Association between speech-language, general cognitive functioning and behaviour problems in individuals with Williams syndrome.

BACKGROUND: Williams syndrome (WS) phenotype is described as unique and intriguing. The aim of this study was to investigate the associations between speech-language abilities, general cognitive functioning and behavioural problems in individuals with WS, considering age effects and speech-language characteristics of WS sub-groups. METHODS: The study's participants were 26 individuals with WS and their parents. General cognitive functioning was assessed with the Wechsler Intelligence Scale. Peabody Picture Vocabulary Test, Token Test and the Cookie Theft Picture test were used as speech-language measures. Five speech-language characteristics were evaluated from a 30-min conversation (clichés, echolalia, perseverative speech, exaggerated prosody and monotone intonation). The Child Behaviour Checklist (CBCL 6-18) was used to assess behavioural problems. RESULTS: Higher single-word receptive vocabulary and narrative vocabulary were negatively associated with CBCL T-scores for Social Problems, Aggressive Behaviour and Total Problems. Speech rate was negatively associated with the CBCL Withdrawn/Depressed T-score. Monotone intonation was associated with shy behaviour, as well as exaggerated prosody with talkative behaviour. WS with perseverative speech and exaggerated prosody presented higher scores on Thought Problems. Echolalia was significantly associated with lower Verbal IQ. No significant association was found between IQ and behaviour problems. Age-associated effects were observed only for the Aggressive Behaviour scale. CONCLUSIONS: Associations reported in the present study may represent an insightful background for future predictive studies of speech-language, cognition and behaviour problems in WS.

Echocardiographic assessment of hemodynamic changes produced by two methods of inducing fluid deficit in dogs.

BACKGROUND: Hydration status is important to the cardiovascular system because of its effects on preload. Decreased preload can alter echocardiographic measurements of systolic and diastolic function, potentially confounding interpretation of results. HYPOTHESIS/OBJECTIVES: Mild fluid deficits are associated with measurable echocardiographic changes that are validated by physical and biochemical markers of decreased intravascular volume. ANIMALS: Twenty-five healthy staff/student-owned dogs with no evidence of cardiac or renal disease. METHODS: Prospective, interventional laboratory study. Dogs were randomly assigned to water deprivation (WD) alone for 8 hours (n = 13) or to furosemide treatment (FTx, 2.5mg/kg IV) followed by WD for 8 hours (n = 12). Echocardiograms, biochemical sampling, and physical parameters were measured at baseline, and after 4 and 8 hours. RESULTS: Both protocols induced fluid deficit as indicated by significant (P < .00001) decreases in weight at 4 hours (WD, 1.1%; FTx, 3.7%) and 8 hours (WD, 2.7%; FTx, 4.5%). Furosemide significantly decreased left ventricular end-diastolic volume (54.3 +/- 19.3-42.1 +/- 17.3 mL, P < .0001), cardiac index (4.2 +/- 1.1-2.9 +/- 0.9 L/min/M2, P < .0001), and mitral valve E wave velocity (0.79 +/- 0.2-0.66 +/- 0.2 m/s, P = .0004). These changes were accompanied by significant increases in blood urea nitrogen concentration (13.8 +/- 2.6-14.8 +/- 2.7 mg/dL, P = .04), vasopressin concentration (1.4 +/- 1.2-3.3 +/- 1.9 pg/mL, P = .045), and PCV (49.8 +/- 4.5-53.2 +/- 6.5%, P = .006). Effects of water deprivation alone were similar, but less pronounced. CONCLUSIONS AND CLINICAL IMPORTANCE: Mild fluid deficits have measurable hemodynamic effects in dogs. Hydration status should be considered when evaluating cardiac function by echocardiogram.

Oropharyngeal dysphagia and language delay in partial trisomy 9p: case report.

The phenotype of partial trisomy 9p includes global developmental delay, microcephaly, bulbous nose, downturned oral commissures, malformed ears, hypotonia, and severe cognitive and language disorders. We present a case report and a comparative review of clinical findings on this condition, focusing on speech-language development, cognitive abilities and swallowing evaluation. We suggest that oropharyngeal dysphagia should be further investigated, considering that pulmonary and nutritional disorders affect the survival and quality of life of the patient. As far as we know, this is the first study of a patient with partial trisomy 9p described with oropharyngeal dysphagia.

Ask-Upmark kidney associated with renal and extrarenal arterial aneurysms.

Reports of Ask-Upmark kidney, initially described as a congenital defect in renal development, are uncommon. We report a case with the features of bilateral asymmetrical segmental atrophy in a patient with childhood-onset hypertension. As an adult, she developed cerebral, celiac, and renal artery aneurysms. She underwent successful clipping of the cerebral aneurysm and renal artery repair with preservation of renal function. Novel radiologic techniques make possible the noninvasive diagnosis of segmental atrophy and its complications.

Intermittent cocaine use associated with recurrent dissection of the thoracic and abdominal aorta.

Acute aortic dissection has been reported with the use of cocaine. We report a case of intermittent cocaine use spanning nearly 5 years and leading to recurrent dissection and extension of the false lumen. The patient repeatedly declined surgical correction. Management involved aggressive pharmacologic blood pressure control, close monitoring, and encouragement to enter drug rehabilitation.

Alteration of humoral and peripheral vascular responses during graded exercise in heart failure.

We hypothesized that performance of exercise during heart failure (HF) would lead to hypoperfusion of active skeletal muscles, causing sympathoactivation at lower workloads and alteration of the normal hemodynamic and hormonal responses. We measured cardiac output, mean aortic and right atrial pressures, hindlimb and renal blood flow (RBF), arterial plasma norepinephrine (NE), plasma renin activity (PRA), and plasma arginine vasopressin (AVP) in seven dogs during graded treadmill exercises and at rest. In control experiments, sympathetic activation at the higher workloads resulted in increased cardiac performance that matched the increased muscle vascular conductance. There were also increases in NE, PRA, and AVP. Renal vascular conductance decreased during exercise, such that RBF remained at resting levels. After control experiments, HF was induced by rapid ventricular pacing, and the exercise protocols were repeated. At rest in HF, cardiac performance was significantly depressed and caused lower mean arterial pressure, despite increased HR. Neurohumoral activation was evidenced by renal and hindlimb vasoconstriction and by elevated NE, PRA, and AVP levels, but it did not increase at the mildest workload. Beyond mild exercise, sympathoactivation increased, accompanied by progressive renal vasoconstriction, a fall in RBF, and very large increases of NE, PRA, and AVP. As exercise intensity increased, peripheral vasoconstriction increased, causing arterial pressure to rise to near normal levels, despite depressed cardiac output. However, combined with redirection of RBF, this did not correct the perfusion deficit to the hindlimbs. We conclude that, in dogs with HF, the elevated sympathetic activity observed at rest is not exacerbated by mild exercise. However, with heavier workloads, sympathoactivation begins at lower workloads and becomes progressively exaggerated at higher workloads, thus altering distribution of blood flow.

Effect of anti-calmodulin agents on vasopressin release in vitro to depolarization and calcium ionophore.

Calmodulin has been implicated in transducing the effects of Ca2+ on synaptic transmission and hormone release, including osmotically-stimulated vasopressin (AVP) release. If the anti-calmodulin agents block AVP release secondary to inhibition of Ca2(+)-calmodulin interactions, these drugs should inhibit AVP release to stimuli increasing Ca2+ influx via different mechanisms. Hypothalamo-neurohypophysial complexes (HNC) were exposed to ionomycin, Bay K 8644, or veratridine either alone, with any one of three distinct chemical classes of anti-calmodulin agent, or with a Ca2+ channel antagonist. All the anti-calmodulin agents impaired AVP release to ionomycin, while Ca2+ channel blockade did not. Conversely, Ca2+ channel antagonism completely blocked AVP release in response to Bay K 8644, but the anti-calmodulin agents had no effect. None of the inhibitors prevented veratridine-induced AVP release. These results are consistent with the hypothesis that the anti-calmodulin agents tested inhibit AVP release by their membrane stabilizing properties rather than by antagonizing Ca2(+)-calmodulin in HNC. Depolarization initiated by Na+ influx may stimulate Na(+)-Ca2+ exchange by a mechanism independent of slow Ca2+ channels as well.

Pertussis toxin reverses adenosine receptor-mediated inhibition of renin secretion in rat renal cortical slices.

Adenosine analogs selective for the A1 subclass of adenosine receptors, such as N6-cyclohexyladenosine (CHA), inhibit renin secretion in in vitro preparations. Ca chelation blocks the inhibitory effect, consistent with mediation by increased intracellular free Ca2+, and it has been suggested that intracellular Ca2+ could increase as a result of receptor-induced inhibition of adenylate cyclase followed by decreased Ca efflux from the renin-secreting cells. Pertussis toxin blocks receptor-induced inhibition of adenylate cyclase in many cells, and in others, it blocks receptor-induced phosphotidylinositol response. In the present studies, pertussis toxin treatment stimulated the basal renin secretory rate of rat renal cortical slices and blocked the inhibitory effect of CHA but not the inhibitory effect of K-depolarization. These data support the hypothesis that a pertussis toxin substrate, such as Ni, is involved in CHA-, but not in K-depolarization, -induced inhibition of renin secretion.

Calcium-dependent inhibition of renin secretion: TMB-8 is a non-specific antagonist.

Intracellular Ca (Cai) is an inhibitory second messenger in renin secretion, and it has been hypothesized that some first messengers--especially angiotensin II [A-II] and antidiuretic hormone [ADH], and possibly A1-adenosine receptor antagonists as well--increase Cai and thereby inhibit renin secretion by causing the release or mobilization of Ca from intracellular sites of sequestration. The present experiments were designed to test this hypothesis, by using 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8), a putative antagonist of Ca release from intracellular sequestration sites. The rat renal cortical slices preparation was used. Basal renin secretory rate was unaffected by 1 and 10 microM TMB-8, but more than doubled in response to 100 microM TMB-8. Basal renin secretory rate was inhibited by A-II (1 microM), by ADH (200 units/1), by an A1-adenosine receptor agonist (N6-cyclohexyladenosine, or CHA; 0.5 microM), and by an alpha-adrenergic agonist (methoxamine; 10 microM). Only the inhibitory effect of methoxamine was blocked by 1 and 10 microM TMB-8, but these concentrations had no effect on basal secretory rate. At 100 microM, TMB-8 blocked the inhibitory effects of ADH as well as of methoxamine, but failed to block the inhibitory effects of CHA and A-II. However, these observations cannot be taken as evidence that methoxamine and ADH, but not CHA and A-II, inhibit renin secretion by a mechanism involving release of Ca from intracellular sequestration sites, because 100 microM TMB-8 clearly had non-specific effects. Among them, it completely blocked the inhibitory effect of K-depolarization on renin secretion. Collectively, at least three separate actions of TMB-8 must be invoked to explain the present results. Likely candidates are an Na-channel blocking effect and a Ca channel blocking effect in addition to antagonism of the release of Cai.

Vanadate-induced inhibition of renin secretion is unrelated to inhibition Na,K-ATPase activity.

There is evidence that three inhibitors of Na,K-ATPase activity--ouabain, K-free extracellular fluid, and vanadate--inhibit renin secretion by increasing Ca2+ concentration in juxtaglomerular cells, but in the case of vanadate, it is uncertain whether the increase in Ca2+ is due to a decrease in Ca2+ efflux (inhibition of Ca-ATPase activity, or inhibition of Na,K-ATPase activity, followed by an increase in intracellular Na+ and a decrease in Na-Ca exchange) or to an increase in Ca2+ influx through potential operated Ca channels (inhibition of electrogenic Na,K transport, followed by membrane depolarization and activation of Ca channels). In the present experiments, the rat renal cortical slice preparation was used to compare and contrast the effects of ouabain, of K-free fluid, and of vanadate on renin secretion, in the absence and presence of methoxyverapamil, a Ca channel blocker. Basal renin secretory rate averaged 7.7 +/- 0.3 GU/g/60 min, and secretory rate was reduced to nearly zero by 1 mM ouabain, by K-free fluid, by 0.5 mM vanadate, and by K-depolarization (increasing extracellular K+ to 60 mM). Although 0.5 microM methoxyverapamil completely blocked the inhibitory effect of K-depolarization, it failed to antagonize the inhibitory effects of ouabain, of K-free fluid, and of vanadate. A concentration of methoxyverapamil two hundred times higher (100 microM) completely blocked the inhibitory effects of vanadate, but still failed to antagonize the effects of ouabain and of K-free fluid. Collectively, these observations demonstrate that vanadate-induced inhibition of renin secretion cannot be attributed entirely to Na,K-ATPase inhibition, since in the presence of methoxyverapamil, the effect of vanadate differed from the effects of either ouabain (a specific Na,K-ATPase inhibitor) or K-free fluid. Moreover, it cannot be attributed entirely to a depolarization-induced influx of Ca2+ through potential-operated Ca channels, since methoxyverapamil antagonized K-depolarization-induced inhibition of renin secretion much more effectively than it antagonized vanadate-induced inhibition.

Cyclosporine A inhibits prostaglandin E2 release, and has no effect on renin secretion, from rat renal cortical slices.

These experiments were designed to test the hypothesis that cyclosporine A (CSA) inhibits renin secretion and stimulates renal prostaglandin E2 (PGE2) release in vitro. In rat renal cortical slices incubated at 37 degrees C in a buffered and oxygenated physiological saline solution containing 4 mM KCl, CSA concentrations ranging from 1 to 30 microM had no significant effect on renin secretion. Furthermore, partial depolarization of the cells, produced by increasing extracellular KCl concentration to 20 mM, failed to reveal any latent inhibitory or stimulatory effects of CSA on renin secretion. On the other hand, PGE2 release was significantly inhibited by CSA over the same range of concentrations. This inhibitory effect might be explained by the previous findings of others, that CSA inhibits phospholipase A2 activity, thereby decreasing arachidonic acid production, the rate-limiting step in PG synthesis. In conclusion, CSA inhibits PGE2 release but fails to affect renin secretion in vitro. These results suggest that the occasional effects of CSA on renin secretion in intact animals must be attributable to indirect and/or chronic effects.

Kappa opiate agonist RU 51599 inhibits vasopressin gene expression and osmotically-induced vasopressin secretion in vitro.

Kappa (kappa) opioid agonists induce a water diuresis and inhibit vasopressin (AVP) secretion. Hypothalamic and neurohypophysial sites have both been implicated in the response. The present study was designed to ascertain if kappa-agonist inhibition of osmotically-stimulated AVP secretion is associated with parallel changes in AVP gene expression. Experiments were performed using the selective kappa-agonist RU 51599 (RU) in compartmentalized hypothalamo-neurohypophysial explants. When added to either the hypothalamus or the neural lobe, RU dose dependently inhibited osmotically-induced AVP secretion that was reversed by the highly selective kappa-antagonist nor-binaltorphimine (nor-BNI) only at the hypothalamic, not the neurohypophysial level. AVP mRNA content paralleled the changes in AVP secretory rate induced by hypothalamic kappa-agonism. AVP mRNA levels were unaltered when RU was applied to the neural lobe. Neurohypophysial AVP content did not change. These data indicate that hypothalamic kappa-agonism inhibits osmotically induced AVP secretion and that a non-kappa1 opiate receptor mediates posterior pituitary opioid inhibition of AVP release. Neural or receptor inputs to the hypothalamus or magnocellular cell body may downwardly modulate AVP mRNA content by altering AVP gene transcription and/or message stability. Inhibition of AVP release directly at the neurohypophysis can be uncoupled from the cellular mechanisms that generate changes in AVP mRNA content.

Disordered water metabolism: hyponatremia.

Normal osmoregulation is maintained by the proper function and interplay of factors influencing thirst, renal water metabolism, and vasopressin secretion. In pathophysiologic states, body water homeostasis is disrupted and hyponatremia ensures. Hyponatremia associated with cardiac failure, hepatic failure, respiratory failure, diabetes mellitus, the postoperative state, and other disorders is commonly found in the critical care setting. The pathophysiology, diagnosis, and treatment of hyponatremia are discussed.

Hemodynamic and biochemical alterations in dogs with lymphoma after induction of chemotherapy.

BACKGROUND: Doxorubicin is a common antineoplastic agent with dose-dependent cardiotoxic adverse effects, and pre-existing myocardial dysfunction is a contraindication to its use. OBJECTIVES: To systematically define the hemodynamic and biochemical alterations in dogs undergoing chemotherapy for newly diagnosed lymphoma and assess the reversibility of these alterations with fluid administration. ANIMALS: Twenty-one client-owned dogs with newly diagnosed lymphoma were evaluated 1 week after induction of chemotherapy. Underlying degenerative valve disease was exclusionary. Eighteen healthy age- and weight-matched dogs were used as controls. METHODS: Physical examination, blood pressure by Doppler, echocardiography, and biochemical evaluation (routine serum biochemistry, plasma renin activity and aldosterone concentrations, plasma and urine osmolalities, and urine electrolyte concentrations) were measured in dogs with lymphoma and compared to controls. Dogs with lymphoma received crystalloids IV at 6 mL/kg/h for 24 hours. All variables were reassessed at 4 and 24 hours. Deuterium oxide dilution and bromide dilution were used to determine total body water and extracellular water space, respectively. RESULTS: Baseline echocardiograms showed significantly smaller chamber dimensions in dogs with lymphoma compared to controls. These changes were reversed by fluid administration. Systolic blood pressure and urine sodium concentration were significantly increased, and bromide dilution space, PCV, urine specific gravity, and urine potassium concentration were significantly decreased compared to controls. CONCLUSION AND CLINICAL IMPORTANCE: Echocardiographic and biochemical abnormalities in dogs with lymphoma appear consistent with volume depletion, and may be the result of systemic hypertension and subsequent pressure natriuresis.

Role of paraventricular nucleus vasopressin V1A receptors in the response to endothelin 1 activation of the subfornical organ in the rat.

Endothelin (ET) acts at selected brain loci to elicit a pressor response and vasopressin (AVP) secretion. The pressor action of centrally acting ET is mediated via enhanced efferent sympathetic nerve activity. ET-induced VP secretion depends upon the ET receptor subtype and the brain region involved. ET(A)R activation at the subfornical organ (SFO) increases mean arterial pressure and renal sympathetic nerve activity (RSNA) as well as AVP secretion in awake rats. These effects are only partly mediated by glutamatergic receptors in paraventricular nucleus (PVN). Recent data indicate dendritic release of AVP may act as a neurotransmitter. We therefore hypothesized that dendritic release of AVP from magnocellular PVN neurons contributes to the increase in arterial pressure and RSNA due to ET(A) receptor activation at SFO. Male Sprague Dawley rats equipped with vascular catheters, renal nerve electrodes, and intracerebral cannulae directed into SFO and magnocellular PVN bilaterally were studied 48hr after recovery in the awake state. Hemodynamic and neural parameters were monitored continuously. Microinjection of 5 pmol ET1 into SFO increased mean arterial pressure by 15.8 +/- 4.2 mmHg accompanied by reflex decreases in heart rate and RSNA. Microinjection of 100 ng of the V(1a) receptor antagonist alone bilaterally into the PVN did not change baseline parameters; however, the pressor response to ET1 was significantly attenuated with mean arterial pressure increasing only by 6.1 +/- 3.0 mmHg (P<0.05). Reflex changes in heart rate and RSNA did not change. These findings support the concept that dendritic release of VP from magnocellular neurons within the PVN mediates, at least in part, the pressor response to ET(A) receptor activation at the SFO.

Effect of endothelin-3 on vasopressin release in vitro and water excretion in vivo in Long-Evans rats.

1. The endothlins (ETs) are a family of homologous peptides originally isolated and purified from cultured porcine endothelial cells. Although initial studies focused on the ETs as potent vasoconstrictor substances, recent findings support a role for ET in vasopressin (AVP) secretion and action. We used cultured explants of the hypothalamo-neurohypophysial complex (HNC) to examine the effects of ET-3 on AVP release. 2. ET-3 produced a significant and concentration-dependent rise in AVP release from the explants of Long-Evans rats at 48 h, independent of medium osmolality. AVP release during two sequential control periods did not differ, and osmotically stimulated AVP release was comparable to that exhibited by HNC explants from Sprague-Dawley rats. ET-3 (1 nM) induced a 3-fold rise in AVP that was completely blocked by rabbit antiET serum, which did not alter basal AVP secretion. 3. Clearance experiments were performed in anaesthetized water-loaded rats given a non-pressor dose of ET-3 (0.40 nmol (kg body weight)-1 intravenously). The means of body weight, arterial blood pressure, plasma Na+ concentrations, and plasma osmolalities did not differ between the first and second periods nor among the groups. Despite no changes in renal plasma flow and inulin clearance, free water clearance significantly increased in the ET-treated group. This response could not be attributed to changes in osmolal clearances or Na+ reabsorption. The concurrent administration of antiET serum not only blocked this effect, but was associated with the free water clearance falling significantly below the pretreatment level. 4. Taken together, our in vivo and in vitro findings support the hypothesis that ET-3 stimulates AVP secretion. Furthermore, our data are consistent with the site of action of ET-3 residing within the blood-brain barrier, though an independent effect by a higher concentration of ET at neural loci outside the barrier cannot be totally excluded. Finally, the subpressor dose of ET-3 amplifies free water excretion independent of systemic and renal haemodynamics, Na+ excretion, osmolal clearance, or circulating AVP levels.

Cation channel mechanisms in ET-3-induced vasopressin secretion by rat hypothalamo-neurohypophysial explants.

Endothelins modulate not only vasoregulation but also neurotransmission and hormone secretion, specifically vasopressin (AVP) secretion. The present studies were designed to ascertain the site of action and the participation of membrane cation channels mediating endothelin-3-induced AVP release. Experiments were performed using standard and compartmentalized hypothalamo-neurohypophysial explants. The stimulatory action of endothelin-3 on AVP release occurred at the neural lobe, consistent with the failure of sodium channel blockade to decrease AVP secretion. Calcium channel antagonism or chelation of extracellular calcium inhibited neurohormone release, but blockade of calcium mobilization from intracellular stores with 8-(diethyl-amino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) did not. Inhibition of the calcium-activated potassium channel with charybdotoxin increased AVP levels dose dependently. Potassium ionophore abolished this response, as did TMB-8, but inhibition of calcium entry failed to do so. A subthreshold dose of charybdotoxin potentiated AVP secretion to submaximal stimulation with endothelin-3 that was prevented only by concomitant blockade of calcium influx and intracellular mobilization. The data support interaction between calcium and potassium channels at the secretory terminal. Collectively, these data are consistent with endothelin-3 receptor activation at the secretory terminal initiating calcium entry, thereby leading to depolarization independent of sodium conductances. This mechanism is opposed by hyperpolarizing forces linked to calcium accumulation, namely, the charybdotoxin-sensitive calcium-activate potassium channel. Interaction of the depolarizing and repolarizing systems enables grade AVP secretion from the neural lobe. These findings do not preclude the participation of other systems as well.

Dopaminergic control of angiotensin II-induced vasopressin secretion in vitro.

Because dopamine influences arginine vasopressin (AVP) release, the present studies were designed to ascertain the dopamine receptor subtype that potentiates angiotensin II-induced AVP secretion in cultured hypothalamo-neurohypophysial explants. Dopamine (a nonselective D1/D2 agonist), apomorphine (a D2 >> D1 agonist), and SKF-38393 (a selective D1 agonist) dose dependently increased AVP secretion. Maximal AVP release was observed with 5 microM dopamine, 307 +/- 66% . explant-1 . h-1, 1 microM SKF-38393, 369 +/- 41% . explant-1 . h-1, and 0.1 microM apomorphine, 374 +/- 67% . explant-1 . h-1. Selective D1 antagonism with 1 microM SCH-23390 blocked AVP secretion to values no different from basal. Domperidone (D2 antagonist), phenoxybenzamine (nonselective adrenergic antagonist), and prazosin (alpha1-antagonist) failed to prevent release. D1 antagonism also prevented AVP secretion to 1 microM angiotensin II [angiotensin II, 422 +/- 87% . explant-1 . h-1 vs. angiotensin II plus SCH-23390, 169 +/- 28% . explant-1 . h-1 (P < 0.05)], but D2 and alpha1-adrenergic blockade did not. In contrast, AT1 receptor inhibition with 0.5 microM losartan blocked angiotensin II- but not dopamine-induced AVP release. AT2 antagonism had no effect. Although subthreshold doses of the agonists did not increase AVP secretion (0. 05 microM dopamine, 133 +/- 44% . explant-1 . h-1; 0.01 microM SKF-38393, 116 +/- 26% . explant-1 . h-1;and 0.001 microM angiotensin II, 104 +/- 29% . explant-1 . h-1 ), the combination of dopamine and angiotensin II provoked a significant rise in AVP [420 +/- 83% . explant-1 . h-1 (P < 0.01)]. Similar results were observed with SKF-38393 and angiotensin II, and the AVP response was blocked to basal levels by either D1 or AT1 antagonism. These findings support a role for D1 receptor activation to increase AVP release and mediate angiotensin II-induced AVP release within the hypothalamo-neurohypophysial system. The data also suggest that the combined subthreshold stimulation of receptors that use distinct intracellular pathways can prompt substantial AVP release.

Anti-calmodulin agents affect osmotic and angiotensin II-induced vasopressin release.

Calcium ions and particularly calcium influx play a crucial part in initiating the intracellular events that result in arginine vasopressin (AVP) release to both osmotic and nonosmotic stimuli. Calmodulin appears to modulate the effects of calcium on synaptic transmission and hormone release in other systems. This study tested the effects of three distinct classes of anti-calmodulin agents on the release of AVP to either a rise in osmolality of 20 mosmol/kg water or to 1 X 10(-5) angiotensin II (ANG II) in cultured hypothalamo-neurohypophysical complexes. Micromolar concentrations of R 24571, the active naphthalenesulfonamides, W 7 and W 13, and trifluoperazine (TFP) inhibited AVP release to osmotic stimulation. In contrast, W 5, a severalfold less active anti-calmodulin agent, had no effect on osmotically stimulated AVP release. The active naphthalenesulfonamides, but not R 24571 or TFP, blocked release of AVP to ANG II. In contrast, neither R 24571 nor TFP inhibited AVP release to ANG II stimulation. Collectively, the data demonstrated a dissociation between inhibition of AVP release and the anti-calmodulin properties of the drugs, thereby suggesting that nonspecific actions masked the calmodulin-blocking effects of the drugs or that the inhibition occurred by some alternative mechanism(s).