Dietary salt with nitric oxide deficiency induces nocturnal polyuria in mice via hyperactivation of intrarenal angiotensin II-SPAK-NCC pathway.

Nocturnal polyuria is the most frequent cause of nocturia, a common disease associated with a compromised quality of life and increased mortality. Its pathogenesis is complex, and the detailed underlying mechanism remains unknown. Herein, we report that concomitant intake of a high-salt diet and reduced nitric oxide (NO) production achieved through Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) administration in mice resulted in nocturnal polyuria recapitulating the clinical features in humans. High salt intake under reduced NO production overactivated the angiotensin II-SPAK (STE20/SPS1-related proline-alanine-rich protein kinase)-NCC (sodium chloride co-transporter) pathway in the kidney, resulting in the insufficient excretion of sodium during the day and its excessive excretion at night. Excessive Na excretion at night in turn leads to nocturnal polyuria due to osmotic diuresis. Our study identified a central role for the intrarenal angiotensin II-SPAK-NCC pathway in the pathophysiology of nocturnal polyuria, highlighting its potential as a promising therapeutic target.

Lesions of hypothalamic mammillary body desynchronise milk-ejection bursts of rat bilateral supraoptic oxytocin neurones.

Successful milk ejection depends on a bolus release of oxytocin, which results from the synchronised burst firing of magnocellular oxytocin neurones in several hypothalamic nuclei. Despite extensive studies of the mechanism underlying the burst synchrony of oxytocin neurones in the same nucleus, brain regions controlling burst synchronisation among different nuclei remain elusive. We hypothesised that some structures in the ventroposterior hypothalamus may function as the major component of neural circuits controlling burst synchronisation of bilateral oxytocin neurones. To test this hypothesis, we recorded burst firing of bilateral oxytocin neurones in the two supraoptic nuclei after microsurgical disconnection of different hypothalamic regions in anaesthetised lactating rats. The results obtained showed that the interhemispheric section of the caudal part of the hypothalamus but not the rostral hypothalamus resulted in burst desynchronisation. The difference in burst onset time between paired bursts of bilateral oxytocin neurones was 129.2 ± 34.7 s, which is significantly (P < 0.01) longer than that of sham-lesioned controls (0.24 ± 0.02 s). Hypothalamic lesions leading to the desynchronisation involved the mammillary body, supramammillary nucleus and tuberomammillary nucleus in the ventroposterior hypothalamus. Consistently, electrolytic lesion of the median part of this mammillary body region also desynchronised the burst of bilateral oxytocin neurones and disrupted milk ejections. These results indicate that the mammillary body region is critically involved in the burst synchronisation of bilateral oxytocin neurones during suckling and possibly functions as the major component of a putative synchronisation centre.

Relativistic jet activity from the tidal disruption of a star by a massive black hole.

Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close, producing a bright flare in ultraviolet and X-ray spectral regions from stellar debris that forms an accretion disk around the black hole. The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies, but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.

Association between minor physical anomalies and lateral ventricular enlargement in childhood and adolescent onset schizophrenia.

OBJECTIVE: The primary purpose of this study was to investigate the association between morphological abnormalities of brain and minor physical anomalies (MPAs) in childhood and adolescent onset schizophrenia. METHOD: Twenty-seven patients who had been diagnosed with schizophrenia according to DSM-IV criteria before 18 years of age were included in the study. MPAs were evaluated with the modified version of Waldrop scale (WS) by Green et al. Morphological abnormalities of brain was evaluated with ventricular-brain ratio (VBR) by using cerebral magnetic resonance imaging (MRI) examination. RESULTS: A significant positive correlation was observed between WS scores and VBRs. CONCLUSION: This result indicates a relationship between MPAs and lateral ventricular enlargement, and supports neurodevelopmental etiology in childhood or adolescent onset schizophrenia.

The contribution of the median preoptic nucleus to renal sympathetic nerve activity increased by intracerebroventricular injection of hypertonic saline in the rat.

The median preoptic nucleus (MnPO) of the hypothalamus is involved in the osmotic control of neurohypophysial hormone release and drinking behavior. At the same time, renal sympathetic nerves exert multiple effects on renal functions such as regulating renal blood flow and urinary sodium excretion. We made the hypothesis that the MnPO may also regulate body fluid balance by exerting an influence on renal sympathetic nerve activity (RSNA). In this study we examined the effect of electrical stimulation of the MnPO on RSNA and the contribution of the MnPO to the change of RSNA induced by intracerebroventricular injection of hypertonic saline in the male Wistar rat. Electrical stimulation of the MnPO and the paraventricular nucleus of the hypothalamus (PVN) elicited an increase in RSNA. This increase of RSNA elicited by electrical stimulation of the MnPO was reduced by microinjections (100 nl) of 10% lidocaine or 4 mM cobaltous chloride (a synaptic transmission blocking agent) bilaterally into the PVN. Both RSNA and the mean arterial pressure (MAP) were increased by the injection of 1.5 M NaCl into the third ventricle, although heart rate (HR) was not significantly changed. These responses of RSNA and MAP were diminished by microinjection of 10% lidocaine (100 nl) into the MnPO. Our results suggest that the MnPO is involved in body fluid regulation not only by controlling vasopressin secretion and water intake but also by modulating central sympathetic outflow which regulates body fluid balance through an effect on the kidney.

Activation of gastric afferents increases noradrenaline release in the paraventricular nucleus and plasma oxytocin level.

Effects of electrical stimulation of the gastric vagal nerves on plasma levels of oxytocin (OXT) and arginine vasopressin (AVP) were examined in rats anesthetized with urethane. Electrical stimulation of the gastric vagal nerves increased the plasma levels of OXT, but not AVP. The concentrations of extracellular noradrenaline (NA) in the paraventricular nucleus (PVN) were measured by in vivo microdialysis in rats anesthetized with urethane. Electrical stimulation of the gastric vagal nerves evoked an increase followed by a slight decrease in the concentrations of NA. The responses of spontaneous firing magnocellular neurosecretory neurons in the PVN to both electrical stimulation of the gastric vagal nerves and intravenous (i.v.) administration of CCK-8 were examined. Most of the putative OXT-secreting cells recorded were excited by both electrical stimulation of gastric vagal nerves and i.v. administration of CCK-8. These results suggest that gastric vagal afferents activate the central noradrenergic system from the brainstem to the PVN and secretion of OXT.

Excitation of oxytocin cells in the hypothalamic supraoptic nucleus by electrical stimulation of the dorsal penile nerve and tactile stimulation of the penis in the rat.

In urethane-anaesthetized male rats, electrical stimulation of the dorsal penile nerve (DPN) excited 29 of 48 (60%) oxytocin cells in the contralateral supraoptic nucleus, whereas only 5 of 28 (18%) vasopressin cells were excited by the stimulation. The stimulus applied to the ipsilateral DPN to the recorded neurone also excited a similar proportion of oxytocin cells (25 of 43; 58%). Tactile stimulation of the glans penis excited 7 of 12 (58%) oxytocin cells, whereas the same stimulation excited only 3 of 16 (19%) vasopressin cells. The results suggest that sensory information arising from the penis preferentially excites oxytocin cells in the supraoptic nucleus.

Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus.

BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.

Elevated serum lipoprotein (a) levels associated with ulcerative colitis in a young Japanese patient.

Thromboembolism has been shown to play a role in the pathogenesis of inflammatory bowel disease (IBD). A possibility exists that lipoprotein (a) [Lp(a)], a newly-discovered prothrombotic factor, also participates in the development of at least some cases of IBD. Marked elevation of serum Lp(a) levels was observed in a young patient with ulcerative colitis. A biopsy specimen of the rectal mucosa showed findings compatible with ulcerative colitis, as well as small vessel thrombus occurring within the muscularis mucosa in the rectum. Serum Lp(a) levels were markedly elevated on admission (71 mg/dl), with a gradual decrease to 46 mg/dl on discharge. Moreover, serum Lp(a) levels decreased in parallel with clinical improvement. In the quiescent clinical stage, no small vessel thrombus was observed in the mucosa on follow-up colonoscopy. The association between IBD and hyper-Lp(a)-emia would be presumable but it has been, to our knowledge, previously unreported. The case reported here would be the first young patient, suggesting the presence of hyper-Lp(a)-emia and small vessel thrombus formation occurring in association with the development of ulcerative colitis.

Effect of interhemispheric sections of the hypothalamus on milk-ejection bursts of supraoptic oxytocin neurones during bilateral and unilateral suckling in the rat.

The burst activity of oxytocin neurones was recorded from the supraoptic nucleus of lactating rats with or without interhemispheric sectioning of the hypothalamus during bilateral or unilateral suckling. The results showed that extensive interhemispheric sectioning did not abolish the burst of oxytocin neurones during bilateral and contralateral suckling (100% of 25 neurones and 95% of 20 neurones, respectively), but significantly reduced the number of oxytocin neurones that showed the burst during ipsilateral suckling (5.3% of 19 neurones). To orientate the crossing site of the signals for bilateral synchronization of the bursts of oxytocin neurones, interhemispheric sectioning of the rostral or caudal hypothalamus was attempted, but either sectioning partially blocked the occurrence of the bursts during ipsilateral suckling. These results suggest that there are two separate gates located on different sides of the hypothalamus and that the neural connections between the gates seem distributed diffusely.

The effect of systemic and central nitric oxide administration on milk availability in lactating rats.

This study examined the effect of nitric oxide (NO) on milk transfer in rats. Pups nursed by mothers that received chronic systemic injections of sodium nitroprusside (SNP) weighed significantly less than pups of mothers treated with either saline or N omega-nitro-L-arginine (NNLA). Intracerebroventricular injection of SNP or L-arginine (L-arg) but not NNLA or saline, caused a significant reduction of milk transfer from mother to pups after a 12 h separation period. Systemic oxytocin (OT) injection reversed the effect of central injection of SNP. Furthermore, SNP and L-arg inhibited, whereas NNLA permitted the characteristic milk ejection burst of OT neurones without changing myoepithelial tissue response to systemic OT. These observations suggest that NO may be involved in the regulation of milk ejection bursts and milk transfer.

Afferents originating from the dorsal penile nerve excite oxytocin cells in the hypothalamic paraventricular nucleus of the rat.

Electrical stimulation of the dorsal penile nerve (DPN) produced orthodromic excitation in about half of oxytocin cells in the paraventricular nucleus (PVN). In contrast, less than 10% of vasopressin cells were excited. Tactile stimulation of the glans penis by a paintbrush produced excitation in 40% of oxytocin cells. Castration did not prevent activation of oxytocin cells. These results suggest that somatosensory information from the penis is transmitted to the PVN through the DPN and that such afferent input preferentially innervates oxytocin cells.

Milk ejection bursts of supraoptic oxytocin neurones during bilateral and unilateral suckling in the rat.

Extracellular recordings of the electrical activity of oxytocin neurones were made from the supraoptic nuclei (SON) of lactating rats, and the milk-ejection bursts and the background activity of oxytocin neurones were investigated during unilateral and bilateral suckling. When application of pups was limited to the nipples on either the same side (ipsilateral suckling) or the side opposite (contralateral suckling) to the oxytocin neurone recorded, the burst amplitude and background firing rate were significantly (P < 0.05) lower and the inter-burst interval was significantly (P < 0.05) longer than during bilateral suckling. Furthermore, the burst amplitude was significantly (P < 0.05) lower during ipsilateral suckling than during contralateral suckling. The majority of the oxytocin neurones showed a gradual increase in the burst amplitude during bilateral (88.9%) and contralateral (77.3%) suckling, but during ipsilateral suckling only 40% of the neurones did. The inter-burst interval became shorter with the progress of the milk ejection reflex during any mode of suckling. Three pairs of oxytocin neurones recorded simultaneously from both SON were successfully tested for the effect of bilateral and unilateral suckling on the electrical activity, and the results showed the same direction of change in the burst amplitude, background activity and burst interval as shown in single side recordings. These findings indicate that the burst amplitude mainly depends on the amount of afferent suckling signals arising from the nipples on the side opposite to the recording side, and that there may exist bilateral summation centres coordinating with the synchronization mechanism of milk-ejection bursts of oxytocin neurones.

Amplitudes and time courses of milk ejection bursts of oxytocin neurons in the midbrain-hemitransected lactating rat.

In the midbrain-hemitransected rats, 22 pairs of oxytocin neurons were recorded from 17 rats. Of the bursts on the lesioned side, the amplitude was smaller, the onset time was later and the burst span was shorter (P < 0.01). These results indicated that the amplitude and time course of the burst of oxytocin neurons mainly depend on suckling information from the nipples on their opposite side.

Median preoptic neurones projecting to the supraoptic nucleus are sensitive to haemodynamic changes as well as to rise in plasma osmolality in rats.

Extracellular single unit activity was recorded from 73 neurones in the median preoptic nucleus (MnPO), identified by antidromic activation as projecting to the supraoptic nucleus (SON) area in urethane-anaesthetized male rats. Thirteen of 73 identified MnPO neurones were silent, and 44 of 60 spontaneously active MnPO neurones were tested for their responses to electrical stimulation of the nucleus tractus solitarius (NTS). The cells were divided into 4 groups according to their responses; those which were excited orthodromically (OD+; n = 15), those which were unresponsive (UN; n = 21), those which were inhibited orthodromically (OD-; n = 4), those which showed initial inhibition followed by excitation (OD-+ n = 4). Some of these neurones were further tested for their responses to haemorrhage and/or produced by intraperitoneal injection of 1.5 M NaCl. Six out of 10 OD+ cells were excited by haemorrhage, 6 out of 11 OD+ cells were inhibited by phenylephrine, and 5 out of 9 OD+ cells were excited by hypertonic saline. On the other hand the UN cells tended to be unresponsive to each type of stimulus. Three out of 7 OD+ cells were excited by both haemorrhage and hypertonic saline, and 3 out of 8 OD+ cells were inhibited by phenylephrine and excited by hypertonic saline. The results may suggest that MnPO neurones which receive afferent input from the NTS may be sensitive not only to haemodynamic change but also to change in plasma osmotic pressure and that such population of MnPO neurones may integrate a part of the haemodynamic and osmotic information and contribute to the control of neurohypophysial hormone release.

Effect of ovarian steroid hormones and the presence of the fetus on oxytocin gene expression in the uterus.

Oxytocin (OT) is a neurohypophysial hormone with potent stimulating activity of the pregnant uterus, but its physiological role in parturition is still unclear. Recently, OT was found to be synthesized in the pregnant uterus, indicating that OT originating from the uterus, not from the posterior pituitary gland, may trigger the onset of labour. In order to define the factors responsible for the induction of uterine OT, the effect of ovarian steroid hormones and conceptus on the induction of OT mRNA in the rat uterus was examined by Northern and dot blot hybridization analysis. OT mRNA in the uterus started to increase on day 14 of pregnancy and showed very high levels at the time of parturition. Uterine OT mRNA was not altered by any steroid treatment, oestradiol-17 beta (0.2 microgram), progesterone (4 mg) or both in combination, for 6 days. The gravid horn of the uterus had 3.6-fold as much OT mRNA as the non-gravid horn on day 21 of pregnancy in hemipregnant rats with one ligated oviduct. The ovarian steroid hormones could not induce accumulation of OT mRNA in the uterus of ovariectomized rats, at least under the conditions used, but the presence of a conceptus may be critical for the very high levels of OT mRNA.

Effects of hemitransection of the midbrain on milk-ejection burst of oxytocin neurones in lactating rat.

Unilateral knife cuts were performed in the midbrain of lactating rats and the activities of oxytocin neurones were recorded extracellularly from the supraoptic nuclei (SON) in order to investigate the location of the neural mechanism responsible for the synchronization of milk-ejection bursts of oxytocin neurones in different magnocellular nuclei of the hypothalamus. The lesions involved the mesencephalic lateral tegmentum, the intermedial tegmentum and the central grey. Ninety-six SON neurones were antidromically activated by neurohypophyseal stimulation and were also identified as oxytocin neurones, which included 17 pair-recorded neurones. First, the response of oxytocin neurones recorded from the unilateral SON to bilateral or unilateral suckling was tested. During bilateral suckling, not only the oxytocin neurones recorded from the SON on the intact side (n = 34) but also those recorded from the SON on the lesioned side (n = 58) displayed milk-ejection bursts. When only the nipples ipsilateral to the lesion were suckled (ipsilateral suckling), bursts were induced in most of the oxytocin neurones on the intact (83.3%, n = 12) and lesioned side (88.9%, n = 27). In contrast, none of the oxytocin neurones (n = 37) produced bursts and none of the rats tested (n = 23) showed milk ejections during contralateral suckling. Secondly, some characteristics of the bursts of pair-recorded neurones during bilateral suckling and their response to different modes of suckling were investigated.(ABSTRACT TRUNCATED AT 250 WORDS)