The sympathetic nervous system and blood pressure in humans: implications for hypertension

A neurogenic component to primary hypertension (hypertension) is now well established. Along with raised vasomotor tone and increased cardiac output, the chronic activation of the sympathetic nervous system in hypertension has a diverse range of pathophysiological consequences independent of any increase in blood pressure. This review provides a perspective on the actions and interactions of angiotensin II, inflammation and vascular dysfunction/brain hypoperfusion in the pathogenesis and progression of neurogenic hypertension. The optimisation of current treatment strategies and the exciting recent developments in the therapeutic targeting of the sympathetic nervous system to control hypertension (for example, catheter-based renal denervation and carotid baroreceptor stimulation) will be outlined.     

Sources of Uncertainty and Their Association with Medical Decision Making: Exploring Mechanisms in Fanconi Anemia

Background

Effects of different sources of medical uncertainty on people’s health-related cognitions, emotions, and decision making have yet to be systematically examined.

Purpose

The aim of this study is to examine how uncertainties arising from different sources are associated with decision making regarding stem cell transplantation in Fanconi anemia, a rare, inherited bone marrow failure syndrome that typically presents during childhood.

Methods

Data were collected through a cross-sectional survey of 178 parents of 126 Fanconi anemia patients.

Results

Two distinct sources of uncertainty were associated with decision outcomes: probability was associated with a lower likelihood of choosing stem cell transplantation, and ambiguity due to conflicting expert opinions was associated with greater decision-making difficulty. Concern about transplantation may mediate these associations.

Conclusions

Different sources of uncertainty have different effects on Fanconi anemia treatment decisions, which may be mediated by parents’ emotional reactions. Further research is needed to elucidate these effects and help Fanconi anemia families cope with uncertainty.     

Comparison of Dexmedetomidine–Ketamine with Isoflurane for Anesthesia of Chinchillas (Chinchilla lanigera)

The objective of this study was to compare isoflurane with a combination of dexmedetomidine and ketamine, administered intramuscularly, for anesthesia in chinchillas (Chinchilla lanigera). In a prospective, complete crossover study, adult chinchillas (n = 8; age, 2 to 5 y) were anesthetized with a combination of dexmedetomidine (0.015 mg/kg IM) and ketamine (4 mg/kg IM). Atipamezole (0.15 mg/kg) was injected subcutaneously 45 min after dexmedetomidine–ketamine administration. For comparison, anesthesia also was induced and maintained with isoflurane in 100% oxygen, delivered by facemask. Anesthetic and physiologic parameters were recorded during each anesthesia, including various reflexes, heart rate, respiratory rate, body temperature, and SpO₂. Food intake, fecal output, and body weight were recorded daily for 6 d after each anesthetic trial. Induction time, heart rate, respiratory rate, and body temperature did not differ significantly between the 2 anesthetic protocols. Recovery times were shorter and SpO₂ was higher in animals that received isoflurane delivered in 100% oxygen. Food intake and fecal output were reduced in the dexmedetomidine–ketamine group for as long as 3 d after anesthesia, whereas isoflurane had no signifcant effect on food intake or fecal output. Both anesthetic protocols provided effective anesthesia in chinchillas. However, when anesthetized with dexmedetomidine–ketamine, chinchillas received room air and became hypoxemic. Future studies are needed to evaluate the effect of oxygen supplementation on anesthetic recovery and on the recovery of food intake and fecal output in chinchillas.Abbreviation: DK, dexmedetomidine–ketamineChinchillas are used extensively in research to study otitis media, hearing loss, and ototoxicity.^1,11,19,25 In addition, chinchillas are becoming increasingly popular as companion animals and, therefore, are more frequently presented for veterinary care. Common diseases of chinchillas include dental disease, gastrointestinal disorders, and ocular disorders.^13,14 Chemical immobilization is often required to perform diagnostic (for example, radiography, CT), therapeutic, or experimental procedures.^3,5,7,21 Research regarding the efficacy and safety of anesthetic protocols in chinchillas is limited and currently recommended protocols rely largely on extrapolation from other species or anecdotal reports.^13,21,27Isoflurane is used routinely in chinchillas for the induction and maintenance of anesthesia. A study investigating the echocardiographic effects of isoflurane in chinchillas found significant effects on several echocardiographic parameters, but no complications or other side effects were reported.¹² Isoflurane typically is delivered by facemask to chinchillas, given that endotracheal intubation is technically challenging and therefore not performed routinely.^10,21 However, using a facemask increases the risk of exposure of the veterinary staff to waste gases, which is a significant occupational health concern.^20,23 Therefore, alternative anesthetic protocols that reduce waste-gas exposure are desired, such as exclusively using injectable anesthetic drugs for induction and maintenance of anesthesia. Intravascular access is challenging to obtain in conscious chinchillas, and thus parenteral, nonvascular protocols provide the most accommodating route for anesthesia induction and maintenance.¹⁴ Only one study in chinchillas has investigated the effects of various injectable anesthetics: a combination of medetomidine (0.06 mg/kg) and ketamine (5 mg/kg) was compared with other parenteral protocols.¹⁴ Although anesthesia was successful with this protocol, the authors reported respiratory and cardiac depression in the animals. Furthermore, although atipamezole is commonly administered in clinical and research settings to promote rapid recovery and prevent complications, such as hypothermia, it was not used in the cited study.¹⁴To our knowledge, no studies have been published that assess the effects of anesthetic protocols on recovery of food intake and fecal output in chinchillas. The objective of this study was to compare the anesthesia induced in chinchillas by using either dexmedetomidine and ketamine or isoflurane and to evaluate the effects of both anesthetic protocols on subsequent food intake, fecal output, and body weight.     

Ischaemia-induced sympathoexcitation in spinalyzed rats

Systemic ischaemia increases sympathetic activity via both reflex and direct effects on the nervous system, which include the hypothalamus and brainstem structures that provide excitatory drive to sympathetic pre-ganglionic motoneurones. Using an arterially perfused working heart-brainstem preparation (WHBP), we evaluated the sympathoexcitatory response recorded from the thoracic sympathetic chain (tSC) in response to systemic ischaemia (produced by arresting perfusion for 30 s) before and after transecting consecutively at both the ponto-medullary and medullary-spinal cord junctions. Ischaemia produced a striking increase in tSC activity that persisted after transecting at both the ponto-medullary and medullary-spinal cord levels (intact: 70+/-3%; ponto-medullary: 77+/-7%; medullary-spinal cord: 61+/-6%; n=9). In sino-aortic denervated (SAD) rats (n=4), sympathoexcitatory responses were smaller in both intact and ponto-medullary, but not in medullary-spinal cord transected versus intact rats. Following administration of a ganglionic blocker [hexamethonium (hex), 25 mg/kg] after medullary-spinal cord transection the ischaemia-induced sympathoexcitatory response was reduced (12+/-6% increase relative to control, n=4). In medullary-spinal cord transected preparations, intrathecal injection of N2-saturated saline increased tSC discharge (22+/-3%, n=4), which was attenuated by hex (5+/-1%). We propose that neural mechanisms within the cervical-thoracic segments can make a substantial contribution to the sympathoexcitatory response during systemic ischaemia.     

Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior

Peripheral immune activation can have profound physiological and behavioral effects including induction of fever and sickness behavior. One mechanism through which immune activation or immunomodulation may affect physiology and behavior is via actions on brainstem neuromodulatory systems, such as serotonergic systems. We have found that peripheral immune activation with antigens derived from the nonpathogenic, saprophytic bacterium, Mycobacterium vaccae, activated a specific subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus (DRI) of mice, as measured by quantification of c-Fos expression following intratracheal (12 h) or s.c. (6 h) administration of heat-killed, ultrasonically disrupted M. vaccae, or heat-killed, intact M. vaccae, respectively. These effects were apparent after immune activation by M. vaccae or its components but not by ovalbumin, which induces a qualitatively different immune response. The effects of immune activation were associated with increases in serotonin metabolism within the ventromedial prefrontal cortex, consistent with an effect of immune activation on mesolimbocortical serotonergic systems. The effects of M. vaccae administration on serotonergic systems were temporally associated with reductions in immobility in the forced swim test, consistent with the hypothesis that the stimulation of mesolimbocortical serotonergic systems by peripheral immune activation alters stress-related emotional behavior. These findings suggest that the immune-responsive subpopulation of serotonergic neurons in the DRI is likely to play an important role in the neural mechanisms underlying regulation of the physiological and pathophysiological responses to both acute and chronic immune activation, including regulation of mood during health and disease states. Together with previous studies, these findings also raise the possibility that immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors. Consequently, selective activation of specific subsets of serotonergic neurons may have distinct behavioral outcomes.