Increased Arginine Vasopressin Levels Research Articles

THIRSTY FOR FRUCTOSE: Arginine Vasopressin, Fructose, and the Pathogenesis of Metabolic and Renal Disease.

We review the pathways by which arginine vasopressin (AVP) and hydration influence the sequelae of the metabolic syndrome induced by high fructose consumption. AVP and inadequate hydration have been shown to worsen the severity of two phenotypes associated with metabolic syndrome induced by high fructose intake–enhanced lipogenesis and insulin resistance. These findings have implications for those who frequently consume sweeteners such as high fructose corn syrup (HFCS). Patients with metabolic syndrome are at higher risk for microalbuminuria and/or chronic kidney disease; however, it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension, impaired glucose metabolism, and obesity. It is not surprising the prevalence of chronic renal insufficiency is growing hand in hand with obesity, insulin resistance, and metabolic syndrome in those who consume large amounts of fructose. Higher AVP levels and low hydration status worsen the renal insufficiency found in patients with metabolic syndrome. This inter-relationship has public health consequences, especially among underserved populations who perform physical labor in environments that place them at risk for dehydration. MesoAmerican endemic nephropathy is a type of chronic kidney disease highly prevalent in hot ambient climates from southwest Mexico through Latin America. There is growing evidence that this public health crisis is being spurred by greater fructose consumption in the face of dehydration and increased dehydration-dependent vasopressin secretion. Work is needed at unraveling the mechanism(s) by which fructose consumption and increased AVP levels can worsen the renal disease associated with components of the metabolic syndrome.

Chapter 21 - Nocturnal enuresis in children: The role of arginine–vasopressin

Nocturnal enuresis is the involuntary pass of urine during sleep beyond the age of 5 years. It is a common condition in childhood and has an impact on the child's well-being. Research into the pathophysiology of the condition in the last decades has led to a paradigm shift, and enuresis is no longer considered a psychiatric disorder but rather a maturation defect with a somatic background. An excess urine production during sleep is a common finding in children with enuresis and disturbances in the circadian rhythm of arginine-vasopressin (AVP) is found in the majority of children with nocturnal polyuria. Children with enuresis and nocturnal polyuria lack the physiologic increase in AVP levels during sleep and treatment with the AVP analogue desmopressin can restore this rhythm and lead to dry nights. The reasons for this aberrant circadian AVP rhythm are not established. Furthermore, not all children with enuresis and nocturnal polyuria can be successfully treated with desmopressin suggesting that factors beyond renal water handling can be implicated such as natriuresis, hypercalciuria, and sleep-disordered breathing. The advances in the research of the genetic background of the condition may shed further light on the enuresis pathophysiology.

Regulation and role of arginine vasopressin in myocardial infarction/reperfusion

Abstract Background Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction contributes to ischaemia-reperfusion (I-R) injury. One proposed mechanism is a persistent vasoconstrictor tone during MI/reperfusion. Arginine vasopressin (AVP) has a vasoactive effect on the coronary microvessels. Moreover, cardiac AVP synthesis was found in an animal model. To exert vasoconstriction, AVP binds to its receptor 1a (AVPR1a). Aims (i) To analyse the AVP levels during MI/reperfusion (ii) To assess cardiac AVP and AVPR1a expressions in MI/reperfusion mouse models. Methods We took arterial blood samples from ST elevation MI (STEMI) patients admitted to our hospital over the course of MI/reperfusion for AVP levels quantification. We also measured AVP through its more stable surrogate biomarker, copeptin. Cardiac MRI was done to evaluate coronary microvasculature, infarct size, and left ventricular ejection fraction (LVEF) 1 week post-admission. Cardiac AVP and AVPR1a expressions were assessed by polymerase chain reaction (PCR) in mouse models. Results STEMI patients displayed bothAVPand copeptinlevels elevation at baseline (130.8±20.5 pmol/l, n=23) until 90 min post-reperfusion (55.7±6.2 pmol/l, n=23). Their concentrations began to approach normal levels at 24h. Patients with poorer reperfusion outcomes had copeptin concentrations that remained above normal level after 24h following reperfusion. Copeptin levels at 24h post-reperfusion were significantly higher in patients who developed larger infarct size (p=0.004) and lower LVEF (p=0.009). Patients with microvascular obstruction tended to have higher copeptin levels from admission until 24h post-reperfusion. Mouse models showed no cardiac AVP expression but significantly high AVPR1a expression at 2h post-reperfusion. Conclusion In STEMI patients, circulating AVP level is elevated over the course of MI/reperfusion. In MI/reperfusion mouse models, cardiac AVP synthesis is absent but cardiac AVPR1a is upregulated. The combination of delayed decline in AVP concentrations and AVPR1a upregulation may increase the possibility for AVP to mediate I-R injury through microvascular disturbance. Increased AVP levels at 24h post-reperfusion are significantly associated with poor reperfusion outcome. These results warrant further studies concerning the use of AVP receptor antagonist in STEMI patients undergoing reperfusion therapy Copeptin levels and reperfusion outcomes Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Newcastle University MRes Programme

TRPC3 determines osmosensitive [Ca2+]i signaling in the collecting duct and contributes to urinary concentration.

It is well-established that the kidney collecting duct (CD) plays a central role in regulation of systemic water homeostasis. Aquaporin 2 (AQP2)-dependent water reabsorption in the CD critically depends on the arginine vasopressin (AVP) antidiuretic input and the presence of a favorable osmotic gradient at the apical plasma membrane with tubular lumen being hypotonic compared to the cytosol. This osmotic difference creates a mechanical force leading to an increase in [Ca2+]i in CD cells. The significance of the osmosensitive [Ca2+]i signaling for renal water transport and urinary concentration remain unknown. To examine molecular mechanism and physiological relevance of osmosensitivity in the CD, we implemented simultaneous direct measurements of [Ca2+]i dynamics and the rate of cell swelling as a readout of the AQP2-dependent water reabsorption in freshly isolated split-opened CDs of wild type and genetically manipulated animals and combined this with immunofluorescent detection of AVP-induced AQP2 trafficking and assessment of systemic water balance. We identified the critical role of the Ca2+-permeable TRPC3 channel in osmosensitivity and water permeability in the CD. We further demonstrated that TRPC3 -/- mice exhibit impaired urinary concentration, larger urinary volume and a greater weight loss in response to water deprivation despite increased AVP levels and AQP2 abundance. TRPC3 deletion interfered with AQP2 translocation to the plasma membrane in response to water deprivation. In summary, we provide compelling multicomponent evidence in support of a critical contribution of TRPC3 in the CD for osmosensitivity and renal water handling.

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia-ischaemia in near-term fetal sheep.

•Therapeutic hypothermia needs to be started as early as possible in the first 6h after acute injury caused by hypoxia-ischaemia (HI), but the severity and timing of HI are often unclear. In this study we evaluated whether measures of heart rate variability (HRV) might provide early biomarkers of HI. •The duration but not magnitude of suppression of HRV power and conversely increased sample entropy of the heart rate were associated with severity of HI, such that changes in the first 3h did not discriminate between groups. •Relative changes in HRV power bands showed different patterns between groups and therefore may have the potential to evaluate the severity of HI. •Aberrant fetal heart rate patterns and increased arginine vasopressin levels in the first hour after moderate and severe HI were correlated with loss of EEG power after 3days' recovery, suggesting potential utility as early biomarkers of outcome. Therapeutic hypothermia is partially neuroprotective after acute injury caused by hypoxia-ischaemia (HI), likely because the timing and severity of HI are often unclear, making timely recruitment for treatment challenging. We evaluated the utility of changes in heart rate variability (HRV) after HI as biomarkers of the timing and severity of acute HI. Chronically instrumented fetal sheep at 0.85 gestational age were exposed to different durations of umbilical cord occlusion to produce mild (n=6), moderate (n=8) or severe HI (n=8) or to sham occlusion (n=5). Heart rate (HR) and HRV indices were assessed until 72h after HI. All HI groups showed suppressed very low frequency HRV power and elevated sample entropy for the first 3h; more prolonged changes were associated with greater severity of HI. Analysis of relative changes in spectral power showed that the moderate and severe groups showed a shift towards higher HRV frequencies, which was most marked after severe HI. This shift was associated with abnormal rhythmic HR patterns including sinusoidal patterns in the first hour after HI, and with elevated plasma levels of arginine vasopressin, which were correlated with subsequent loss of EEG power by day3. In conclusion, absolute changes in HRV power in the first 3h after acute HI were not significantly related to the severity of HI. The intriguing relative shift in spectral power towards higher frequencies likely reflects greater autonomic dysfunction after severe HI. However, sinusoidal HR patterns and elevated vasopressin levels may have utility as biomarkers of severe HI.

Increased von Willebrand factor parameters in children with febrile seizures.

IntroductionPrimary blood coagulation and wound sealing are orchestrated by von Willebrand factor (VWF), a large multimeric glycoprotein. Upon release of arginine vasopressin (AVP), VWF containing high molecular weight multimers is secreted. By measuring copeptin, the C-terminal part of the AVP prohormone, we recently found strongly increased AVP levels in children with febrile seizures (FS) as compared to children with fever but without seizures. It is unknown if increased AVP levels in FS are of any biological function. Therefore, our a priori hypothesis was that children with FS have increased VWF parameters in parallel with higher AVP levels.MethodsWe conducted a prospective, cross-sectional study of children aged between 6 months and 5 years. Children that presented at our emergency department with fever or a recent FS (within four hours) were evaluated to be included to the study. We measured serum copeptin and VWF parameters, including analyses of VWF:Antigen (WVF:Ag), VWF:collagen binding activity (VWF:CB) and VWF multimers in children with FS, febrile infections without seizures and additionally, in a non-febrile control group.ResultsWe included 54 children in our study, 30 with FS, 10 in the febrile control group, and 14 in the non-febrile control group. Serum copeptin levels were significantly higher in children with FS (median [IQR] 24.73 pmol/l [13.65–68.65]) compared to the febrile control group (5.66 pmol/l [4.15–8.07], p = 0.002) and the non-febrile control group (4.78 pmol/l [3.33–5.3], p<0.001). VWF:CB levels were also significantly higher in children with FS (VWF:CB 2.29 U/ml [1.88–2.97]) as compared to the febrile (VWF:CB 1.41 U/ml [1.27–1.93], p = 0.048) and the non-febrile control group (VWF:CB 1.15 U/ml [0.98–1.21], p<0.001). VWF:Ag tended to be higher in children with FS compared to both control groups. Multivariate regression analysis revealed FS and copeptin as major determinants of VWF:CB.ConclusionsOur results suggest that increased secretion of AVP in children with FS is associated with higher plasma levels of VWF parameters. Especially VWF:CB may serve as additional biomarker in the diagnosis of FS.

Excitatory GABAergic Action and Increased Vasopressin Synthesis in Hypothalamic Magnocellular Neurosecretory Cells Underlie the High Plasma Level of Vasopressin in Diabetic Rats.

Diabetes mellitus (DM) is associated with increased plasma levels of arginine-vasopressin (AVP), which may aggravate hyperglycemia and nephropathy. However, the mechanisms by which DM may cause the increased AVP levels are not known. Electrophysiological recordings in supraoptic nucleus (SON) slices from streptozotocin (STZ)-induced DM rats and vehicle-treated control rats revealed that γ-aminobutyric acid (GABA) functions generally as an excitatory neurotransmitter in the AVP neurons of STZ rats, whereas it usually evokes inhibitory responses in the cells of control animals. Furthermore, Western blotting analyses of Cl- transporters in the SON tissues indicated that Na+-K+-2Cl- cotransporter isotype 1 (a Cl- importer) was upregulated and K+-Cl- cotransporter isotype 2 (KCC2; a Cl- extruder) was downregulated in STZ rats. Treatment with CLP290 (a KCC2 activator) significantly lowered blood AVP and glucose levels in STZ rats. Last, investigation that used rats expressing an AVP-enhanced green fluorescent protein fusion gene showed that AVP synthesis in AVP neurons was much more intense in STZ rats than in control rats. We conclude that altered Cl- homeostasis that makes GABA excitatory and enhanced AVP synthesis are important changes in AVP neurons that would increase AVP secretion in DM. Our data suggest that Cl- transporters in AVP neurons are potential targets of antidiabetes treatments.

A potential biomarker for bipolar I disorder: serum arginine vasopressin levels

Objective: The neuropeptide arginine vasopressin (AVP) has effects on behavior and stress regulations which are impaired in bipolar disorder (BD). Only a very limited number of studies have investigated AVP levels in bipolar disorder in contrast to depressive disorders. The study aimed to investigate serum AVP levels during the manic, depressive, or remission periods and after treatment response in patients with bipolar I disorder (BD-I) and healthy controls. Methods: The study consisted of 67 patients with BD-I and 24 healthy controls. The patients were in the manic, depressive, or remission periods of BD-I. Serum AVP levels were assayed in the three groups of patients with BD-I and the controls at the study onset. Then, a second measurement of the AVP levels were carried out in the manic or depressive periods after treatment response. The treatment response was defined as a 50% decrease in the Young Mania Rating Scale and the Hamilton Depression Rating Scale scores for manic and depressive episodes, respectively. Results: The main finding was the significantly lower serum AVP levels in BD-I during manic, depressive, or remission periods compared to healthy controls. After-treatment-response serum AVP levels in depressive BD-I patients increased to the levels of healthy controls and became higher than in the remission period of BD-I. Conclusions: The global reduction in serum AVP levels may be an indicator of impaired neuronal function and neuroprogressive deterioration seen in BD. Notably, given the increased AVP levels in major depressive disorder, serum AVP levels may contribute to distinguishing depressive BD-I from major depressive disorder.

Involvement of Central Endothelin ETA and Cannabinoid CB1 Receptors and Arginine Vasopressin Release in Sepsis Induced by Cecal Ligation and Puncture in Rats.

We previously reported that endothelin-1 (ET-1) reduced the frequency of spontaneous excitatory currents in vasopressinergic magnocellular cells through the activation of endothelin ETA receptors in rat brain slices. This effect was abolished by a cannabinoid CB1 receptor antagonist, suggesting the involvement of endocannabinoids. The present study investigated whether the blockade of ETA or CB1 receptors during the phase of increased levels of ET-1 after severe sepsis increases the survival rate of animals concomitantly with an increase in plasma arginine vasopressin (AVP) levels. Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). Treatment with the CB1 receptor antagonist rimonabant (Rim; 10 and 20 mg/kg, orally) 4 h after CLP (three punctures) significantly increased the survival rate compared with the CLP per vehicle group. Intracerebroventricular treatment with the ETA receptor antagonist BQ123 (100 pmol) or with Rim (2 μg) 4 and 8 h after CLP but not the ETB receptor antagonist BQ788 (100 pmol), also significantly improved the survival rate. Sham-operated and CLP animals that were treated with Rim had significantly lower core temperature than CLP animals. However, oral treatment with Rim did not change bacterial count in the peritoneal exudate, neutrophil migration to the peritoneal cavity, leucopenia or increased plasma interleukin-6 levels induced by CLP. Both Rim and BQ123 also increased AVP levels 12 h after CLP. The blockade of central CB1 and ETA receptors in the late phase of sepsis increased the survival rate, reduced body temperature and increased the circulating AVP levels.

Effects of Peritoneal Sepsis on Rat Central Osmoregulatory Neurons Mediating Thirst and Vasopressin Release.

Sepsis is a life-threatening condition caused by the systemic inflammatory response to bacterial infection. Although the early phase of sepsis features impaired thirst and enhanced vasopressin release, the basis for these defects is unknown. Here, we show that cecal ligation and puncture (CLP) in rats impairs the osmoresponsiveness of neurons in the organum vasculosum lamina terminalis (OVLT; which drives thirst) and attenuates that of neurosecretory neurons in the supraoptic nucleus (SON; which secrete oxytocin and vasopressin). Notably, we found that OVLT neurons are hyperpolarized and electrically silenced. In contrast, CLP increased the proportion of SON neurons displaying spontaneous electrical activity. Therefore, CLP affects the properties of osmoregulatory neurons in a manner that can affect systemic osmoregulation.

Impact of Childhood Adversity and Vasopressin receptor 1a Variation on Social Interaction in Adulthood: A Cross-Sectional Study.

BackgroundArginine vasopressin (AVP) plays a role in social behavior, through receptor AVPR1A. The promoter polymorphism AVPR1A RS3 has been associated with human social behaviors, and with acute response to stress. Here, the relationships between AVPR1A RS3, early-life stressors, and social interaction in adulthood were explored.MethodsAdult individuals from a Swedish population-based cohort (n = 1871) were assessed for self-reported availability of social integration and social attachment and for experience of childhood adversities. Their DNA samples were genotyped for the microsatellite AVPR1A RS3.ResultsAmong males, particularly those homozygous for the long alleles of AVPR1A RS3 were vulnerable to childhood adversity for their social attachment in adulthood. A similar vulnerability to childhood adversity among long allele carriers was found on adulthood social integration, but here both males and females were influenced.LimitationData were self-reported and childhood adversity data were retrospective.ConclusionsEarly-life stress influenced the relationship between AVPR1A genetic variants and social interaction. For social attachment, AVPR1A was of importance in males only. The findings add to previous reports on higher acute vulnerability to stress in persons with long AVPR1A RS3 alleles and increased AVP levels.

Dialysis Hypotension: A Role for Inadequate Increase in Arginine Vasopressin Levels? A Systematic Literature Review and Meta-Analysis

Background: Intradialytic hypotension is a common complication of hemodialysis (HD). Some studies have suggested that inadequate arginine vasopressin (AVP) increase could play a role in the pathogenesis of intradialytic hypotension. However, AVP levels during HD and its relation to hypotension has never been systematically studied. Summary: PubMed and Embase were searched (1970-2013, search terms ‘vasopressin' and ‘hemodialysis') for studies reporting on AVP levels during standard HD or other dialysis techniques. Observational studies reporting on AVP levels pre- and postdialysis were additionally included in a meta-analysis. Thirty-seven studies were included in the systematic literature review, of which 26 studies were eligible for meta-analysis. The main findings were that pretreatment AVP levels were higher in dialysis patients compared with healthy controls (6.4 ± 3.5 vs. 2.5 ± 1.3 pg/ml, p = 0.003) and that plasma AVP levels showed little or no increase during HD (from 7.0 ± 4.9 to 8.8 ± 9.3, p = 0.433). Significant heterogeneity was found between studies. Meta-regression analysis revealed no significant associations between AVP and patient or study characteristics. Studies on other dialysis techniques showed mixed results regarding the AVP course. The eight studies that addressed the relation between intradialytic hypotension and AVP also showed inconsistent results. Key Messages: Plasma AVP levels are higher in dialysis patients compared with healthy controls, but show little or no increase during HD. The lack of a rise in AVP levels during HD may be pathophysiologically involved in the onset of intradialytic hypotension, but firm conclusions are not possible from our review of the literature.

Superoxide anions involved in sympathoexcitation and pressor effects of salusin‐β in paraventricular nucleus in hypertensive rats

Salusin-β in paraventricular nucleus (PVN) increases renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR) and arginine vasopressin (AVP) release in hypertensive rats but not in normal rats. The present study was designed to investigate the downstream molecular mechanism of salusin-β in the PVN in hypertension. Renovascular hypertension was induced by two-kidney, one-clip (2K1C) in male SD rats. Acute experiments were carried out 4 weeks after 2K1C or sham operation under anaesthesia. MrgA1 mRNA expression and salusin-β level in the PVN as well as plasma salusin-β level were increased in 2K1C rats. Bilateral PVN microinjection of salusin-β increased the RSNA, MAP and HR in 2K1C rats, which were abolished by the pre-treatment with polyethylene glycol-superoxide dismutase (PEG-SOD), the superoxide anion scavenger tempol, the NAD(P)H oxidase inhibitor apocynin or the protein kinase C (PKC) inhibitor chelerythrine chloride (CLC), but not affected by the AT1 receptor antagonist losartan, the Mas receptor antagonist A-779, the NOS inhibitor L-NAME or the GABAA and GABAB receptor antagonists gabazine+CGP-35348. Salusin-β-induced increases in superoxide anion level and NAD(P)H oxidase activity in the PVN were abolished by the PVN pre-treatment with CLC. Salusin-β increased AVP levels in rostral ventrolateral medulla and plasma, which were prevented by the pre-treatment with PEG-SOD, apocynin or CLC in 2K1C rats. Salusin-β augmented the enhanced activity of PKC in the PVN in 2K1C rats. Protein kinase C-NAD(P)H oxidase-superoxide anions pathway in the PVN is involved in salusin-β-induced sympathetic activation, pressor response and AVP release in renovascular hypertension.

Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis

BackgroundIn women with chronic schizophrenia, higher levels of peripheral oxytocin have been associated with lower levels of positive but not negative symptoms. Sex-specific associations between endogenous levels of oxytocin (OT) and arginine vasopressin (AVP) with clinical symptoms and cognition in untreated early course patients have not been examined. MethodClinical ratings and neuropsychological testing were performed in thirty-eight acutely ill, unmedicated first-episode schizophrenia patients (14 women, 24 men). Serum hormone assays were obtained in patients and thirty-eight demographically similar healthy controls. ResultsPatients demonstrated increased AVP levels compared to controls (p=0.01). Higher AVP levels were associated with greater positive symptoms (r=0.58, p=0.03) and worse verbal learning (r=−0.63, p=0.02) in female, but not male, patients. OT levels did not statistically differ between patients and controls, and were unrelated to clinical symptoms or cognition in patients. ConclusionResults suggest an association of endogenous AVP with increased positive symptom severity and worse cognition in untreated female, but not male, schizophrenia patients. Findings support the role of neuroendocrine alterations in acute psychosis and the importance of examining sex-specific neuroendocrine alterations early in the course of schizophrenia.

Association of Arginine Vasopressin Levels With Outcomes and the Effect of V2 Blockade in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction

Background— Arginine vasopressin (AVP) levels are elevated in proportion to heart failure severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction is unclear. Methods and Results— The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial investigated the effects of tolvaptan in patients with worsening heart failure and ejection fraction ≤40%. The present analysis examined baseline and follow-up AVP levels in 3196 EVEREST patients with valid AVP measurements. Coprimary end points included all-cause mortality, and the composite of cardiovascular mortality or heart failure hospitalization. Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased all-cause mortality (hazard ratio, 1.33; 95% confidence interval, 1.13–1.55) and cardiovascular mortality or heart failure hospitalization (hazard ratio, 1.23; 95% confidence interval, 1.08–1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival ( P =0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP ( P &lt;0.001), but this had no effect on mortality (hazard ratio, 0.95; 95% confidence interval, 0.72–1.24). Conclusions— Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.

Noradrenergic regulation in mouse supraoptic nucleus involves a nitric oxide pathway only to regulate arginine‐vasopressin expression and not oxytocin expression

Noradrenalin (NA) regulates the expression of arginine-vasopressin (AVP) and oxytocin (OT) by magnocellular neurons in the supraoptic nucleus (SON) of the hypothamalus. Nitric oxide (NO) may be one of the factors involved in the NA signaling pathway regulating AVP and OT expression. To test this possibility, we used an ex vivo experimental model of mouse hypothalamus slices. Increases in AVP and OT levels in the SON were detected by immunohistochemistry and immunoenzyme assays after 1 hr and 4 hr incubations with NA (10(-4) M). There was also an increase in the expression and activity of neuronal NOS and inducible NOS in the SON as assessed by immunohistochemical and histoenzymological analysis of NADPH-diaphorase, whereas endothelial NOS was undetectable. To specify the role of NO, the slices were treated with NA and L-arginine methyl ester (L-NAME, an NOS inhibitor; 3 microM). This treatment for 1 hr abolished the NA-induced increase in AVP. Treatment with sodium nitroprusside (SNP, an NO donor; 0.1 mM) increased AVP levels, confirming that NO regulates AVP expression. Addition of 1 mM EGTA during the incubation with NA reduced the AVP increase by half, indicating that both nNOS and iNOS activities are involved in the regulation. A 1-hr treatment with L-NAME did not prevent the increase in OT induced by NA; similarly, treatment with SNP had no effect. These findings show that NO is involved in the regulation of AVP expression by NA and that NA control of OT expression is independent of NO.

Regulation of Arginine Vasopressin in the Human Heart

The role of arginine vasopressin (AVP) in the heart has yet to be determined. The present study was designed to examine whether AVP is regulated in the human heart. The subjects were 93 patients who underwent coronary angiography and left ventriculography. Blood samples were collected at the aortic root (AO) and the coronary sinus (CS) to measure the plasma levels of AVP. The patients who showed increases in AVP levels at the CS and AO were assigned to the increased AVP group and those who showed no change or a decrease were assigned to the non-increased AVP group. Cardiac function was compared between these 2 groups. There was a significant difference (p<0.0234) in left ventricular end-diastolic volume index between the increased AVP group (125.5 +/-53.4 ml/m2) and the non-increased AVP group (102.2+/-30.6 ml/m2). There was also a significant difference (p<0.0137) in left ventricular stroke volume index between the increased AVP group (66.6+/-23.2 ml/m2) and the non-increased AVP group (54.4+/-18.6 ml/m2). These results suggest that both the production of AVP and synthesis with its receptors may be enhanced at regional sites of the human heart in the volume load.

Chapter 23 Treatment of the diabetic patient: focus on cardiovascular and renal risk reduction

Diabetes mellitus increases the risk for hypertension and associated cardiovascular diseases, including coronary, cerebrovascular, renal and peripheral vascular disease. The risk for developing cardiovascular disease is increased when both diabetes and hypertension co-exist; in fact, over 11 million Americans have both diabetes and hypertension. These numbers will continue to climb, internationally, since the leading associated risk for diabetes development, obesity, has reached epidemic proportions, globally. Moreover, the frequent association of diabetes with dyslipidemia, as well as coagulation, endothelial, and metabolic abnormalities also aggravates the underlying vascular disease process in patients who possess these comorbid conditions. The renin-angiotensin-aldosterone system (RAS) and arginine vasopressin (AVP) are overactivated in both hypertension and diabetes. Drugs that inhibit this system, such as ACE inhibitors and more recently angiotensin receptor antagonists (ARBs), have proven beneficial effects on the micro- and macrovascular complications of diabetes, especially the kidney. The BRILLIANT study showed that lisinopril reduces microalbuminuria better than CCB therapy. Numerous other long-term studies confirm this association with ACE inhibitors including the HOPE trial. Furthermore, the European Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) study, showed that lisinopril slowed the progression of renal disease, even in individuals with mild albuminuria. In fact, there are now five appropriately powered randomized placebo-controlled trials to show that both ACE inhibitors and ARBs slow progression of diabetic nephropathy in people with type 2 diabetes. These effects were shown to be better than conventional blood pressure lowering therapy, including dihydropyridine CCBs. In patients with microalbuminuria, ACE inhibitors and ARBs reduce the progression of microalbuminuria to proteinuria and provide a risk reduction of between 38 and 60% for progression to proteinuria. This is important since microalbuminuria is known to be associated with increased vascular permeability and decreased responsiveness to vasodilatory stimuli. Recently, increased AVP levels have been lined to microalbuminuria and hyperfiltration in diabetes. The microvascular and macrovascular benefits of ACE inhibition, ARBs and possible role of AVP antagonists in diabetic patients will be discussed, as will be recommendations for its clinical use.

Resistance to vasopressin action on the kidney in patients with Cushing's disease.

To assess the plasma levels and action of arginine vasopressin (AVP) in patients with Cushing's disease. There are many reports that patients with Addison's disease have increased AVP levels associated with hyponatraemia and hypoosmolality, but none on the dynamics of secretion of this neurohormone during osmolality-based stimulation in patients with chronic hypercortisolism. The plasma AVP concentration and the urinary and plasma osmolality after a 7.5-h water deprivation test (WDT) were evaluated in 13 patients with Cushing's disease and 15 normal (control) individuals. In patients with Cushing's disease we also assessed the urinary osmolality in response to 10 micrograms i.v. desmopressin (DDAVP) administered at the end of the WDT. At the end of the WDT, urinary osmolality was significantly lower in patients with Cushing's disease (511.5 +/- 148.5 mOsm/l) than in the normal subjects (981.1 +/- 107.1 mOsm/l, P < 0.001), whereas plasma osmolality did not differ between the two groups. Consequently, the urine/plasma osmolality ratio (Uosm/Posm) was lower in patients with Cushing's disease than in normal individuals (1.8 +/- 0.5 compared with 3.4 +/- 0.4, P < 0.001). The AVP concentration also was greater (7.3 +/- 3.1 pmol/l) in those with Cushing's disease than in the controls (3.9 +/- 2.3 pmol/l, P < 0.005). After administration of DDAVP to the hypercortisolaemic patients, the urinary osmolality attained (718.0 +/- 200.0 mOsm/l) was still lower than that in the normal group at the end of WDT (P < 0.005). Patients with Cushing's disease presented higher AVP levels and smaller Uosm/Posm ratios than normal subjects. After DDAVP, the patients with Cushing's disease were unable to concentrate the urine adequately. These data suggest that the kidney shows resistance to the action of both endogenous and exogenous AVP in patients with Cushing's disease.

Vasopressin release within the ventral septal area of the rat brain during drug-induced antipyresis.

The techniques of push-pull perfusion and radioimmunoassay were used to determine concentrations of arginine vasopressin (AVP) in extracellular fluid derived from the ventral septal area (VSA) of the rat brain following antipyresis elicited by acetaminophen or indomethacin in conscious and unrestrained rats. Reduction of bacterial lipopolysaccharide (LPS)-induced fever by intraperitoneal indomethacin resulted in significant increases in AVP levels in VSA perfusion fluid (P < 0.05). In contrast, antipyresis after acetaminophen treatment was without significant effect on AVP output from VSA nerve terminals. In control animals (non-pyrogen treated), body temperature rose in apparent response to the perfusion procedure. Despite this elevation in core temperature, subsequent treatment with acetaminophen or indomethacin did not result in significant changes in AVP release from VSA perfusates. We conclude that AVP release into VSA extracellular fluids following intraperitoneal indomethacin is dependent upon the neuronal sequelae inherent to pyrogen-evoked fever and not nonspecific rises in body temperature. These results support the hypothesis that endogenous AVP, acting within the VSA, participates in the neuronal mechanisms mediating indomethacin-induced antipyresis.