Effects of oxytocin and angiotensin II on mean arterial pressure and heart rate.

<p>Mean arterial blood pressure (mmHg) and heart rate (beats/min) after 1, 7 and 28 days of subcutaneous infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent medians with interquartile range (n = 5–8). Asterisks (*) indicate significant difference from the control group on the same day (* P<0.05, ** P<0.01). Clear bars represent saline, low dose oxytocin (LDOT) or high dose oxytocin (HDOT) controls, and filled bars represent angiotensin II, or a combination of angiotensin II and low or high dose oxytocin.</p

Effects of oxytocin on angiotensin II-induced renal damage.

<p>Representative Masson’s trichrome stained histological sections of the renal cortex and medulla showing effects of oxytocin on angiotensin II induced renal damage. Pathological changes in the kidney were assessed by histological evaluation of glomerular necrosis, tubular degeneration, necrosis and epithelial sloughing and interstitial fibrosis (‡), and vascular congestion and extravasation (†). The original magnification was x100. Changes in renal function due to intra-renal damage were also evaluated as plasma urea to creatinine ratio and creatinine clearance. Measurements were made 28 days following the infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT), or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent the mean ± SEM (n = 6) and asterisks (*) on bar graphs indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Effects of oxytocin on angiotensin II-induced cardiac hypertrophy.

<p>Representative hematoxylin and eosin stained histological sections of the interventricular septal wall of the heart (original magnification x400) showing changes in cardiac myocyte size, left ventricular mass and heart to body weight ratio. Left ventricular mass index and heart weight were quantified at day 21 and 28 respectively following the infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data on bar graphs represent mean ± SEM (n = 6–8). Asterisks (*) indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Effects of oxytocin and angiotensin II on systolic and diastolic blood pressure.

<p>Systolic and diastolic blood pressure (mmHg) after 1, 7 and 28 days of subcutaneous infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent medians with interquartile range (n = 5–8). Asterisks (*) indicate significant difference from the control group on the same day (* P<0.05, ** P<0.01). Clear bars represent saline, low dose oxytocin (LDOT) or high dose oxytocin (HDOT) controls, and filled bars represent angiotensin II, or a combination of angiotensin II and low or high dose oxytocin.</p

Effects of oxytocin and angiotensin II on plasma urea and creatinine concentrations, and plasma electrolytes and osmolality.

<p>Data represent mean ± SEM, n = 5–6 per group, asterisks (*) and bold indicate significant difference from control group (* P<0.05, ** P<0.01). LDOT, low dose oxytocin; HDOT, high dose oxytocin; AngII, angiotensin-II.</p><p>Effects of oxytocin and angiotensin II on plasma urea and creatinine concentrations, and plasma electrolytes and osmolality.</p

Effects of oxytocin and angiotensin II on plasma ANP and renin concentration.

<p>Plasma ANP and, prorenin and renin concentrations were quantified following the administration of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT) for 28 days. Data represent mean ± SEM (n = 5). Asterisks (*) indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Effects of oxytocin and angiotensin II on myocardial calcineurin activity.

<p>Activity of the myocardial calcium-dependent calcineurin phosphatase was quantified following the administration of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT) for 28 days. Data represent mean ± SEM (n = 5). Asterisks (*) indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Echocardiographic Evaluations of Left Ventricular Dimensions and Function.

<p>Data represent the mean ± SEM, n = 7–8 per group. Asterisks (*) and bold indicate significant difference compared with control (P < 0.05). LDOT, low dose oxytocin; HDOT, high dose oxytocin; AngII, angiotensin II; IVS_s, interventricular septum thickness during systole; IVS_d, interventricular septum thickness during diastole; LVID_s, left ventricular internal diameter during systole; LVID_d, left ventricular internal diameter during diastole; PW_s, left ventricle posterior wall thickness during systole; PW_d, left ventricle posterior wall thickness during diastole; FS, fractional shortening; EF, ejection fraction.</p><p>Echocardiographic Evaluations of Left Ventricular Dimensions and Function.</p

Molecular Validation of the Acute Phencyclidine Rat Model for Schizophrenia: Identification of Translational Changes in Energy Metabolism and Neurotransmission

Administration of the noncompetitive <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents is widely used as preclinical model for schizophrenia. Most studies on this model employ methods investigating behavior and brain abnormalities. However, little is known about the corresponding peripheral effects. In this study, we analyzed changes in brain and serum molecular profiles, together with alterations in behavior after acute PCP treatment of rats. Furthermore, abnormalities in peripheral protein expression of first and recent onset antipsychotic free schizophrenia patients were assessed for comparison with the preclinical model. PCP treatment induced hyperlocomotion and stereotypic behavior, which have been related to positive symptoms of schizophrenia. Multiplex immunoassay profiling of serum revealed molecular abnormalities similar to those seen in first and recent onset, antipsychotic free schizophrenia patients. Also, increased insulin levels were detected after administration of a glucose tolerance test (GTT), consistent with previous studies showing changes in insulin signaling in patients with schizophrenia. Finally, schizophrenia-relevant alterations in brain molecules were found in the hippocampus and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and ¹H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia

Molecular Validation of the Acute Phencyclidine Rat Model for Schizophrenia: Identification of Translational Changes in Energy Metabolism and Neurotransmission

Administration of the noncompetitive <i>N</i>-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents is widely used as preclinical model for schizophrenia. Most studies on this model employ methods investigating behavior and brain abnormalities. However, little is known about the corresponding peripheral effects. In this study, we analyzed changes in brain and serum molecular profiles, together with alterations in behavior after acute PCP treatment of rats. Furthermore, abnormalities in peripheral protein expression of first and recent onset antipsychotic free schizophrenia patients were assessed for comparison with the preclinical model. PCP treatment induced hyperlocomotion and stereotypic behavior, which have been related to positive symptoms of schizophrenia. Multiplex immunoassay profiling of serum revealed molecular abnormalities similar to those seen in first and recent onset, antipsychotic free schizophrenia patients. Also, increased insulin levels were detected after administration of a glucose tolerance test (GTT), consistent with previous studies showing changes in insulin signaling in patients with schizophrenia. Finally, schizophrenia-relevant alterations in brain molecules were found in the hippocampus and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and ¹H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia