Tadalafil: protective action against the development of multiple organ failure syndrome

Abstract Introduction: Multiple organ failure syndrome (MOFS) is a pathology associated to unspecified and severe trauma, characterized by elevated morbidity and mortality. The complex inflammatory MOFS-related reactions generate important ischemia-reperfusion responses in the induction of this syndrome. Nitric oxide elevation, through the activation of cyclic guanosine monophosphate (cGMP), has the potential of counteracting the typical systemic vasoconstriction, and platelet-induced hypercoagulation. Tadalafil would possibly act protectively by reducing cGMP degradation with consequent diffuse vasodilatation, besides reduction of platelet-induced hypercoagulation, thus, preventing multiple organ failure syndrome development. Methods: The experimental protocol was previously approved by an institution animal research committee. Experimental MOFS was induced through the stereotaxic micro-neurosurgical bilateral anterior hypothalamic lesions model. Groups of 10 Wistar rats were divided into: a) Non-operated control; b) Operated control group; c) 2 hours after tadalafil-treated operated group; d) 4 hours after tadalafil-treated operated group; e) 8 hours after post-treated operated group. The animals were sacrificed 24 hours after the neurosurgical procedure and submitted to histopathologic examination of five organs: brain, lungs, stomach, kidneys, and liver. Results: The electrolytic hypothalamic lesions resulted in a full picture of MOFS with disseminated multiple-organs lesions, provoked primarily by diffusely spread micro-thrombi. The treatment with tadalafil 2 hours after the micro-neurosurgical lesions reduced the experimental MOFS lesions development, in a highly significant level (P<0.01) of 58.75%. The treatment with tadalafil, 4 hours after the micro-neurosurgically-induced MOFS lesions, also reduced in 49.71%, in a highly significant level (P<0.01). Finally, the treatment with tadalafil 8 hours after the neurosurgical procedure resulted in a statistically significant reduction of 30.50% (P<0.05) of the experimentally-induced MOFS gravity scores. Conclusion: The phosphodiesterase 5 inhibitor, tadalafil, in the doses and timing utilized, showed to protect against the experimentally-induced MOFS.

study on the postnatal development and aging changes of the neurosecretory nuclei of the hypothalamus [supraoptic and paraventricular nuclei] in the albino rat

The hypothalamus is a distinct neurological entity concerned with a variety of regulatory processes. Recently, the prescence of variations in the level of neurosecretions wth the progress of age was reported. To study the changes in the structure of magnocellular neurons in the paraventricular and supraoptic nuclei during the period of postnatal development. Furthermore, to study the changes which occurred in the structure of these neurons in the old age had been studied. A total of 52 albino rats were used. The age groups of the animals include: one day, 10 days, 20 days, 2 months and 2 years old animals. Brains were processed to be studied with Einarson's gallocyanin-chrome alum stain, Golgi- Cox method and transmission electron microscope. In addition, the number of cells in the magnocellular part of the paraventricular and supraoptic nuclei were measured in all studied age groups and statistically analyzed. In the newly born rats, the paraventricular and supraoptic nuclei were composed of small rounded condensed cells. At the age of 10 days old rats, the paraventricular nucleus appeared to be well differentiated into ventromedial [parvocellular] and dorsolateral [magnocellular] parts. With the progress of age from 10 days up to the adult stage, the cells of the supraoptic nucleus and the magnocellular part of the paraventricular nucleus appeared to be densely stained which indicated increase in the Nissl granules. Ultrastructural study showed that the cells had abundant amount of free ribosomes, rough endoplasmic reticulum and mitochondria. The nucleus had fine dispersed chromatin. Golgi-Cox study showed marked increase in extension and branching of dendrites with the progress of age during the developmental period. Morphometric study showed significant increase in the number of cells from the new born up to the adult stage. In old aged rats, the cells of the paraventricular nucleus and the supraoptic nucleus appeared to be faintly stained. Some cells had vacuolated cytoplasm. Ultrastructural study showed marked decrease in the free ribosomes and the presence of many lipofuscin pigment in the cytoplasm of cells. The nucleus showed chromatin condensation and irregularity of the nuclear membrane. In addition, there was apparent decrease in the amount of the synaptic vesicles in the presynaptic terminals making contacts with the magnocellular neurons. Golgi-Cox study revealed marked decrease in the extension and branching of dentrites. Morphometric analysis showed significant decrease in the number of cells. This study demonstrated in the presence of structural changes in the magnocellular part of the paraventricular nucleus and supraoptic nucleus during the period of development. In old age, the presence of many degenerative changes was observed. This cytoarchitectonic analysis and morphological study could help in the explanation of the functional differences in the various ages

Safe Sedation and Hypnosis using Dexmedetomidine for Minimally Invasive Spine Surgery in a Prone Position

Dexmedetomidine, an imidazoline compound, is a highly selective alpha2-adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an alpha2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus.

Safe Sedation and Hypnosis using Dexmedetomidine for Minimally Invasive Spine Surgery in a Prone Position

Dexmedetomidine, an imidazoline compound, is a highly selective alpha2-adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an alpha2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus.

A Case of Adipsic Hypernatremia Associated with Anomalous Corpus Callosum in Adult with Mental Retardation

Adipsic hypernatremia cause chronic hyperosmolality and hypernatremia through a combination of impaired thirst and osmotically stimulated antidiuretic hormone secretion. This syndrome can be grouped together as disorders of osmoreceptor dysfunction due to the various degrees of osmoreceptor destruction related with different types of intracranial lesions around the anterior hypothalamus, consistent with the location of primary osmoreceptor cells. Adipsic hypernatremia, associated with developmental disorder of corpus callosum, is very rare. Most cases are diagnosed at infancy and early childhood; the replacement of desmopressin is necessary. Herein, we report adipsic hypernatremia associated with anomalous corpus callosum in adult with mental retardation; they were treated with only free water without desmopressin.

Gabaergic mechanisms of anterior and ventromedial hypothalamic nuclei in the expression of freezing in response to a light-conditioned stimulus

The amygdala, dorsal periaqueductal gray (dPAG), and medial hypothalamus have long been recognized to comprise a neural system responsible for the generation and elaboration of unconditioned fear in the brain. This neural substrate is well known to be under tonic inhibitory control exerted by ã-aminobutyric acid (GABA) mechanisms. Some evidence also suggests that these structures integrate conditioned fear. A recent study using the fear-potentiated startle paradigm showed that GABAergic mechanisms in the anterior hypothalamic nucleus (AHN) and dorsomedial part of the ventromedial hypothalamic nucleus (VMHDM) regulate conditioned fear. The present study examined the extent to which GABAergic mechanisms in these brain regions are involved in conditioned fear by measuring freezing in response to a light used as a conditioned stimulus (CS). The GABA A receptor agonist muscimol and the GABA-synthesizing enzyme glutamic acid decarboxylase inhibitor semicarbazide were used as an enhancer and inhibitor of GABA mechanisms, respectively. Muscimol and semicarbazide were injected into the AHN or VMHDM of rats before fear conditioning. Muscimol injections into the AHN and VMHDM significantly reduced conditioned freezing, whereas inhibition of GABA transmission increased this conditioned response in the AHN. The present study further supports the hypothesis that GABAergic mechanisms in the AHN and VMHDM exert inhibitory control on the neural substrates of conditioned fear in the hypothalamus.

Mammalian Molecular Clocks

As a consequence of the Earth's rotation, almost all organisms experience day and night cycles within a 24-hr period. To adapt and synchronize biological rhythms to external daily cycles, organisms have evolved an internal time-keeping system. In mammals, the master circadian pacemaker residing in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus generates circadian rhythmicity and orchestrates numerous subsidiary local clocks in other regions of the brain and peripheral tissues. Regardless of their locations, these circadian clocks are cell-autonomous and self-sustainable, implicating rhythmic oscillations in a variety of biochemical and metabolic processes. A group of core clock genes provides interlocking molecular feedback loops that drive the circadian rhythm even at the single-cell level. In addition to the core transcription/translation feedback loops, post-translational modifications also contribute to the fine regulation of molecular circadian clocks. In this article, we briefly review the molecular mechanisms and post-translational modifications of mammalian circadian clock regulation. We also discuss the organization of and communication between central and peripheral circadian oscillators of the mammalian circadian clock.

Effects of gypsum on the firing of pyrogen-treated thermosensitive neurons in PO/AH of cats / 中国应用生理学杂志

<p><b>AIM</b>To investigate the possible central mechanism of antipyretic effects of Chinese medicine gypsum.</p><p><b>METHODS</b>Gypsum was injected after the fever model was established. The firing rate of thermosensitive neurons in preoptic-anterior hypothalamus(PO/AH) region was recorded by using extracellular microelectrode technique.</p><p><b>RESULTS</b>The injection of pyrogen evoked decrease in firing rate of the warm-sensitive neurons and increase in the cold-sensitive neurons in the region of PO/AH; the changes of the firing rate of pyrogen- treated warm-sensitive and cold-sensitive neurons could be reversed by the injection of gypsum.</p><p><b>CONCLUSION</b>The result may suggest that antipyretic action of gypsum is mediated by its influences on the thermosensitivity neurons in the region of PO/AH.</p>

Neuroanatomy of Sleep-Wake Regulation and its Application to Pharmacotherapy / 대한정신약물학회지

A current hypothesis of sleep-wake regulation proposes that the sleep process starts with the activation of sleep-promoting neurons located in the preoptic area of the anterior hypothalamus. This activation leads to the inhibition of wake-promoting neurons located in the posterior hypothalamus, basal forebrain, and mesopontine tegmentum, which, in turn removes inhibition from the sleep-promoting structures(i.e., disinhibition) to initiate the sleep process. Mutual inhibition between these wake- and sleep-promoting neurons results in switching properties that define discrete wakeful and sleep states with sharp transitions between them. Wake-promoting nuclei include the orexinergic lateral hypothalamic/perifornical area, the histaminergic tuberomammillary nucleus, the cholinergic pedunculopontine tegmental nucleus, the noradrenergic locus coeruleus, the 5-hydroxytryptaminergic raphe nuclei, and possibly the dopaminergic ventral tegmental area. The major sleep-promoting nucleus is the GABAergic ventrolateral preoptic nucleus of the hypothalamus. The regulation of sleep is classically viewed as the dual interaction of circadian(SCN-based) and homeostatic processes, and the propensity to be asleep or awake at any given time is a consequence of a sleep debt and its interaction with signals from the SCN circadian clock. To better understand the mechanisms of sleep and wakefulness, the focus of pharmacotherapy is on targeting specific therapies to the particular defect in sleep-wake regulation.

Bases psiconeuroendócrinas del dimorfismo sexual cerebral / Psychoneuroendocrine bases for brain sexual dimorphism

Con el avance de las neurociencias, cada vez se conoce más sobre las características morfológicas y funcionales del cerebro, la acción de los neuroesteroides y los aspectos genómicos y no genómicos involucrados en la modulación de las características específicas de cada sexo, con sus aspectos biomorfológicos, fisiológicos, psicológicos y sociales. El presente artículo aborda los avances en el conocimiento del dimorfismo sexual cerebral a fin de intentar comprender estas peculiaridades biológicas y funcionales y su posible influencia en las conductas sanas y en las diferencias sexuales clínicamente evidentes en las formas de expresión, evolución, pronóstico y respuesta al tratamiento de las enfermedades mentales. Pone además el énfasis en el estudio integrativo de la persona, desde un abordaje psiconeuroinmunoendocrinológico.

Efectos hipotalámicos de la angiotensina -[1-7] en ratas con coartación aórtica / Hypothalamic effects of angiotensin -[1-7] in rats with aortic coarctation

El objetivo del presente trabajo fue evaluar el efecto de la administración intrahipotalámica de la angiotensina -[1-7](Ang-[1-7]) sobre la presión arterial y la frecuencia cardíaca y sobre la actividad presora de la angiotensina II (Ang-II) en ratas con operación simulada (OS) o con coartación aórtica (CoAo) en un estadio temprano y en uno crónico de la hipertensión. Se utilizaron ratas Wistar. A los 7 y 42 días de la operación correspondiente se canuló una arteria carótida para la medición de la presión arterial media (PAM) en ratas anestesiadas y se insertó una aguja inyectora en el hipotálamo anterior para la administración de Ang-II (50 ng), Ang-[1-7] (50ng) y Ang-II + Ang-[1-7] (50 + 50 ng). La administración hipotálamica de Ang-II produjo un aumento de la PAM en las ratas CoAo con respecto al grupo control en los estadios temprano y crónico de hipertensión, mientras que la Ang-[1-7] redujo la actividad presora de la Ang-II en las ratas CoAo, mientras que careció de efecto sobre la actividad presora de la Ang-II en las ratas normotensas. En conclusión, la actividad presora de la Ang-II está aumentada en ratas en los estadios temprano y crónico de hipertensión arterial, mientras que el efecto antagónico de la Ang-[1-7] indicaría que ésta modularía la actividad presora de la angiotensina II cuando la Ang-II estuviera exacerbada, ya que se ha observado únicamente en el grupo de ratas hipertensas.

A case of fever of unknown origin after removal of hypothalamic tumor / 대한내과학회지

The preoptic area and anterior hypothalamus plays a pivotal role in body temperature regulation, and damage in this region causes hyperthermia. This hyperthermia is particularly troublesome because of the possibility that it may reflect an occult infectious process. We report a case of fever of unknown origin in a patient after removal of neoplasm involving the hypothalamus. A 29-year old man underwent craniotomy and removal of hypothalamic choroid meningioma. Seventy days after the removal of his tumor, his body temperature began to rise. But, there was no evidence of infection, inflammatory disease, metabolic disease, drug fever and recurred tumor. Repeated administration of antipyretic agent did not reduce body temperature. So, we considered that the elevated temperature had a central basis. The patient was treated with chlorpromazine in an attempt to lower his temperature. This drug reduced successfully his body temperature.

Neonatal handling and the expression of immunoreactivity to tyrosine hydroxylase in the hypothalamus of adult male rats

Neonatal handling has long-lasting effects on behavior and stress reactivity. The purpose of the present study was to investigate the effect of neonatal handling on the number of dopaminergic neurons in the hypothalamic nuclei of adult male rats as part of a series of studies that could explain the long-lasting effects of neonatal stimulation. Two groups of Wistar rats were studied: nonhandled (pups were left undisturbed, control) and handled (pups were handled for 1 min once a day during the first 10 days of life). At 75-80 days, the males were anesthetized and the brains were processed for immunohistochemistry. An anti-tyrosine hydroxylase antibody and the avidin-biotin-peroxidase method were used. Tyrosine hydroxylase-immunoreactive (TH-IR) neurons were counted bilaterally in the arcuate, paraventricular and periventricular nuclei of the hypothalamus in 30-æm sections at 120-æm intervals. Neonatal handling did not change the number of TH-IR neurons in the arcuate (1021 + or - 206, N = 6; 1020 + or - 150, N = 6; nonhandled and handled, respectively), paraventricular (584 + or - 85, N = 8; 682 + or - 62, N = 9) or periventricular (743 + or - 118, N = 7; 990 + or - 158, N = 7) nuclei of the hypothalamus. The absence of an effect on the number of dopaminergic cells in the hypothalamus indicates that the reduction in the amount of neurons induced by neonatal handling, as shown by other studies, is not a general phenomenon in the brain

Pacemaker interactions in the mammalian circadian system

Circadian rhythms in mammals are generated by pacemaker cells located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The identity of these cells, however, is not known, and little information exists regarding the mechanisms by which they communicate with each other and with the organism. Nonetheless, pacemaker interactions must occur to produce single, coherent rhythms of behavior and physiology. Recently it has become possible to observe the result of these interactions using circadian chimeras, animals with two clocks with distinct periods, that have been produced by SCN transplantation. Using the tau mutation in golden hamsters, chimeras expressing two circadian rhythms of behavior simultaneously were created. The two rhythms exhibited complex interactions including cases of relative coordination. This basic result indicates that pacemaker interactions are rhythmic and phase dependent. Further analysis should help to elucidate the nature of the coupling signal and the identity of the pacemaker cells.

Electrical and chemical stimulation of the same hypothalamic loci in relation to agressive behaviour in cats: a comparison study.

Chemitrodes which permit electrical and chemical stimulation of the same hypothalamic loci were implanted in anterior hypothalamic and preoptic regions. These sites were stimulated electrically using biphasic square wave pulse (1 ms, 60 Hz) at a current strength ranging from 150-800 microA to evoke an aggressive response. At lower current strength of 150-200 micro A, defence response, a sort of non-specific response can be elicited from these regions. Increasing the current strength to 400 microA led to the recruitment of affective and somatic components and changed the response pattern either to affective attack or flight. The loci producing affective attack response were localized more laterally and ventrally while the loci producing flight response were located in the dorsomedial regions of the hypothalamus. In this response the animal made a goal-directed attempt to escape through an escape route. Increasing the current strength to 500 microA in the dorsomedial regions changed the flight response to violent flight, which involved vigorous running with unsheathed claws and attacking objects if obstructed. Similar increase in current strength at loci producing affective attack only led to a decrease in the latency of response and made the attack more vigorous. Microinfusion of carbachol in graded doses of 2-15 microgram at all these loci produced a profound affective display. At lower doses of 2 and 5 microgram, only some components of affective display like alertness, pupillary dilation and ear flatness were exhibited. Increasing the dose to 10 micrograms and 15 micrograms led to the recruitment of other affective components like piloerection, salivation, hissing and baring of teeth. Microinfusion of carbachol at all loci producing affective attack on electrical stimulation produced a prononced affective display while microinfusion of carbachol at loci producing flight response led to the development of defence posture. At six loci a typical flight response was obtained while violent flight was never exhibited at any of these sites. Microinfusion of atropine (10 microgram in 1.0 microliter saline) at these loci completely blocked the carbachol induced response. Both somatomotor and affective components were completely inhibited. However, the responses obtained on electrical stimulation were not totally blocked following atropine infusion and some of the somatomotor and affective components could be elicited with higher current strength. These studies indicate the involvement of cholinoceptive mechanisms in the elicitation of hypothalamically induced aggresive behaviour. Microinfustion of hexamethonium bromide, a nicotinic blocker in 50 micrograms doses did not affect the aggressive response.

Vasopressin: an approach to its actions in the central nervous system

A vasopressina é um hormônio neurohipofisário que age de forma anti-diurética e sobre a pressäo. Além destas açöes periféricas, diversas açöes centrais lhe säo atribuídas, especialmente no que diz respeito aos processos de memória e de aprendizado. O presente estudo enfatiza alguns aspectos neuroanatomofisiológicos e farmacológicos da vasopressina, bem como seu envolvimento nos processos centrais. Discutem-se aqui, ainda, várias teorias que pretendem explicar os mecanismos de açäo deste hormônio sobre os processos cognitivos, seu possível envolvimento em vários processos ligados ao acordar, sono REM, estresse, emotividade, ansiedade, neuromodulaçäo e os efeitos de determinadas drogas

Comportamento muricida em ratos com lesäo eletrolítica bilateral do hipotálamo anterior pré-tratados com morfina / Muricide behavior in eletrolitic bilateral anterior hypothalamus lesioned rats pre-treated with morphine

Estudamos o aparecimento de agressividade, caracterizada pelo comportamento muricida, em ratos com lesäo eletrolítica bilateral do hipotálamo anterior, pré-tratados com morfina. Observamos a presença desta agressäo com morfina nas doses de 10,20 e 40mg/kg, chegando a atingir um nível de 79 por cento dos animais. Constatamos que este efeito é resultado da associaçäo da lesäo e morfina, uma vez que a lesäo ou a morfina apenas, näo produz agressividade. O comportamento muricida foi bloqueado pelo Nalaxone, indicando que este efeito é próprio do opióide