Plasma Vasopressin Levels Research Articles

Excretion of urinary exosomal AQP2 in rats is regulated by vasopressin and urinary pH

Urinary exosomes are small vesicles secreted into urine from all renal epithelial cell types and known to contain proteins that are involved in renal secretion and reabsorption. Among these proteins, urinary exosomal aquaporin-2 (AQP2) has been suggested to be useful for diagnosis of renal disease. However, the mechanisms underlying the excretion of urinary exosomal AQP2 are largely unknown. In this study, we examined the mechanisms of urinary exosomal AQP2 excretion in vivo, using diuretics including furosemide (FS), an inhibitor of the sodium-potassium-chloride symporter; acetazolamide (ACTZ), an inhibitor of carbonic anhydrase; OPC-31260 (OPC), a vasopressin type 2 receptor antagonist; and NaHCO3, a urinary alkalizing agent. Samples of urine from rats were collected for 2 h just after treatment with each diuretic, and urinary exosomes were isolated by ultracentrifugation. Urinary exosomal AQP2 excretion was dramatically increased by treatment with FS accompanied by urine acidification or with ACTZ accompanied by urine alkalization. Immunohistochemistry showed that apical localization of AQP2 was clearly evident and the plasma vasopressin level was increased after each treatment. Although treatment with OPC alone had no significant effect, coadministration of OPC completely inhibited the FS-induced and partially reduced the ACTZ-induced responses, respectively. Treatment with NaHCO3 increased the excretion of urinary exosomal AQP2 accompanied by urine alkalization. This increased response was partially inhibited by coadministration of OPC. These data suggest that an increased plasma level of vasopressin promoted the excretion of urinary exosomal AQP2 and that urine alkalinization also increased it independently of vasopressin.

Long-term programming of enhanced aggression by peripuberty stress in female rats

Human literature has linked adverse early life experiences with an increased risk to develop violent behaviors in both boys and girls. We have previously shown that male rats submitted to stress during the peripuberty period display as adults abnormal aggressive behavior against both male intruders and female partners. In the present study, we examined whether the same stress protocol would affect the development of aggressive behaviors in female rats. We evaluated the behavior of these peripuberty stressed female rats when confronted, at adulthood, with either female or male intruders, and during their cohabitation with male partners. Given that estrus cycle influences mood and aggressive behaviors, female aggressive behavior was assessed at different estrus cycle phases: estrus and diestrus, and during pregnancy and lactancy. Additionally, we evaluated postpartum plasma levels of vasopressin, oxytocin and corticosterone, hormones associated with aggression and the regulation of social behavior. Compared to control females, females submitted to stressful events during puberty exhibited higher and more sustained rates of aggression during adulthood independently on the estrus cycle or the sex of the intruder, and they had higher levels of plasma vasopressin. Significant correlations between plasma levels of vasopressin and corticosterone and aggressive behavior were also found. Strikingly, our results showed opposite intragroup correlations suggesting a different role of these hormones on aggression depending on life experiences. We provide here an animal model, devoid of cultural influences strongly supporting a role for biological factors in the development of aggressive behaviors following exposure to stressful events at puberty in females.

Interactions of Enhanced Urocortin 2 and Mineralocorticoid Receptor Antagonism in Experimental Heart Failure

Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. Ucn2 and an MRA (canrenoic acid [CA]) were infused for 4 hours, both singly and together, in 8 sheeps with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance but without eliciting a supplementary reduction in arterial pressure. Ucn2 cotreatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II, and vasopressin concentrations. Although both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2- to 3-fold greater than that elicited by separate CA. Ucn2 cotherapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 cotreatment reduced potassium concentrations. Ucn2 cotreatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, while also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF.

Psychological condition in patients with intractable Meniere's disease

Conclusions: Physicians should consider additional treatment strategies for Meniere's disease patients with a long history of disease and hearing loss in the secondary affected ear and also provide psychological support regarding future progressive bilateral hearing loss. Objectives: To treat intractable Meniere's disease patients effectively, we need to understand the psychological condition of each patient. We examined the state of neurosis and depression in patients and correlated this with demographic and background information. Methods: Between 1998 and 2009, we enrolled 207 patients with intractable Meniere's disease in this prospective study. We used the Cornell Medical Index and the Self-rating Depression Scale to evaluate their psychological condition. We also obtained demographic and background information relating to sex, age, duration of disease, vertigo frequency, hearing level in bilateral sides, and plasma vasopressin level. Results: Neurosis and depression was diagnosed in 40.1% and 60.4%, respectively, of patients with intractable Meniere's disease. Our results showed that surgical treatment significantly improved vertigo and hearing ability in patients with no psychological symptoms compared with those exhibiting psychological symptoms. Patients with a longer duration and worse hearing level in the secondary affected ear had a significantly higher incidence of mental illness than those with a shorter duration and better level of hearing.

Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality

The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 ± 1, vs. sham: 22 ± 2 c-Fos/AVP cells) and SON (26 ± 4, vs. sham: 11 ± 1 c-Fos/AVP cells), plasma vasopressin levels (21 ± 8, vs. sham: 6.6 ± 1.3 pg/ml), pressor responses (25 ± 7 mmHg, vs. sham: 7 ± 2 mmHg), water intake (17.5 ± 0.8, vs. sham: 11.2 ± 1.8 ml/2 h), and natriuresis (4.9 ± 0.8, vs. sham: 1.4 ± 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 ± 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality.

Vasopressin V1A receptors mediate the increase in gastric mucosal oxygenation during hypercapnia

Hypercapnia (HC) improves systemic oxygen delivery (DO₂) and microvascular hemoglobin oxygenation of the mucosa (μHbO₂). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V(1A) receptor blockade ([Pmp¹,Tyr(Me)²]-Arg⁸-Vasopressin, 35 μg/kg) on hemodynamic variables and μHbO₂ during normocapnia or HC (end-tidal CO₂ 70 mmHg). In a control group, animals were subjected to HC alone. μHbO₂ was measured by reflectance spectrophotometry, systemic DO₂ was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean±s.e.m. for n=5 animals. During HC alone, DO₂ increased from 12±1 to 16±1 ml/kg per min and μHbO₂ from 70±4 to 80±2%. By contrast, additional vasopressin V(1A) receptor blockade abolished the increase in μHbO₂ (80±2 vs. 69±2%) without altering the increase in DO₂ (16±1 vs. 19±2 ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO₂ (13±1 vs. 14±1 ml/kg per min) nor μHbO₂ (75±3 vs. 71±5%). Vasopressin V(1A) receptor blockade abolished the increase in μHbO₂ during HC independent of DO₂. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC.

Circulating levels of copeptin predict outcome in patients with pulmonary arterial hypertension

ObjectiveTo determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment.BackgroundVasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH.MethodsSerum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome.ResultsCirculating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02).ConclusionsPatients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH.

Neurohypophyseal response to fluid resuscitation with hypertonic saline during septic shock in rats

Septic shock is a serious condition with a consequent drop in blood pressure and inadequate tissue perfusion. Small-volume resuscitation with hypertonic saline (HS) has been proposed to restore physiological haemodynamics during haemorrhagic and endotoxic shock. In the present study, we sought to determine the effects produced by an HS infusion in rats subjected to caecal ligation and perforation (CLP). Male Wistar rats were randomly grouped and submitted to either CLP or sham surgery. Either HS (7.5% NaCl, 4 ml kg(-1) i.v.) or isotonic saline (IS; 0.9% NaCl, 4 ml kg(-1) i.v.) was administered 6 h after CLP. Recordings of mean arterial pressure and heart rate were made during this protocol. Moreover, measurements of electrolyte, vasopressin and oxytocin secretion were analysed after either the HS or the IS treatment. Six hours after CLP, we observed a characteristic decrease in mean arterial pressure that occurs after CLP. The HS infusion in these rats produced a transient elevation of the plasma sodium concentration and osmolality and increased plasma vasopressin and oxytocin levels. Moreover, the HS infusion could restore the mean arterial pressure after CLP, which was completely blunted by the previous injection of the vasopressin but not the oxytocin antagonist. The present study demonstrated that rats subjected to CLP and an infusion of hypertonic saline respond with secretion of neurohypophyseal hormones and a transient increase in blood pressure mediated by the V(1) receptor.

Cytochrome P450 1B1 Gene Disruption Minimizes Deoxycorticosterone Acetate-Salt–Induced Hypertension and Associated Cardiac Dysfunction and Renal Damage in Mice

Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt–induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA-salt–induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type ( Cyp1b1 +/+ ) mice that were minimized in Cyp1b1 −/− mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1 +/+ but not in Cyp1b1 −/− mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt–treated Cyp1b1 −/− mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids.

Syndrome of Inappropriate ADH Secretion and Severe Osteoporosis

Recent studies indicate an association between hyponatremia and osteoporosis. We report a clinical case that supports this statement. A 36-yr-old man was diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) at the age of 22. In the years that followed, sodium levels in the blood remained low from 111-130 mmol/liter (137-144). At the age of 34, he was diagnosed with osteoporosis after a magnetic resonance imaging scan showed moderate compression fractures at Th9-11 and L2. A dual energy x-ray absorptiometry scan showed a Z-score of -3.9 at the lumbar spine (L3-L4) and a Z-score of -1.3 in the total hip. He had no other known risk factors for osteoporosis. Urinary excretion of calcium and sodium were elevated. Plasma vasopressin level was inappropriately elevated. One year after treatment with 5-mg zoledronic acid, there has been no significant change in the bone mineral density in the lumbar spine and a small increase in bone mineral density in the total hip. The symptoms from SIADH have not changed. The case illustrates that severe idiopathic SIADH and chronic hyponatremia can have severe side effects on bone metabolism and can lead to secondary osteoporosis. We support the recommendation that patients with chronic SIADH should be screened for osteoporosis and suggest that early bone protective treatment should be considered to reduce or delay osteoporosis onset.

Ethanol consumption impairs the hemodynamic response to hemorrhagic shock in rats

Alcohol intoxication can exacerbate hemodynamic instability following hemorrhagic shock. Impairment of hormonal, neurohumoral, and immune responses can contribute to such instability; however, the relationship between blood alcohol levels and the progression of hemorrhagic shock accompanied with these responses has not been clearly demonstrated. Herein, we examined this relationship in rats treated with various dose of alcohol. After oral administration of alcohol and then hemorrhage, the recovery of mean blood pressure (MBP); increase in plasma level of norepinephrine, epinephrine, and vasopressin; and survival interval decreased in a dose-dependent manner as the blood alcohol level increased. There were no significant differences in the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β among the groups. The present results demonstrated alcohol aggravates hemorrhagic shock in a dose-dependent manner not by alerting the immune response, but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic autoregulation and shortening the survival interval.

30. Plasma oxytocin and vasopressin and social functioning

In animal studies, the neuropeptides oxytocin and vasopressin have been implicated in social behaviors. In humans, plasma levels of oxytocin covary with perceptions of relationship quality, but little is known about the association between plasma vasopressin and social behaviors in humans. The goal of this study was to evaluate the relationships among plasma oxytocin and vasopressin and self-reported social functioning. Thirty-seven couples completed measures of social functioning and provided blood samples for neuropeptide analysis during a 24-hour admission to a hospital-based research unit. Higher plasma oxytocin was associated with less hostility among men, p = .001, but not women, p = .67. Across both men and women greater levels of vasopressin were associated with larger social networks, p = .05, less negative spousal interactions, p = .03, less attachment avoidance, p = .03, more attachment security p = .04, and marginally with greater spousal social support, p = .06. Overall, higher social functioning was associated with greater plasma vasopressin levels. This study provides evidence that plasma vasopressin levels have small, but significant associations with dimensions of social functioning in humans.

Abstract 213: Neuron-specific (Pro)renin Receptor Deletion Attenuates Neurogenic Hypertension and is Associated With Improvement of Autonomic Function

Although (pro)renin receptor (PRR) is highly expressed in the brain, the physiological importance of brain PRR remains to be determined. We previously showed that PRR mRNA levels were up-regulated in the brain regions involved in blood pressure (BP) regulation including the subfornical organs (SFO), paraventricular nuclei (PVN), and rostral ventrolateral medulla (RVLM) in the DOCA-salt-induced hypertensive mice. To elucidate whether the increase of PRR expression contributes to the development of hypertension, we developed a neuron-specific PRR knockout mouse (Nefh-PRR) model by crossing PRR-floxed mice with mice that express Cre-recombinase with neurofilament-H (Nefh-Cre) promoter. Immunostaining showed that PRR expression was significantly reduced in cardiac regulatory brain regions including SFO (0.35± 0.15), PVN (0.34 ± 0.09), and RVLM (0.41 ± 0.1), where the Cre-recombinase was expressed, in Nefh-PRR compared to Nefh-cre mice (1 ± 0.1, 1 ± 0.19 and 1 ± 0.06). Nefh-PRR mice and Nefh-cre mice with wild type PRR gene (WT, n=8/group) were implanted with telemetric probes. BP (mmHg) and heart rate (HR, bpm) were recorded for baseline and following DOCA-salt treatment (50mg DOCA, 0.9%NaCl drinking solution, 21 days). Nefh-PRR mice exhibited normal baseline BP and HR. Following DOCA-salt treatment, BP was significantly lower in Nefh-PRR mice (108 ± 3) compared to WT mice (132 ± 6, P&lt;0.05). The cardiac sympathetic tone (HR response to propranolol, ΔHR: -128±46vs. -180±45) and the vasomotor sympathetic tone (BP response to chlorisondamine, ΔBP: -46 ±17vs.-68± 12) were lower in Nefh-PRR than WT mice after DOCA-salt treatment. Moreover, HR response to methylatropine (ΔHR: 98±38 vs. 43±19) was greater in Nefh-PRR. In addition, DOCA-salt treatment increased plasma vasopressin (AVP) levels (33.6 ± 5.3 vs.3.0 ± 0.3pg/ml) in WT mice. PRR deletion significantly attenuated the increase in plasma AVP levels (19.0 ± 2.0pg/ml) induced by DOCA-salt. The data suggest PRR deletion prevents the development of DOCA-salt hypertension and is associated with reduction of plasma AVP levels and improvement of autonomic function. We conclude that brain PRR may be a novel therapeutic target for the treatment of hypertension.

Plasma vasopressin and interpersonal functioning

The neuropeptide vasopressin has traditionally been associated with vasoconstriction and water reabsorption by the kidneys. However, data from experimental animal studies also implicate vasopressin in social bonding processes. Preliminary work suggests that vasopressin also plays a role in social behaviors in humans. The goal of this cross-sectional study was to evaluate associations among plasma vasopressin and self-reported interpersonal functioning in a sample of married couples. During a 24-h admission to a hospital-based research unit, 37 couples completed measures of interpersonal functioning and provided blood samples for neuropeptide analyses. Results showed that vasopressin was associated with markers of interpersonal functioning, but not with general psychological distress. Specifically, greater plasma vasopressin levels were related to a larger social network, fewer negative marital interactions, less attachment avoidance, more attachment security, and marginally greater spousal social support. These results indicate that vasopressin is likely implicated in different relationship maintenance processes in humans.

Development of Oxytocin- and Vasopressin-Network in the Supraoptic and Paraventricular Nuclei of Fetal Sheep

The hypothalamic supraoptic and paraventricular nuclei consist of oxytocin and arginine vasopressin synthesizing neurons that send projections to the neurohypophysis. A growing body of evidence in adult animals and young animals at near term confirmed the structure and function in the vasopressinergic and oxytocinergic network. However, whether those distinctive neural networks are formed before near term is largely unknown. This study determined the special patterns in location and distribution of oxytocin- and vasopressin-neurons in the paraventricular and supraoptic nuclei from preterm to term in the ovine fetuses. The results showed that oxytocin- and vasopressin-neurons were present in both nuclei at the three gestational time periods (preterm, near term, and term). In the paraventricular nuclei, vasopressin-cells concentrated mainly in the core of the middle magnocellular paraventricular nuclei, and oxytocin-cells were scattered surrounding the core. In the supraoptic nuclei, vasopressin-cells mostly located in the ventral part, and oxytocin-cells in the dorsal part. The data demonstrated that the special distributed patterns of vasopressin- and oxytocin-neuron network have formed in those two nuclei at least from preterm. Intracerebroventricular injection of angiotensin II significantly increased fetal plasma oxytocin and vasopressin levels at preterm, which was associated with an increase of oxytocin- and vasopressin-neuron activity marked with c-fos expression. The data provided new evidence for the structural and functional development of the oxytocin- and vasopressin-network before birth.

Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats

Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

Brain-Targeted (Pro)renin Receptor Knockdown Attenuates Angiotensin II–Dependent Hypertension

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor short hairpin RNA was used to knockdown (pro)renin receptor expression in the brain of nontransgenic normotensive and human renin-angiotensinogen double-transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor, and vasopressin mRNA levels. Plasma vasopressin levels were determined by ELISA. Double-transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor short-hairpin RNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared with the control virus treatment in double-transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double-transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease in sympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with downregulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice.

Central Actions of the Chemokine Stromal Cell-Derived Factor 1 Contribute to Neurohumoral Excitation in Heart Failure Rats

The ample expression of chemokines and their receptors by neurons in the brain suggests that they play a functional role beyond the coordination of inflammatory and immune responses. Growing evidence implicates brain chemokines in the regulation of neuronal activity and neurohormonal release. This study examined the potential role of brain chemokines in regulating hemodynamic, sympathetic, and neuroendocrine mechanisms in rats with ischemia-induced heart failure (HF). Immunohistochemical analysis revealed that the chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 was highly expressed in the hypothalamic paraventricular nucleus and subfornical organ and that SDF-1 expression was significantly increased in HF rats compared with sham-operated (SHAM) control rats. ICV injection of SDF-1 induced substantial and long-lasting increases in blood pressure, heart rate, and renal sympathetic nerve activity in both SHAM and HF rats, but responses were exaggerated in HF rats. Bilateral microinjection of SDF-1 into the paraventricular nucleus also elicited exaggerated increases in blood pressure, heart rate, and renal sympathetic nerve activity in the HF rats. A 4-hour ICV infusion of SDF-1 increased plasma levels of arginine vasopressin, adrenocorticotropic hormone, and norepinephrine in normal rats, responses that were prevented by pretreatment with ICV SDF-1 short-hairpin RNA (shRNA). ICV administration of SDF-1 shRNA also reduced plasma arginine vasopressin, adrenocorticotropic hormone, and norepinephrine levels in HF rats. These data suggest that the chemokine SDF-1, acting within the brain, plays an important role in regulating sympathetic drive, neuroendocrine release, and hemodynamic function in normal and pathophysiological conditions and so may contribute to the neural and humoral activation in HF.

The osmotically and histamine-induced enhancement of the plasma vasopressin level is diminished by intracerebroventricularly administered orexin in rats

The effects of the centrally administered neuropeptides orexin-A on water intake and vasopressin (VP) secretion were studied in male Wistar rats (180-250g). Different doses (10, 30, and 90μg/10μl) of the orexins and the specific orexin receptor-1 (OX(1)) antagonist SB 408124 (30μg/10μl) were administered intracerebroventricularly (i.c.v.) under anaesthesia, and the water consumption was measured during 6h. A plasma VP level elevation was induced by histamine (10mg/kg) or 2.5% NaCl (10ml/kg) administered intraperitoneally (i.p.). The plasma VP levels were measured by radioimmunoassay. Increased water consumption was observed after the administration of 30μg/10μl orexin-A. There were no changes in basal VP secretion after the administration of different doses of the orexins. A significant increase in plasma VP concentration was detected following histamine administration. After 2.5% NaCl administration, there was a moderate VP level enhancement. Intracerebroventricularly administered orexin-A (30μg/10μl) blocked the VP level increase induced by either histamine or 2.5% NaCl administration. The inhibitory effects were prevented by the specific OX(1) receptor antagonist. In conclusion, the orexins increased water consumption. After 30μg/10μl orexin-A administration, the polydipsia was more pronounced. The OX(1) receptor antagonist significantly decreased the polydipsia. Histamine or hyperosmotic VP release enhancement was blocked by previously administered orexin. This inhibition was not observed following OX(1) receptor antagonist administration. Our results suggest that the effects of the orexins on water consumption or blockade of the histamine and osmosis-induced VP level increase are mediated by the OX(1) receptor.

Canine Model of Cardiorenal Failure

The heart and the kidneys act in tandem to regulate blood pressure, vascular tone, diueresis and to maintain intravascular volume homeostasis. Besides, the kidneys have a neuroendocrine function with interdependent physiological actions regulated by the renin-angiotensin-aldosterone system, sympathetic nervous system, and vasopressin and aterial natriuretic peptide. To investigate these complex pathophysiological mechanisms, a canine model for Congestive Heart Failure (CHF) compromised with Renal Dysfunction (RF) was used, to characterize the hemodynamic and neurohumoral aspects of renal function in 21 dogs. Five dogs were used as controls. Bipolar epicardial pacemaker leads were implanted at the apex of the right ventricle in 8 dogs and the dogs were subjected to ventricular pacing at 250-270 beats/min with an external pacemaker (Nihon Kohden) for a period of 11-21 days. This rapid pacing produced CHF. RF was induced by removal of the right kidney with ligation of the small branches of the left kidney in 8 dogs. Three dogs of each of the CHF and RF groups were used to produce CHF and RF in combination; one dog died due to infection. The glomerular filtration rates of the dogs with RF, CHF and CHF+RF were significantly lower than those of the controls, although among the dogs with RF, CHF and CHF+RF, there were no significant differences. In spite of no differences in blood pressure and renal hemodynamics, the levels of plasma renin activity, norepinephrine and vasopressin of CHF+RF group were significantly higher than those of RF and CHF groups. Taken together, these data suggest that in patients with CHF compromised by RF neurohumoral factors are maximally activated.