MI) sham-infarcted rats; p < 0.001 (MI + MLT) infarcted and MLT-treated rats; (MI + VEH) infarcted and VEH- 20 p < 0.001 treated rats; (PX/MI) pinealectomized/ infarcted rats; (SHAM-PX/MI) sham- 15 pinealectomized/infarcted rats, (PX/MI p < 0.001 + MLT) pinealectomized/infarcted and
MLT-treated rats; (PX/MI + VEH) pin- AVP (ng/mg) ealectomized/infarcted and VEH- 10 treated rats (the mean ± SEM); number of animals presented in the columns 5
9 11 1112 88 811 0 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT - PX/MI + VAH + MLT
Pharmacological Reports, 2012, 64, 14421454 1445 4000 Vasopressin content in the neurohypophysis
3500 Fig. 2. Vasopressin content in the neu- p < 0.001 rohypophysis. Bars designations see 3000 Figure 1 (the mean ± SEM); number of p < 0.05 animals presented in the columns p < 0.001 2500
2000
AVP (ng/NH) 1500
1000
500 12 10 109 1010 810
0 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT - PX/MI + VEH + MLT
40 Vasopressin concentration in blood plasma 35 Fig. 3. Vasopressin concentration in blood plasma. Bars designations see 30 Figure 1 (the mean ± SEM); number of animals presented in the columns p < 0.001 25 p < 0.05 p < 0.001 20 p < 0.001
AVP (pg/ml) 15
10
5 10 9 7 8 9 10 8 8
0 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT - PX/MI + VEH + MLT
18 Oxytocin content in the hypothalamus 16 Fig. 4. Oxytocin content in the hypo- thalamus. Bars designations see Fig- 14 ure 1 (the mean ± SEM); number of p < 0.001 12 animals presented in the columns g) 10 /m
g p < 0.02 ( n 8 p < 0.001
OT 6
4
2 9 12 9 9 8 8 8 11
0 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT - PX/MI + VEH + MLT
differences were found in osmolality values after content (Fig. 1. PX/MI vs. SHAM-PX/MI: p < 0.001) MLT treatment (Fig. 7. MI + MLT vs. MI + VEH), and increased neurohypophysial AVP storage (Fig. 2. however, the hematocrit index was higher in these con- PX/MI vs. SHAM-PX/MI: p < 0.001). After left CAL, ditions (Fig. 8. MI + MLT vs. MI + VEH: p < 0.05). the plasma AVP concentration was significantly lower The animals with MI induced one week after the in pinealectomized rats in comparison to sham- PX experienced both decreased hypothalamic AVP operated rats (Fig. 3. PX/MI vs. SHAM-PX/MI: p <
1446 Pharmacological Reports, 2012, 64, 14421454 Melatonin and neurohypophysis function in infarcted rats Joanna Ciosek and Jacek Drobnik
0.001). MI was associated with higher plasma osmo- higher as compared with vehicle-injected animals lality but a lower hematocrit index value (Fig. 7 and 8. subjected to the same experimental procedure (Fig. 1. PX/MI vs. SHAM-PX/MI: p < 0.001 and p < 0.05, re- PX/MI + MLT vs. PX/MI + VEH: p < 0.001). In the spectively). same animals, MLT distinctly intensified AVP release In pinalectomized and infarcted rats treated with from the NH, which was the cause of plasma AVP MLT, the hypothalamic AVP content was significantly level increase (Fig. 2 and 3. PX/MI + MLT vs. PX/MI
2000 Oxytocin content in the neurohypophysis 1800 Fig. 5. Oxytocin (OT) content in the neurohypophysis. Bars designations 1600 see Figure 1 (the mean ± SEM); number of animals presented in the 1400 p < 0.001 columns 1200
p < 0.01 1000 p < 0.01
800 p < 0.05 OT (ng/NH)
600
400 9 10 10 200 12 10 10 9 9
0 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT -PX/MI + VEH + MLT
20 Oxytocin concentration in blood plasma 18 Fig. 6. Oxytocin (OT) concentration in blood plasma. Bars designations see 16 Figure 1 (the mean ± SEM); number of p < 0.001 animals presented in the columns 14
12 p < 0.001 10 p < 0.05 p < 0.01 8 OT (pg/ml) 6
4
2 9 12 9 8 10 8 9 10
SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT PX/MI + VEH + MLT
400 Osmolality values 380 Fig. 7. Osmolality values. Bars desig- nations see Figure 1 (the mean ± SEM); 360 number of animals presented in the columns 340
O p < 0.001 2 320 p < 0.001 p < 0.001 300
280 mOsm/Kg H 260
240 9 12 8 10 9 8 8 220 8
200 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT -PX/MI + VEH + MLT
Pharmacological Reports, 2012, 64, 14421454 1447 70 Hematocrit index Fig. 8. Hematocrit index (Ht). Bars de- 65 signations see Figure 1 (the mean ± SEM); number of animals presented in the columns 60
p < 0.05 55 ) p < 0.05 % ( 50 Ht 45
40
35 9 11 9 10 9 8 9 8
30 SHAM-MI MI MI MI SHAM PX/MI PX/MI PX/MI + VEH + MLT -PX/MI + VEH + MLT
+ VEH: p < 0.05 and p < 0.001). These MLT-treated Discussion rats were characterized by smaller osmolality values without any change of hematocrit index (Fig. 7. PX/MI + MLT vs. PX/MI + VEH: p < 0.001). The procedure of CAL in the rat is a convenient model of experimental chronic left ventricular failure which may correspond to the human condition. Ani- MI, PX and MLT treatment and OT release mals with infarction show reduced cardiac output as well as increased peripheral resistance [31]. Acute or As with augmented AVP release, the left CAL proce- chronic MI caused by ligation of the left coronary ar- dure resulted in greater OT secretion from the NH tery is characterized by left ventricular dysfunction into the blood in comparison to sham-operated control and low-output heart failure [73], as well as the ten- animals (Fig. 5 and 6. MI vs. SHAM-MI: p < 0.01); dency for the left ventricle to dilate. However, the left hypothalamic OT content then diminished (Fig. 4. MI ventricle weight in the infarcted rats did not change at vs. SHAM-MI: p < 0.001). 4 to 5 weeks after infarction [22, 95]. It has been Injections of MLT to infarcted rats distinctly inhib- known that MI leads to distinct changes in the central ited OT release from the hypothalamo-neurohypo- mechanisms controlling the cardiovascular system. In physial system, resulting in reduced plasma OT level the post-infarct period increased activity of renal sym- (Fig. 4, 5 and 6. MI + MLT vs. MI + VEH: p < 0.001, pathetic nerve as well as brain angiotensin and min- p < 0.001 and p < 0.01). eralocorticoid receptors has been noted [21, 30, 34, The MI carried out in pinealectomized animals did 95, 96]. Important fluctuations in the neurohumoral not modify OT content in the hypothalamus but regulation of intravascular volume and vascular tone has been observed after coronary ligation [41]. The stimulated its release from the NH into the circula- distinct participation of AVP in these compensatory tion; OT plasma concentration distinctly rose (Fig. 5 mechanisms is worthy of notice. The tendency for and 6. PX/MI vs. SHAM-PX/MI: p < 0.01 and p < plasma AVPlevel to increase one month after CAL, to 0.001, respectively). which accompanies hypoosmolality and hyponatre- On the other hand, reduced OT secretion from the mia has been noted [38, 41, 83]. Similarly, Francis et hypothalamus and NH was seen in pinealectomized al. [34] observed high plasma AVP levels 3 weeks af- and infarcted rats simultaneously treated with MLT ter CAL procedure. Watanabe et al. [87] have noted (Fig. 4 and 5. PX/MI + MLT vs. PX/MI + VEH: p < that both AVP production and its binding with AVP 0.02 and p < 0.01, respectively); in this case, the OT receptors may be enhanced at regional sites of the hu- concentration in blood plasma was distinctly lower man heart in the blood volume load. In a series of the (Fig. 6. PX/MI + MLT vs. PX/MI + VEH: p < 0.001). experiments Szczepañska-Sadowska et al. [12, 13, 22]
1448 Pharmacological Reports, 2012, 64, 14421454 Melatonin and neurohypophysis function in infarcted rats Joanna Ciosek and Jacek Drobnik
demonstrated that brain AVP V1 receptors contribute jected subcutaneously (sc), or intraperitoneally (ip), to enhanced cardiovascular responses to different or intravenously (iv), or intracerebroventricularly (icv) types of acute and chronic stress in rats with MI. Patel in higher doses (for example 100 µg/100 g b.w.) [51] et al. [70] observed that the increased number of Fos AVP and OT release from the NH was stimulated, staining neurons and AVP producing neurons both in while lower doses (25 µg per animal) had no signifi- the PVN and SON, and the medial preoptic area, acted cant effect [49, 54]. In lactating female rats MLT in- as an index of augmented neuronal activity in response hibited OT secretion from the posterior lobe only at to heart failure in rats. Postmortem morphological ob- a concentration similar to its physiological level in the servations in patients with CHT showed a significant blood [56]. Moreover, MLT did not change biosynthe- increase of AVP-ergic neurons in the hypothalamic sis rate of AVP and OT in rats with intact pineal gland SON as well as density of AVP-immunoreactivity in but inhibited AVP biosynthesis in pinealectomized the posterior pituitary [81]. rats [47]. Treatment with MLT was followed by de- Our results clearly show that the experimental MI creased AVP and OT content in the NH of euhydrated causes a magnified level of AVP in the hypothalamus rats [51, 53]. On the other hand, MLT did not modify (related to intensified biosynthesis or impairment of AVP and OT release from the NH of dehydrated or axonal neurohormonal transport) as well as an intensi- hemorrhaged rats [51, 53]. Therefore, it is clear that fied release of this neurohormone into the blood. In MLT modulates neurosecretory activity of the poste- fact, plasma AVP concentration was found to be dis- rior lobe but this influence is not uniform and numer- tinctly higher in the infarcted rats in comparison to the ous factors may change the character of MLT action. sham-operated rats; a significant decrease in the os- The present study has shown, for the first time, that molality value was also shown in these animals. In MLT administered to the infarcted rats exerts an in- this respect, our results confirm the data presented in hibitory influence on AVP and OT release into the related studies [34, 38, 83]. The augmented release of blood. AVP and OT plasma level diminution has been AVP, along with its antidiuretic action, may be con- observed in these animals. Surprisingly, MLT was sidered a response aimed at normalizing the function found to stimulate OT biosynthesis in the hypothala- of the circulatory system. Some authors emphasize mus of infarcted rats. Hence, it seems reasonable to the increased role of AVP in regulation of blood pres- suppose that MLT may change the neurohumoral sure and heart rate in the infarcted rats [12, 22]. These mechanisms engaged in the regulation of some as- authors found that in the infarcted rats intracerebrov- pects of the circulatory system concerned with the ac- entricular administration of a specific V1 receptor an- tivity of the hypothalamo-neurohypophysial system tagonist resulted in significant decrease the baseline during chronic heart failure. Moreover, MLT was seen mean arterial blood pressure (MABP). to increase the rate of hypothalamic AVP and OT bio- In addition, OT secretion from the NH was also in- synthesis as well as AVP release into the blood of pin- creased in the rats which had experienced CAL- ealectomized and infarcted rats; OT secretion was evoked heart failure. The observed low OT content in then decreased. It may be assumed that MLT adminis- the hypothalamus may be the result of increasing ax- tered to the pinealectomized rats with MI exerts the onal transport of this neurohormone towards the NH. same influence on OT biosynthesis and release as in Hence, centrally-released endogenous OT may be en- MLT-treated infarcted rats. In coronary heart disease gaged in the regulation of blood pressure and heart rate in MLT production has the tendency to fall [23]. On the rats with a MI [91]. other hand, MLT acting as a strong antioxidant may The pineal gland and its hormone, MLT, play a sig- reduce the damage of the cardiomyocytes of the in- nificant role in the regulation of hypothalamo- farcted hearts induced by chemical hypoxia and re- neurohypophysial function. Previous in vivo and in vi- oxygenaration [24, 79]. It cannot be therefore ex- tro experiments have demonstrated that the influence cluded that exogenous MLT may correct the cardio- of MLT on the AVP and/or OT biosynthesis and re- vascular conditions in the infarcted rats and lead to lease depends on the concentration of this indo- restricted release of both neurohypophysial hormones. leamine and experimental conditions [45]. MLT has The removal of the pineal gland may be the reason been shown to inhibit AVP and OT release from the of the important dysfunctions of different organs and hypothalamo-neurohypophysial complex in vitro [7, may lead to intensification of the existing distur- 44, 46]. In in vivo experiments, when MLT was in- bances [43]. PX, leading to a deficiency of MLT in the
Pharmacological Reports, 2012, 64, 14421454 1449 body, was found to affect the secretion of both neuro- over, removal of the pineal gland increases binding hypophysial hormones in the state of equilibrated of 2-[125I]-iodomelatonin to the spleen crude mem- water-electrolyte balance as well as disturbed condi- branes [74]. tions due to dehydration, hemorrhage or hyperosmotic These facts suggest that the effects of MLT in ani- stimulation. Pineal removal resulted in a decrease of mals may differ between those with intact or removed hypothalamic and neurohypophysial AVP and OT pineal gland. For example, while MLT increases col- storage in euhydrated [16], dehydrated [82], osmoti- lagen gene expression in the pinealectomized rats, cally challenged animals [90], and hemorrhaged ani- this effect was not observed in animals with an intact mals [53]. AVP and OT plasma levels had a tendency pineal gland [27]. Hence, the state of prolonged MLT to rise in euhydrated or dehydrated rats [52, 82]. The deficiency evoked by PX might be the reason for the earlier studies of De Vries et al. [19, 20] showed that varying susceptibility of MLT receptors to this indo- the pineal removal led to a diminution of the neurose- leamine in the hypothalamo-neurohypohysial tract re- cretory activity in the supraoptic and paraventricular sulting in the differential release of both neurohor- neurons. No such hormonal consequences of pineal mones. removal have been observed sooner than eight weeks To summarize, present study shows that exogenous after surgery [16, 50, 53]. Other authors noted that MLT distinctly inhibits OT release in MI + MLT-rats this effect was not observed sooner than 8 days after as well as in PX/MI + MLT rats. On the other hand, PX [52]. Later studies by Juszczak et al. [47] con- MLT action on AVP release in PX/MI + MLT rats is firmed that after pineal removal, plasma AVP level the opposite to that observed in the rats with MI (MI + was significantly elevated and the neurohypophysial MLT). It may be therefore assumed that MLT inverts content of this neurohormone was then decreased. On the effect of PX with regard to AVP release. the other hand, PX was the reason of inhibited AVP The mechanism(s) underlying the influence on release in the response to plasma hyperosmolality in AVP and OT biosynthesis and release by the pineal salt-loaded rats [17]. gland and its indoleamine, MLT, are still not clear. There are some data supporting the inhibitory in- MLT may cross the blood brain-barrier easily and fluence of MLT on AVP biosynthesis in the hypo- reach the hypothalamus, among others the hypotha- thalamus of pinealectomized rats [47]. In addition, lamic PVN, as well as the pituitary [65, 75]. MLT re- MLT was found to decrease AVP secretion from the ceptors are localized in several rat brain structures NH in the same animals [47]. with high density in the SCN and magnocellular SON In the present study, the CAL procedure realized in and PVN nuclei [92] as well as in pars tuberalis of the pinealectomized rats is the reason for the distinct de- crease of AVP storage seen in the hypothalamus. Si- pituitary [67, 89]. The influence of MLT on AVP multaneously, a significant inhibition of AVP release and/or OT biosynthesis may involve the receptors lo- from the NH into the circulation was also noted in this calized in the SCN; the neural transmission being state. Moreover, OT release is dramatically intensified generated in the SCN and running into the PVN and as a consequence of heart failure in pinealectomized SON [14, 40] may modulate the biosynthesis of both rats. Hence, it is entirely possible that pinealectomy neurohormones. However, a direct MLT influence on completely changes neurohormonal response to the genome of magnocellular neurons cannot be ex- CAL-evoked MI. The differential secretion of both cluded [76]. Some data indicated that MLT may exert neurohormones in pinealectomized and infarcted rats its cellular effects via the cAMP which may act as in- under the influence of MLT is difficult to interpret. tracellular second messenger [5, 63]. It has been noted The relationship between the deficiency of MLT and that MLT inhibits the generation of cAMP in the rat high blood pressure in pinealectomized rats has been pars tuberalis of the pituitary [85]. The studies of described earlier [57]. It could be the cause of abated Wiesenberg et al. [88] show that MLT acts as a ligand AVP release despite the provocation of MI in these for the brain-specific orphan nuclear receptor RZRb, rats. OT secretion can not undergo such regulation. a member of the RZR/ROR family of orphan receptors, On the other hand, the sensitivity of the tissue to MLT however, other studies suggest that the involvement of is changed by PX, the upregulation of MLT receptors these receptors in the mediation of MLT effect is contro- have been observed in SCN and pars tuberalis of pin- versial. Wiesenberg et al. [88] have shown common lo- ealectomized rats. However, 7 days after PX, the calization for MLT receptors in the pineal gland and the number of MLT receptors was decreased [35]. More- SCN and the brain-specific RTR family member RZRb.
1450 Pharmacological Reports, 2012, 64, 14421454 Melatonin and neurohypophysis function in infarcted rats Joanna Ciosek and Jacek Drobnik
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