Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K, 1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar-Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K,1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular, renal, and endocrine responses to low-dose atrial natriuretic peptide in the fluid-balanced New Zealand genetically hypertensive rats with and without endogenous arginine vasopressin.

In hypertension, the relationship between atrial natriuretic peptide (ANP) and vasopressin (AVP) is not yet clear, although their renal actions are effectively autoregulation. To examine the possible interaction further, the responses to ANP infusion (75 ng x min (-1), i.v.) have been investigated in both hypertensive and normotensive AVP-replete (HT and NT) and AVP-deficient (HTDI and NTDI) rats. This study aimed to assess the renal function and the plasma hormone concentrations of AVP, angiotensin II (AII), ANP, aldosterone, and corticosterone in the conscious, chronically catheterized, fluid-balanced rats, and to examine the cardiovascular, renal, and endocrine responses to a constant infusion of a low-dose ANP. Data gained from the present study showed, for the first time, the hormone profile, plasma electrolyte composition, and detailed renal function of the servo-controlled, fluid-balanced rats. The similarities of plasma electrolyte composition between servo-controlled and untreated rats indicated that the servo-controlled fluid replacement technique maintained the differences between the strains and maintained body fluid balance during the experimental periods. Following ANP administration, there were no changes in glomerular filtration rate (GFR) in all groups, but an enduring diuresis and natriuresis were observed in HT and NT, which were milder in HTDI rats. However, the hypotensive effect of ANP was of a similar magnitude in all rat strains. HTDI rats exhibited an inhibition of the renin-angiotensin system (RAS), which may have participated in the reduced mean arterial blood pressure (MAP) and natriuresis observed in these rats. The renal actions of ANP appear to rely upon renal tubular events, as indicated by increased fractional electrolyte excretions in the AVP-replete rats. This study highlights the importance of AVP to the profile of the renal actions of ANP in normal rats.     

Effect of rehydration on atrial natriuretic peptide release during exercise in the heat

In an attempt to investigate their relationships with plasma volume (PV), heart rate (HR), and other hormonal systems, plasma atrial natriuretic peptide (ANP) levels were determined in response to exercise in the heat, associated with dehydration and rehydration with various fluids. Five normal subjects underwent four 3-h experiments, in a 36 degree C environment, in which 25-min exercise periods on a cycle ergometer at 90 W alternate with 5-min rest periods. Blood samples were collected hourly and ANP, arginine vasopressin (AVP), adrenocorticotropin (ACTH), and cortisol were analyzed in four experimental sessions: without fluid supplement (DH) and with progressive rehydration either with water (W), acid isotonic solution (AISO), or neutral isotonic solution (NISO). Exercise in the heat, accompanied by a decrease in PV and an increase in osmolality, elicited an increase of 28 +/- 1.6 pg/ml in plasma ANP, with concomitant increases in AVP (5.1 +/- 1.4 pg/ml), ACTH (49.6 +/- 12.3 pg/ml), and cortisol (8.4 +/- 2.0 micrograms/100 ml). Progressive rehydration maintained PV and blunted ANP, AVP, ACTH, and cortisol responses. These results demonstrate the importance of rehydration, during exercise in a warm environment, in preventing hormonal increases. They suggest that under our conditions, the PV changes and the inferred atrial pressure changes may not be the primary factors controlling ANP release, as under other physiological conditions. The exercise-related activation of pituitary and adrenals and the stimulation of HR counteract the influence of PV changes due to vascular fluid shifts.     

Atrial natriuretic peptide and vasopressin in human plasma

Using a specific radioimmunoassay for atrial natriuretic peptide (ANP), plasma immunoreactive ANP was measured in 17 normal subjects and 83 patients with various diseases. Plasma ANP concentration in normal subjects was 14.1 +/- 1.7 pg/ml (mean +/- S.E.). Relatively high plasma ANP concentrations were detected in patients with diabetes mellitus, hyperthyroidism, atrial fibrillation and liver cirrhosis. Plasma ANP concentrations in the patients correlated positively with mean arterial blood pressure and plasma AVP concentrations. Plasma ANP concentrations in the patients also had positive correlations with left atrial dimension and left ventricular diastolic dimension determined by echocardiography. Another positive correlation was observed in the patients between plasma AVP concentrations and mean arterial blood pressure. These results suggest that ANP is a volume regulatory hormone but also that ANP may be involved in the blood pressure regulating system.     

Corticotropin releasing factor induces anxiogenic locomotion in trout and alters serotonergic and dopaminergic activity

Corticotropin releasing factor (CRF) and serotonin (5-HT) are strongly linked to stress and anxiety in vertebrates. As a neuromodulator in the brain, CRF has anxiogenic properties often characterized by increased locomotion and stereotyped behavior in familiar environments. We hypothesized that expression of anxiogenic behavior in response to CRF will also be exhibited in a teleost fish. Rainbow trout were treated with intracerebroventricular (icv) injections of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Treatment with either dose of CRF elicited greater locomotion and pronounced head shaking behavior but did not influence water column position. Locomotor and head shaking behaviors may be analogous to the increased stereotypy evoked by icv CRF in rats and may reflect the expression of stress/anxiety behavior. Injection with either aCSF or CRF produced significant increases in plasma cortisol. The absence of behavioral changes in aCSF-injected fish suggests that the behavioral responses following CRF were not due to cortisol. Treatment with 2000 ng CRF significantly increased serotonin, 5-HIAA and dopamine concentrations in the subpallium and raphé and increased 5-HIAA in the preoptic hypothalamus (POA). Concurrent effects of CRF on central monoamines, locomotion and head shaking in trout suggest that anxiogenic properties of CRF are evolutionarily conserved. In addition, positive linear correlations between locomotion and serotonergic and dopaminergic function in the subpallium, POA and raphé nuclei suggest a locomotory function for these monoamines.     

Corticotropin releasing factor induces anxiogenic locomotion in trout and alters serotonergic and dopaminergic activity

Corticotropin releasing factor (CRF) and serotonin (5-HT) are strongly linked to stress and anxiety in vertebrates. As a neuromodulator in the brain, CRF has anxiogenic properties often characterized by increased locomotion and stereotyped behavior in familiar environments. We hypothesized that expression of anxiogenic behavior in response to CRF will also be exhibited in a teleost fish. Rainbow trout were treated with intracerebroventricular (icv) injections of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Treatment with either dose of CRF elicited greater locomotion and pronounced head shaking behavior but did not influence water column position. Locomotor and head shaking behaviors may be analogous to the increased stereotypy evoked by icv CRF in rats and may reflect the expression of stress/anxiety behavior. Injection with either aCSF or CRF produced significant increases in plasma cortisol. The absence of behavioral changes in aCSF-injected fish suggests that the behavioral responses following CRF were not due to cortisol. Treatment with 2000 ng CRF significantly increased serotonin, 5-HIAA and dopamine concentrations in the subpallium and raphé and increased 5-HIAA in the preoptic hypothalamus (POA). Concurrent effects of CRF on central monoamines, locomotion and head shaking in trout suggest that anxiogenic properties of CRF are evolutionarily conserved. In addition, positive linear correlations between locomotion and serotonergic and dopaminergic function in the subpallium, POA and raphé nuclei suggest a locomotory function for these monoamines.     

Modulation of ANP-C receptor signaling by arginine-vasopressin in A-10 vascular smooth muscle cells: role of protein kinase C

We have previously shown that pretreatment of A-10 vascular smooth muscle cells (VSMC) with angiotensin II (Ang II) attenuated atrial natriuretic peptide receptor-C (ANP-C)-mediated inhibition of adenylyl cyclase without altering [125I]ANP binding. In the present studies, we have investigated the modulation of ANP-C receptor signaling by arginine-vasopressin (AVP). Pretreatment of A-10 VSMC with AVP for 24h resulted in a reduction in ANP receptor binding activity by about 50% (B(max); control cells, 22.9+/-2.5 fmol/mg protein, AVP-treated cells, 11.4+/-1.2 fmol/mg protein). In addition, the expression of ANP-C receptor as determined by immunoblotting was also decreased by about 50% by AVP treatment, which was prevented by GF109203X, an inhibitor of protein kinase C (PKC). The decreased expression of ANP-C receptor was reflected in an attenuation of ANP-C receptor-mediated inhibition of adenylyl cyclase. C-ANP(4-23) [des(Gln(18),Ser(19),Gln(20),Leu(21),Gly(22))ANP(4-23)-NH(2)], a ring deleted peptide of ANP that interacts specifically with ANP-C receptor, inhibited adenylyl cyclase activity by about 30% in control cells, which was completely attenuated in AVP-treated cells. This attenuated inhibition was significantly restored by GF 109203X. In addition, AVP treatment augmented the levels of Gialpha-2 and Gialpha-3 proteins; however, the Gi functions were completely attenuated. The increased expression of Gialpha proteins induced by AVP was inhibited by GF109203X as well as by actinomycin D treatments. In addition, AVP treatment also enhanced the expression of Gsalpha protein and Gsalpha-mediated stimulation of adenylyl cyclase by GTPgammaS, N-ethylcarboxamide adenosine (NECA), and forskolin (FSK), whereas the levels of Gbeta were not altered by AVP treatment. These results indicate that AVP-induced PKC signaling may be responsible for the down-regulation of ANP-C receptor that results in the attenuation of C-ANP(4-23)-mediated inhibition of adenylyl cyclase activity, and suggest a cross-talk between vasopressin V(1) and ANP-C receptor-mediated signaling pathways.     

Effect of vasopressin and V1 receptors blockade on hypotensive action of ANP in normotensive (WKY) and spontaneously hypertensive rats.

The aim of the study was to find out whether vasopressin (AVP) modifies hypotensive and heart rate accelerating effects of atrial natriuretic peptide (ANP) in normotensive (WKY) and spontaneously hypertensive (SHR) conscious rats. The effect of i.v. administration of 1; 2 and 4 micrograms of ANP on blood pressure (MP) and heart rate (HR) was compared during i.v. infusion of 0.9% NaCl (NaCl), NaCl+AVP (1.2 ng kg-1 min-1) and NaCl+dEt2AVP (V1 receptors antagonist, 0.5 microgram kg-1 min-1). AVP increased MP in SHR and WKY and decreased HR in SHR. V1 antagonist decreased MP and increased HR only in SHR. In SHR ANP decreased MP and increased HR during NaCl, AVP and V1 antagonist infusion. In WKY these effects were observed only during AVP administration. In each experimental situation hypotension and tachycardia induced by ANP were greater in SHR than in WKY. In both strains ANP induced changes in MP and HR were enhanced during AVP in comparison to NaCl infusion. V1 antagonist did not modify effects of ANP in WKY and SHR. The results indicate that ANP abolishes hypertensive response induced by blood AVP elevation and that the basal levels of endogenous vasopressin acting through V1 receptors does not interfere with hypotensive action of ANP neither in WKY nor in SHR.     

Altered renal response to acute volume expansion in transgenic rats harboring the human tissue kallikrein gene

The renal response to acute volume expansion was investigated in transgenic (TGR) rats harboring the human tissue kallikrein gene. After a primer injection of 0.9% NaCl (3 ml/100 g, i.v), Sprague-Dawley (SD) or TGR rats received a continuous infusion of 0.9% NaCl (15 microl/100 g/min, i.a.) through a catheter placed into the carotid artery. Acute volume expansion was produced by a second injection of 0.9% NaCl (2 ml/100 g, i.v.) 65 min after the first injection. Plasma vasopressin (AVP) and atrial natriuretic peptide (ANP) concentration was measured before and within 10 min of volume expansion. TGR animals presented a blunted response to acute volume expansion evidenced by an attenuated increase in total and fractional water and sodium excretion. Before or after volume expansion, plasma AVP and ANP did not differ between SD and TGR. Pre-treatment with the BK-B2 antagonist HOE-140 (7.5 microg/100 g. i.a) partially improved the renal response of TGRs and severely blunted the response in SD rats. These data show that TGR (hKLK1) rats have an impaired renal response to acute volume expansion that can not be accounted for by changes in the release of AVP or ANP.     

Analysis of the vasopressin system and water regulation in genetically polydipsic mice

Polydipsic mice, STR/N, which show extreme polydipsia and polyuria, were discovered in 1958. In the STR/N, urine outputs are much higher than in control mice. The possibility of an abnormal regulation of the arginine vasopressin (AVP) system, or an abnormality in the renal susceptibility to AVP, should be considered. In this study we investigated the AVP system and water regulation in STR/N. We sequenced the AVP and the AVP V(2)-receptor genes of the STR/N by direct sequencing. No mutation was found in either of them. AVP gene expression examined by in situ hybridization and plasma sodium in 8-wk-old STR/N was significantly lower than in control mice, whereas it was significantly higher at 20 wk. Renal sensitivity to injected AVP was attenuated in 20-wk-old STR/N. The suppression of AVP synthesis due to excessive water retention in 8-wk-old STR/N suggests that polydipsia may be the primary cause in this strain. The 20-wk-old STR/N became dehydrated with the acceleration of AVP synthesis, which might have resulted from secondary desensitization to AVP.     

Increased thirst and vasopressin secretion after myocardial infarction in rats

Impaired regulation of salt and water balance in left ventricular dysfunction and heart failure can lead to pulmonary and peripheral edema and hyponatremia. Previous studies of disordered water regulation in heart failure have used models of low cardiac output with normal cardiac function (e.g., inferior vena cava ligation). We investigated thirst and vasopressin (AVP) secretion in a rat myocardial infarction model of chronic left ventricular dysfunction/heart failure in response to a 24-h water deprivation period. Thirst (implied from water drunk), hematocrit, plasma renin activity, and plasma AVP concentrations increased with water deprivation vs. ad libitum water access. Thirst and plasma AVP concentrations were significantly positively correlated with infarct size after 24-h water deprivation but not under ad libitum water access conditions. The mechanism by which this occurs is unclear but could involve increased osmoreceptor sensitivity, altered stimulation of baroreceptors, the renin-angiotensin system, or altered central neural control.     

Defective renal water handling in transgenic mice over-expressing human CD39/NTPDase1

Ectonucleoside triphosphate diphosphohydrolase-1 hydrolyzes extracellular ATP and ADP to AMP. Previously, we showed that CD39 is expressed at several sites within the kidney and thus may impact the availability of type 2 purinergic receptor (P2-R) ligands. Because P2-Rs appear to regulate urinary concentrating ability, we have evaluated renal water handling in transgenic mice (TG) globally overexpressing hCD39. Under basal conditions, TG mice exhibited significantly impaired urinary concentration and decreased protein abundance of AQP2 in the kidney compared with wild-type (WT) mice. Urinary excretion of total nitrates/nitrites was significantly higher in TG mice, but the excretion of AVP or PGE(2) was equivalent to control WT mice. There were no significant differences in electrolyte-free water clearance or fractional excretion of sodium. Under stable hydrated conditions (gelled diet feeding), the differences between the WT and TG mice were negated, but the decrease in urine osmolality persisted. When water deprived, TG mice failed to adequately concentrate urine and exhibited impaired AVP responses. However, the increases in urinary osmolalities in response to subacute dDAVP or chronic AVP treatment were similar in TG and WT mice. These observations suggest that TG mice have impaired urinary concentrating ability despite normal AVP levels. We also note impaired AVP release in response to water deprivation but that TG kidneys are responsive to exogenous dDAVP or AVP. We infer that heightened nucleotide scavenging by increased levels of CD39 altered the release of endogenous AVP in response to dehydration. We propose that ectonucleotidases and modulated purinergic signaling impact urinary concentration and indicate potential utility of targeted therapy for the treatment of water balance disorders.     

Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans

We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II.     

Effect of high and low sodium intake on urinary aquaporin-2 excretion in healthy humans

The degree of water transport via aquaporin-2 (AQP2) water channels in renal collecting duct principal cells is reflected by the level of the urinary excretion of AQP2 (u-AQP2). In rats, the AQP2 expression varies with sodium intake. In humans, the effect of sodium intake on u-AQP2 and the underlying mechanisms have not previously been studied. We measured the effect of 4 days of high sodium (HS) intake (300 mmol sodium/day; 17.5 g salt/day) and 4 days of low sodium (LS) intake (30 mmol sodium/day; 1.8 g salt/day) on u-AQP2, fractional sodium excretion (FE(Na)), free water clearance (C(H2O)), urinary excretion of PGE(2) (u-PGE(2)) and cAMP (u-cAMP), and plasma concentrations of vasopressin (AVP), renin (PRC), ANG II, aldosterone (Aldo), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) in a randomized, crossover study of 21 healthy subjects, during 24-h urine collection and after hypertonic saline infusion. The 24-h urinary sodium excretion was significantly higher during HS intake (213 vs. 41 mmol/24 h). ANP and BNP were significantly lower and PRC, ANG II, and Aldo were significantly higher during LS intake. AVP, u-cAMP, and u-PGE(2) were similar during HS and LS intake, but u-AQP2 was significantly higher during HS intake. The increases in AVP and u-AQP2 in response to hypertonic saline infusion were similar during HS and LS intake. In conclusion, u-AQP2 was increased during HS intake, indicating that water transport via AQP2 was increased. The effect was mediated by an unknown AVP-independent mechanism.     

Impaired water diuresis in a patient with pseudo-Bartter syndrome.

A 32-year-old man was diagnosed as having pseudo-Bartter syndrome due to surreptitious habitual vomiting and to maldigestion related to decayed teeth. His chief complaints were muscle pain and weakness. In this case, metabolic alkalosis, hypokalemia, hypochloremia, increased plasma renin activity and aldosterone levels were noticed with marked decreases in urinary chloride excretion. Creatinine clearance (GFR) and renal plasma flow (RPF) were also decreased. Blood pressure was normal, but the pressor response to angiotensin II was attenuated. Before treatment with 0.9% saline infusion, plasma vasopressin (AVP) was not suppressed sufficiently by lowering the plasma osmolality (Posm) with an oral water load (WL), but it normally responded to a rise in Posm due to hypertonic saline infusion. Moreover, plasma AVP was normally suppressed by WL after the replenishment of saline. Plasma atrial natriuretic peptide (ANP) was low before WL, but increased normally in response to WL. However, inconsistent with the normal response in this case, decreases in plasma AVP failed to dilute urinary osmolality and to increase urine flow, irrespective of the levels of plasma ANP. These results indicate that chronic inanition due to surreptitious vomiting causes impaired renal diluting ability through decreases in GFR and RPF, irrespective of the levels of plasma AVP and ANP.     

Four-hour atrial natriuretic peptide infusion in conscious rats: effects on urinary volume, sodium, and cyclic GMP

Atrial natriuretic peptide (ANP) is released from the cardiac atria in response to acute volume loads; when infused acutely ANP causes diuresis and natriuresis. Cyclic GMP (cGMP) appears to be the second messenger for ANP in the kidney. The role that ANP plays in the long-term regulation of salt and water balance is unclear, however, since resistance to ANP's natriuretic and diuretic activity develops during prolonged administration. The purpose of the present study is to examine the relationship between the rate of cGMP excretion in response to ANP and the development of resistance to ANP's diuretic and natriuretic activity. Following a 30-min baseline period of infusion of Ringer's solution conscious rats received ANP at 15 micrograms/kg/hr (n = 6) or Ringer's alone (n = 5) for 240 min. ANP-infused rats had a significant diuresis and natriuresis during the first hour of infusion; urinary cGMP excretion also increased compared to baseline. By 120 min after initiating the infusion in ANP-rats urinary volume and sodium excretion had declined to values not significantly different from those of baseline or control. In contrast, urinary cGMP excretion remained elevated for the duration of the ANP infusion, whether compared to baseline values or the control group. Resistance to the diuretic and natriuretic activity of ANP is not a result of mechanisms that involve cGMP generation.     

Lead (Pb) exposure induces physiological alterations in the serotoninergic and vasopressin systems causing anxiogenic-like behavior in Meriones shawi: Assessment of BDMC as a neuroprotective compound for Pb-neurotoxicity and kidney damages

BackgroundStudies have shown that lead (Pb) is one of hazardous heavy metals with various adverse effects on human health including mental health; Pb can induce psychiatric disorders like anxiety. In the present work, we examined the potential of bisdemethoxycurcumin (BDMC) as a neuroprotective agent against lead induced anxiety inMeriones shawi (M. shawi).MethodsWe asses, the potential of three consecutive day exposure to Pb (25 mg/kg body weight) in inducing anxiogenic effect, serotoninergic and vasopressinergic disruptions inM. shawi. This was done using neurobehavioral tests (open field, elevated plus maze), immunohistochemestry by anti-serotonin (5-HT), and anti-vasopressin (AVP) antibodies. We also measured the possible restorative potential of BDMC (30 mg/kg body weight), delivered by oral gavage. After that, a biochemical and histopathological studies were done.ResultsOur results showed that lead exposure for three consecutive days increases significantly the 5-HT-immunoreactivity in dorsal raphe nucleus (DRN) accompanied with a significant enhancement of AVP-immunoreactivity in the cell bodies and fibers in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. In the collecting tube, AVP binds to the V2 receptor of the epithelial cells and increases the water permeability. Our results showed clearly the epithelial cells degeneration after lead exposure, then we suggest that the increased AVP could be a response to the hydric balance disrupted after degenerative effect of lead exposure on epithelial cells. BDMC produced an anxiolytic effect in meriones. Moreover, it restored 5-HT and AVP immunoreactivity within studying nuclei. The biochemical and histopathological studies showed that Pb induced renal damages. In addition, BDMC restored the renal alterations.ConclusionAccording to the obtained results, we suggest new pharmacological effects of BDMC; while it has an anxiolytic effect against Pb-induced anxiety by working on serotoninergic and vasopressinergic systems with an obvious restoration of the renal injuries induced by lead exposure.     

Role of atrial natriuretic peptide and urinary cGMP in the natriuretic and diuretic response to central hypervolemia in normal human subjects

The response of plasma atrial natriuretic peptide (ANP) and urinary cGMP excretion to central hypervolemia induced by water immersion was assessed twice in five healthy male subjects, once while immersed in water to the neck for 3 h and again on a control day. Plasma ANP and urinary cGMP were measured by radioimmunoassay. Compared with the control day, overall change in plasma ANP on the immersion day was significant (p less than 0.05). In response to water immersion, plasma ANP increased from a base-line level of 13.2 +/- 3.1 (mean +/- SEM) to 24.2 +/- 5.5 pg/mL by 0.5 h of immersion and was sustained at that level throughout the immersion period. Plasma ANP returned to the base-line level at 1 h postimmersion. Urinary cGMP excretion increased significantly by 1 h of immersion and was sustained at that level throughout water immersion and 1 h postimmersion (p less than 0.05). During water immersion urine flow, urinary sodium and potassium excretion, free water clearance, and osmolar clearance increased while plasma renin activity, serum aldosterone, and blood pressure fell; all changes were significant (p less than 0.05). Creatinine clearance and hematocrit did not show any significant changes. These data suggest that an increase in plasma ANP may contribute to the natriuretic and diuretic response to central hypervolemia, and that the measurement of urinary cGMP may be a valuable marker of ANP biological responsiveness.     

Atrial and brain natriuretic peptide in adrenal steroidogenesis.

We elucidated the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human and bovine adrenocortical steroidogenesis. The urinary volume, sodium excretion and cyclic GMP (cGMP) excretion and plasma cGMP were markedly increased by the synthetic alpha-human ANP (alpha-hANP) infusion in healthy volunteers. Plasma arginine vasopressin (AVP) and aldosterone levels were significantly suppressed. Both ANP and BNP inhibited aldosterone, 19-OH-androstenedione, cortisol and DHEA secretion dose-dependently and increased the accumulation of intracellular cGMP in cultured human and bovine adrenal cells. alpha-hANP significantly suppressed P450scc-mRNA in cultured bovine adrenal cells stimulated by ACTH. Autoradiography and affinity labeling of [125I]hANP, and Scatchard plot demonstrated a specific ANP receptor in bovine and human adrenal glands. Purified ANP receptor from bovine adrenal glands identified two distinct types of ANP receptors, one is biologically active, the other is silent. A specific BNP receptor was also identified on the human and bovine adrenocortical cell membranes. The binding sites were displaced by unlabelled ANP as well as BNP. BNP showed an effect possibly via a receptor which may be shared with ANP. The mean basal plasma alpha-hANP level was 25 +/- 5 pg/ml in young men. We confirmed the presence of ANP and BNP in bovine and porcine adrenal medulla. Plasma or medullary ANP or BNP may directly modulate the adrenocortical steroidogenesis. We demonstrated that the lack of inhibitory effect of alpha-hANP on cultured aldosterone-producing adenoma (APA) cells was due to the decrease of ANP-specific receptor, which caused the loss of suppression of aldosterone and an increase in intracellular cGMP.     

Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.