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1 Department of Pharmacology and Toxicology, Wright State University School of Medicine, Dayton, Ohio,2 Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic and3 Department of Physiological Sciences, Fundacao Faculdade Federal de Ciencias Medicas, Porto Alegre, Brazil
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Abstract |
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(Received 25 March 2004;
accepted after revision 27 May 2004; first published online 7 June 2004)
Corresponding author M. Morris: Department of Pharmacology and Toxicology, Wright State University School of Medicine, 3640 Colonel Glenn Highwayy, Dayton, OH 45435, USA. Email: mariana.morris{at}wright.edu
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Introduction |
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One way in which to investigate the function of oxytocin is by using OT-deficient mice (Young et al. 1996). These mice are able to procreate, but not to nurse their young. They are characterized by changes in social behaviour and salt appetite (Winslow et al. 2000; Puryear et al. 2001). Cardiovascular studies in oxytocin knockout (OTKO) mice indicate that there are changes in autonomic balance, seen as enhanced baroreflex function, and greater responses to cholinergic blockade (Michelini et al. 2003). OT is also a stress-reactive hormone. Elevated plasma and central levels of OT have been found in a variety of stress models (Lang et al. 1983; Callahan et al. 1992; Jezova et al. 1995; Nishioka et al. 1998) and there are diurnal changes in stress responsiveness (Carter & Lightman, 1986; Key et al. 2003). There is also evidence for a role of central OT in the mediation of cardiovascular and endocrine responses to stress. Hypothalamic lesions or treatment with OT peptide antisense oligonucleotides resulted in attenuation of the heart rate response to immobilization and shaker stress (Callahan et al. 1992; Morris et al. 1995).
The objective of this study was to use the oxytocin gene deletion model to study the role of OT in the cardiovascular and endocrine responses to stress. We employed shaker stress because it provides a mild, reproducible stimulus, which activates the cardiovascular system and adrenal axis (Nakata et al. 1993; Bernatova et al. 2002). Experiments were conducted in male OTKO mice with chronic carotid arterial catheters for continuous cardiovascular recording. Since previous studies had shown that there was a diurnal variation in stress-induced blood pressure changes and oxytocin secretion (Bernatova et al. 2002; Key et al. 2003), we examined the time course of the cardiovascular responses during the light (sleeping) and dark (active) periods of the day. In addition, we examined the effect of chronic stress on adrenal corticosterone (Cort) secretion, water and food intake and body weight.
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Methods |
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Adult male control (wild type, OT+/+) and OTKO (OT–/–) mice with baseline body weights of 24 ± 1 g were used for this study (n= 6–7 per group). Colony founders were produced by W. S. Young III and colleagues (NIH, Bethesda, MD, USA; Young et al. 1996). Mice were bred in our animal facility using heterozygous (OT+/–) parents. Thus, the experimental animals have the same genetic and environmental background. Mice were genotyped using DNA prepared from tail extracts with a polymerase chain reaction (Young et al. 1996). Mice were housed individually at 22°C on a 12 h–12 h dark–light cycle (05.00–17.00 h lights on, 300–350 Lx). Mice were maintained on a standard pellet diet (Harlan Teklad, 0.5% sodium by weight) and tap water, ad libitum. All experiments were approved by Wright State University's Laboratory Animal Care and Use Committee.
Mice were prepared with chronic catheters that were inserted into the left common carotid artery according to the method of Li et al. (1999) under ketemine–xylazine anaesthesia (5:1 mg kg–1, I.M.). A ventral mid-line skin incision (
2 cm long) was made in the neck and the submaxillary glands were separated. The left common carotid artery was isolated under a binocular surgical microscope and a catheter was inserted into the carotid artery. After surgery, a heparinized saline solution (80 U ml–1) was continuously infused into the catheter at 25 µl h–1 using a syringe pump (Model 220, Kd Scientific, Boston, MA, USA). The catheter (Micro-Renathane, MRE-025, Braintree Scientific, Inc., Braintree, MA, USA) was covered with a metal spring that was attached to a fluid swivel at the top of the cage. Mice were allowed to recover from surgery for at least 6 days before experimentation, by which time water and food intake had returned to basal levels.
Shaker stress
The animals' home cages were inserted into a specially designed cage rack, which was attached to the shaking platform (Model 5901; Eberbach Inc., Ann Arbor, MI, USA). The device was computer activated to provide intermittent shaker stress, 2 min of shaking (150 cycles min–1; 2.8 cm stroke) followed by variable rest periods from 13 to 45 min (30 min average). The variable rest periods between shaking sessions were chosen with the aim of introducing unpredictability to the stress exposure. The animals were exposed to 45 shaking sessions per 24 h for 7 days. A previous study in C57BL mice showed that this stress protocol produced only small changes in body weight and the diurnal pattern of water consumption (Bernatova et al. 2002).
Plasma corticosterone
Plasma corticosterone (Cort) levels were compared in control and OTKO mice before stress exposure and after 7 days of stress (30 min after the last stress session, 09.30 h). Blood samples (40 µl) were collected directly from the carotid arterial catheter into heparinized haematocrit tubes. After centrifugation (10 min, 1000 g, 4°C), plasma samples were stored at –30°C until assays were conducted. Plasma Cort was measured using the ImmuChemTM double antibody corticosterone 125I RIA kit (ICN Biochemicals, Inc. Costa Mesa, CA, USA). The assay required less than 5 µl of plasma.
Body weight, food intake and drinking activity
Body weight (BW), food intake and drinking activity were measured before stress exposure (Basal), on stress days 1, 3 and 7 (S1, S3 and S7) and on day 1 of recovery. Food intake was measured by daily weighing of the food. Drinking (licking activity) was recorded using a drinkometer system (Columbus Instruments, Columbus, OH, USA) interfaced with the computerized data acquisition system (MP 150, Biopac Systems Inc., Santa Barbara, CA, USA; Puryear et al. 2001). Circadian data of licking activity were recorded with a sampling rate of 85 Hz and converted from digital to numeric form using acquisition software. Data were processed by calculation of 10 min means, which were averaged for calculation of the dark and light period means. Incidental contacts of mice with the water bottles, registered as single data points, were excluded from the analysis.
Cardiovascular measurements
BP and HR were recorded continuously (24 h) on S1, S3 and S7 and on the day before and after stress (Basal and Recovery) using the chronic carotid arterial catheter that was connected to a pressure transducer (DCX III, Maxxim Medical, Athens, TX, USA). Systolic BP and diastolic BP (for calculation of mean arterial pressure, MAP) and HR were recorded (sampling rate 85 Hz) and converted from digital to numeric form using acquisition software (MP 150, Biopac Systems Inc., Santa Barbara, CA, USA). Data were processed by calculation of 10 min means of the respective variables. These 10 min means were averaged for calculation of the dark and light period means.
Pressor reactivity
Immediate responses of MAP during individual shaking sessions were evaluated before initiation of stress (Basal, without stress), on S1, S3 and S7 and during Recovery (day 1 after cessation of stress). The tests were made during the light and dark periods (08.00 and 19.00 h, respectively). This experimental design (automatic stress delivery and continuous cardiovascular recording) allows for easy measurement during the day–night cycle. Responses were calculated as the values during baseline (2 min preceding shaking), during shaking (2 min) and 16 min after shaking (divided into two 8 min periods).
Statistical analysis
All results are presented as means ±S.E.M. Multifactorial ANOVA and Duncan's test were used for evaluation of differences. Values were considered to differ significantly if P < 0.05.
Differences in plasma Cort were evaluated using 2-way ANOVA (treatment x genotype). BW and food intake were analysed by 2-way ANOVA (genotype x day of experiment). Drinking activity was analysed using 3-way ANOVA (genotype x treatment x day phase). Alterations of 24 h MAP and 24 h HR were analysed using 3-way ANOVA (genotype x day of experiment x day phase). Pressor responses were analysed using 4-way ANOVA (genotype x day of experiment x day phase x time course).
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Results |
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Basal Cort concentrations in control and OTKO mice were not different (29 ± 4.5 versus 18 ± 1.5 ng ml–1, respectively; P= 0.64, Fig. 1). The main effect of treatment showed that stress produced significant increases in plasma Cort (F1,20= 26.0, P < 0.0001). There was also a significant effect of genotype, with a lower plasma Cort response in OTKO mice (F1,20= 6.9, P < 0.02). The Cort increase in controls was 400%, compared to 300% in OTKO mice after 7 days of stress (P < 0.005).
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There were no observed differences in body weight and food intake between the groups (Table 1). Stress significantly decreased drinking activity (F4,114= 9.8, P < 0.0001), but, there were no genotype-related differences (Table 1). Drinking activity was elevated during the dark period (F1,114= 651.1, P < 0.0001, main effect of day phase). Average licking activity was more than 5 times greater in the dark than in the light period (2779 ± 84 versus 506 ± 52 licks per 12 h; P < 0.0001).
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In order to analyse the effect of stress on cardiovascular function, we used 24 h MAP and HR recordings, data pooled for dark and light periods. Basal MAP in controls was 111 ± 2 and 104 ± 3 mmHg during dark and light periods, respectively (Fig. 2). In OTKO mice, basal MAP was 106 ± 2 and 100 ± 1 mmHg during dark and light periods, respectively. The MAP of OTKO mice was significantly lower than that of controls (F1, 102= 24.55, P < 0.0001, main effect of genotype). There was a significant diurnal difference in MAP in both genotypes (F1,102= 98.2, P < 0.0001, main effect of day phase) with higher MAP during the dark period (P < 0.0001). Twenty-four hour MAP was elevated significantly in OTKO mice on S1 and S3 (P < 0.05), while there were no changes in controls.
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For analysis of cardiovascular stress responsiveness, we measured MAP changes produced by shaker stress delivered during the dark and light periods (08.00 and 19.00 h, Figs 4 and 5, respectively). The analysis confirmed that MAP was lower in OTKO mice (F1,392= 12.25, P < 0.0006, main effect of genotype). There were significant increases in MAP (F4,392= 17.04, P < 0.0001, main effect of day of experiment) on stress days 1, 3 and 7 versus basal values (P < 0.01 during all days). A diurnal pattern in MAP was observed in both groups (F1,392= 140.48, P < 0.0001, main effect of day phase) with higher blood pressure noted during the dark period (P < 0.0001 versus light period). Analysis of the main effect of time course (F3,392= 30.98, P < 0.0001) revealed significant pressor responses during the shaking event (P < 0.0001, shaking versus baseline) with a gradual decrease in MAP after cessation of shaking. However, MAP in the time period 9–16 min postshaking was still significantly higher than baseline (P < 0.04).
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In the light period, the immediate pressor responses during shaker stress were similar in both genotypes on all days (+23–31%versus baseline, P < 0.001; Fig. 5) and the pressor responses were maintained through day 7. Overall pressor responses (composite of MAP, before, during and after shaking) were seen in OTKO mice on all stress days (P < 0.005, all stress days versus basal) and even during the recovery period (P < 0.01 versus basal). Overall pressor responses in controls were elevated only on S1 and S3 (P < 0.03 versus basal).
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Discussion |
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There is increased interest in the idea that OT acts as a cardiovascular hormone. This has been spurred by studies which show that OT and its receptors are present in the heart and vasculature and that OT has effects on blood pressure and salt intake (Uvnas-Moberg, 1998; Gutkowska et al. 2000; Michelini, 2001; Puryear et al. 2001). Our studies have focused on the use of OTKO mice for evaluation of the role of OT in cardiovascular function. Results show that OTKO mice have reduced baseline blood pressure, enhanced baroreflex gain and increased pressor response to OT infusion (Rigatto et al. 2003; Michelini et al. 2003). The data suggest that endogenous OT functions as a vasopressor peptide, similar to its complimentary peptide, vasopressin. This is supported by a study which showed that microinjection of OT into the rostral ventrolateral medulla produced a marked hypertension (Mack et al. 2002), in contrast to the lack of change produced by intracisternal OT injection (Petty et al. 1985). Peripheral injection of OT also affects blood pressure, although the responses are variable, with evidence for both pressor and depressor responses (Petty et al. 1985; Petersson et al. 1996; 1999,). Baroreflex function, controlled by brainstem pathways, is modulated by oxytocinergic input. Higa and coworkers reported that OT and OT antagonists injected into the nucleus of the solitary tract and dorsal motor nucleus of the vagus of conscious rats produced opposite effects on baroreflex activity, accentuation or inhibition, respectively (Higa et al. 2002). In contrast, OT injected intracisternally produced a decrease in baraoreflex index (Petty et al. 1985). Our studies in OTKO mice also suggest that OT inhibits baroreflex function, assuming that there is a direct relationship between the change produced by OT deficiency and the physiological action of the peptide
(Higa et al. 2002). The mechanism(s) by which a deficit in OT secretion affects blood pressure and heart rate are not known. While OTKO mice have lower blood pressure than controls, there is not a generalized decrease in BP sensitivity to pressor and depressor stimuli, suggesting that vascular responsiveness is not altered (Michelini et al. 2003). Sodium/osmolar balance affects cardiovascular status; however, there are no demonstrable changes in haematocrit, osmolality or sodium balance in OTKO mice (Amico et al. 2001; Puryear et al. 2001; Goldstein et al. 2002). There is evidence for an enhancement in salt appetite under basal conditions and in response to volume depletion (Puryear et al. 2001; Rigatto et al. 2003), suggesting that there are changes in the central sensing mechanisms. The effects of OT on the heart may also play a role in its cardiovascular actions. OT stimulates cardiac atrial natriuretic peptide (ANP) secretion, resulting in natriuresis (Verbalis et al. 1991; Gutkowska et al. 2000), and elicits direct effects to cause bradycardia and decreased strength of cardiac contraction (Gutkowska et al. 2000; Mukaddam-Daher et al. 2001). However, if OT is critical in the maintenance of ANP secretion, one would predict decreased levels of ANP in OTKO mice, resulting in volume expansion and hypertension, and increased heart rate. These effects were not observed in the OTKO strain. The finding of reduced 24 h MAP and HR in OTKO mice suggests that the central actions of OT may outweigh its peripheral actions. This is supported by a study which showed that microinjection of OT into the rostral ventrolateral medulla produced an increase in heart rate (Higa et al. 2002).
Interactions between the renin–angiotensin system and OT were suggested by the results of studies testing the effect of haemorrhage in dogs. OT treatment prevented haemorrhage-induced hypotension, an effect that was associated with increased plasma renin activity (Brooks et al. 1984). We found that intracerebroventricular injection of angiotensin produced pressor responses in OTKO mice, which were equivalent to those in controls (Rigatto et al. 2003). This indicates that increased sensitivity of central angiotensin signaling cannot explain the blood pressure status. Analysis of cardiovascular stress responsiveness revealed a marked increase in the pressor response when the stress was delivered during the light period (nonactive, sleeping phase for rodents). This diurnal rhythm in stress reactivity confirms the results of a previous study which used C57BL6 mice (Bernatova et al. 2002). It is interesting that, in addition to the pressor rhythm, stress-induced OT secretion is also coordinated with the light cycle (Carter & Lightman, 1986; Key et al. 2003). We found that shaker stress increased plasma OT only when it was administered during the light period. The HPA axis was still active, since stress stimulation of Cort was similar during the light and dark periods (Key et al. 2003). It is thought that the differential changes in stress responsiveness may be associated with changes in the autonomic nervous system. In the light period, when sympathetic outflow is depressed, the pressor response to the same stressor may be higher than during the dark period, when sympathetic drive is active and basal BP is higher. These time-related changes in stress reactivity may have clinical implications related to the timing of cardiovascular pathologies (Muller, 1999).
Although both groups showed diurnal differences in BP reactivity, OTKO mice showed an enhanced BP response to stress. Stress-induced pressor responses during the light period were seen in OTKO mice on all stress days, continuing into the recovery period. In the dark period, a time at which stress reactivity is at a nadir, OTKO mice showed pressor responses on stress days 1 and 3. In controls there were no stress-induced blood pressure changes during the dark period. Similarly, studies in nursing mothers, with physiologically increased OT levels, demonstrated that high plasma OT levels were associated with a reduced BP response to stress (Light et al. 2000). Together, these data support the idea that OT may act as an antistress hormone with regard to the cardiovascular axis.
Investigation of the HPA axis showed that plasma Cort levels were similar under basal conditions, while OTKO mice were less responsive to chronic stress. Previous studies also showed interactions between the OT and HPA axes. In rats, central OT administration blunted noise stress-induced Cort release (Windle et al. 1997; Lightman & Young, 1989), while there was an enhanced CNS effect of acute restraint stress in OTKO mice (Nomura et al. 2003). These studies using OT supplementation and genetic deficiency indicate that OT may inhibit the endocrine stress response. In our studies, there was a marked decrease in stress-induced Cort release in mice lacking OT. However, one difference between these studies is the use of acute versus chronic stress stimulation. Assuming that OTKO mice are hyper-responsive to acute stressors (Nomura et al. 2003), it is feasible that chronic stress exposure (315 sessions per 7 days) may produce HPA exhaustion.
There is other evidence which supports a positive effect of OT on the HPA axis. In vitro studies showed that OT may augment the effect of corticotrophin-releasing hormone on ACTH secretion. There was a reduction in stress-induced ACTH levels when OT was neutralized with a specific antiserum, a type of pharmacological knockout (Gibbs, 1985). These data fit with our findings of lower stress-induced Cort responses in OTKO mice. We assume that the lack of OT may result in attenuation of ACTH-dependent Cort release. However, additional studies are needed to determine the mechanisms by which the endocrine systems interact to regulate stress responsiveness.
In conclusion, deletion of the OT gene and protein altered the endocrine and cardiovascular responses to chronic stress in mice. Shaker stress-induced pressor responses were more pronounced in OTKO mice despite a lower basal MAP and reduced Cort responses. We hypothesize that endogenous OT may play a protective role by attenuation of stress-induced cardiovascular changes.
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References |
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) on the same day, #P < 0.03 versus S1 shaking (
). The overall effect of stress exposure (average of all bars) was significant versus overall basal values before initiation of chronic stress (B) if denoted by ‘x’ under day (P < 0.03).