We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require I.

Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.Nesfatin-1 is an 82-amino acid neuropeptide produced in the hypothalamus that acts on the brain to suppress appetite (1-6), increase energy expenditure (7), and induce cardiovascular changes, leading to body weight reduction (1), blood pressure (BP) elevation (8-10), and increased insulin sensitivity (11) in animals. Intracerebroventricular (ICV) administration of nesfatin-1 reduces food intake and body weight gain and elevates BP, heart rate (HR) (8), and peripheral glucose uptake (11). Thus, central nesfatin-1 may regulate the function of peripheral organs through neural activity to maintain homeostasis and regulate a number of physiological processes.Regarding the neural mechanism of physiological regulation by nesfatin-1, our previous study demonstrated that sympathetic nervous supply to the kidneys in anesthetized rats could be stimulated by the ICV injection of nesfatin-1 (10), suggesting that the sympathetic nervous system mediates the action of nesfatin-1. Recently, it has been reported that increased sympathetic stimulation of white adipose tissue (WAT) and the liver resulted in lipolysis (12) and glucogenesis (13), respectively, with the intracerebral administration of leptin, a feeding regulator and sympathetic activator. Thus, central nesfatin-1 may modulate sympathetic nerve outflow to WAT and the liver and regulate lipid and glucose metabolism; however, there are no studies reporting the effect of ICV nesfatin-1 on the neural activity of sympathetic nerves to WAT and the live...

Background: Patients treated with propranolol, a nonselective ␤-adrenoceptor antagonist, have increased incidence and severity of anaphylaxis. We determined whether ␤ 1 -or ␤ 2 -adrenoceptor antagonist modulated pulmonary vasoconstriction and bronchoconstriction in rat anaphylactic hypotension. Methods: Anesthetized ovalbumin-sensitized male SpragueDawley rats were randomly allocated to the following pretreatment groups (n ϭ 7/group): (1) sensitized control (nonpretreatment), (2) propranolol, (3) the selective ␤ 2 -adrenoceptor antagonist ICI 118,551, (4) the selective ␤ 1 -adrenoceptor antagonist atenolol, and (5) adrenalectomy. Shock was induced by an intravenous injection of the antigen. Mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, portal venous pressure, airway pressure, and aortic blood flow were continuously measured. Results: In either sensitized control or atenolol-pretreated rats, mean arterial pressure and aortic blood flow decreased substantially, whereas pulmonary arterial pressure and airway pressure did not increase soon after antigen injection. In contrast, in rats pretreated with either propranolol, ICI 118,551, or adrenalectomy, airway pressure significantly increased by 14 cm H 2 O, and pulmonary arterial pressure by

The autonomic nervous system plays an important role in rat anaphylactic hypotension. It is well known that sympathetic nerve activity and cardiovascular function are affected by anesthetics. However, the effects of different types of anesthesia on the efferent renal sympathetic nerve activity (RSNA) during anaphylactic hypotension remain unknown. Therefore, we determined the renal sympathetic responses to anaphylactic hypotension in anesthetized and conscious rats and the roles of baroreceptors in these responses. Sprague-Dawley rats were randomly allocated to anesthetic groups that were given pentobarbital, urethane, or ketamine-xylazine and to a conscious group. The rats were sensitized using subcutaneously injected ovalbumin. The systemic arterial pressure (SAP), RSNA and heart rate (HR) were measured. The effects of sinoaortic baroreceptor denervation on RSNA during anaphylaxis were determined in pentobarbital-anesthetized and conscious rats. In all of the sensitized rats, the RSNA increased and SAP decreased after antigen injection. At the early phase within 35 min of the antigen injection, the antigen-induced sympathoexcitation in the conscious rats was significantly greater than that in the anesthetized rats. Anaphylactic hypotension was attenuated in the conscious rats compared to the anesthetized rats. The anesthetic-induced suppression of SAP and RSNA was greater in the order ketamine-xylazine >urethane = pentobarbital. Indeed, in the rats treated with ketamine-xylazine, RSNA did not increase until 40 min, and SAP remained at low levels after the antigen injection. The baroreceptor reflex, as evaluated by increases in RSNA and HR in response to the decrease in SAP induced by sodium nitroprusside (SNP), was suppressed in the anesthetized rats compared with the conscious rats. Consistent with this finding, baroreceptor denervation attenuated the excitatory responses of RSNA to anaphylaxis in the conscious rats but not in the pentobarbital-anesthetized rats. RSNA was increased markedly in conscious rats during anaphylactic hypotension. Anesthetics attenuated this antigen-induced renal sympathoexcitation through the suppression of baroreceptor function.

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