Hepatocyte-specific disruption of soluble epoxide hydrolase attenuates abdominal aortic aneurysm formation: novel role of the liver in aneurysm pathogenesis.

Introduction: Inflammation is a key pathogenic feature of abdominal aortic aneurysm (AAA). Soluble epoxide hydrolase (sEH) is a pro-inflammatory enzyme that converts cytochrome P450-derived epoxides of fatty acids to the corresponding diols, and pharmacological inhibition of sEH prevented AAA formation. Both cytochrome P450 enzymes and sEH are highly expressed in the liver.

Central sympathetic chemosensitivity and Kir1 potassium channels in the cat.

The possible involvement of potassium channels in central chemosensitivity, with special reference to the Kir1.1 potassium channel, was investigated by studying the CO(2) response of presympathetic neurons in the rostroventrolateral medulla (RVLM) in the absence or presence of various K(+) channel inhibitors. Synaptic input to RVLM neurons was blocked by local injection of omega-agatoxin and omega-conotoxin.

Central hypercapnic chemoreflex modulation of renal sympathetic nerve activity in experimental heart failure.

Activation of the sympathetic nervous system plays an important role in the pathophysiology and progression of congestive heart failure (CHF). The precise mechanisms responsible for sympathetic activation in CHF are not yet clearly established. An altered central hypercapnic chemoreflex modulation of sympathetic nerve activity (SNA) might be an explanation.

Lack of neurotrophin-4 causes selective structural and chemical deficits in sympathetic ganglia and their preganglionic innervation.

Neurotrophin-4 (NT-4) is perhaps the still most enigmatic member of the neurotrophin family. We show here that NT-4 is expressed in neurons of paravertebral and prevertebral sympathetic ganglia, i.e.

[Quality assurance (general) at the medical school of Heidelberg as a model].

Because of new social and professional challenges, especially in the developed countries, there is a trend towards change and quality assurance is taking place in medical education over the past 20 years. In Heidelberg, the new way of teaching the students by general practitioners includes quality assurance by questionnaires, reports of practice visits, quality conferences of the teachers, and co-operation of the students. 90% of the students recommended the practice-based structured program as very useful, especially the work with the patients in the general practices, 87% of the teaching general practitioners accepted special criteria for teaching; by this way an academic general practice can be established to meet the future expectations of primary medical care.

Sympathoinhibitory effects of clonidine are transmitted by the caudal ventrolateral medulla in cats.

We examined mechanisms of the central sympathoinhibitory actions of systemically administered clonidine in anesthetized cats. To avoid influences of sympathetic chemo- and baroreflexes, the animals were deafferentated by cutting the carotid sinus and vagal nerves bilaterally. Intravenous (i.

Nitric oxide in the ventrolateral medulla regulates sympathetic responses to systemic hypoxia in pigs.

The role of nitric oxide (NO) in the regulation of sympathetic activity during hypoxia was studied in anesthetized pigs (n = 21). Hypoxia (fractional concentration of O2 in inspired air = 0.1) increased pulmonary arterial pressure and decreased arterial blood pressure and peripheral vascular resistance.

Impaired modulation of sympathetic excitability by nitric oxide after long-term administration of organic nitrates in pigs.

Background: Endogenous nitric oxide (NO) reduces sympathetic vasoconstriction by attenuating neuronal excitability in the brain stem and inhibition of postganglionic neurotransmission. We studied whether this modulation of sympathetic circulatory control by NO may be altered during chronic administration of NO donor drugs in pigs.

Methods And Results: Nitrate tolerance was induced by oral administration of isosorbide dinitrate (ISDN, 4 mg/kg per day for 4 weeks) in eight pigs.

Species differences in the distribution of nitric oxide synthase in brain stem regions that regulate sympathetic activity.

The distribution of nitric oxide synthases (NOS) in the lower brain stem was studied by NADPH-diaphorase staining with emphasis on the nucleus of the solitary tract and the ventrolateral medulla. The order of NOS density was hamster > rabbit = rat > mouse > guinea-pig > cat with little variation within species or between regions. This heterogeneity may partly explain qualitatively and quantitatively variable effects of NO on sympathetic activity in different species.

Activation of chemosensitive neurons in the ventrolateral medulla by capsaicin in cats.

We examined effects of centrally administered capsaicin on sympathetic nerve activity (SNA), blood pressure (BP) and heart rate (HR) in chloralose anesthetized cats (n = 18). Upon perfusion of the lower brain stem via the left vertebral artery, capsaicin (0.1-1.

Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs.

Mechanisms of the modulation of sympathetic activity by neuronal NO were studied in vagotomized anesthetized pigs. Inhibition of neuronal NO synthase (nNOS) within the brain stem by intracerebroventricular (ICV) administration of 7-nitroindazole (7-NI, 1 mmol/L) or S-methyl-L-thiocitrulline (MeTC, 0.1 mmol/L) caused slight increases in renal sympathetic nerve activity (RSNA) but did not affect arterial blood pressure (BP) or cardiac output (CO).

Role of calcium-dependent K+ channels in the regulation of arterial and venous tone by nitric oxide in pigs.

Effects of inhibition of calcium-dependent potassium channels (K+Ca channels) on the regulation of arterial and venous tone by nitric oxide (NO) were studied in anaesthetized pigs following vagotomy and blockade of autonomic ganglia. Selective inhibition of K+Ca channels by charybdotoxin (CTX, 2 microg/kg iv) or iberiotoxin (IbTX, 1 microgram/kg) significantly augmented mean total peripheral resistance (TPR) to levels 30-60% above control. Venous and pulmonary vascular tone were assessed by changes in effective compliances of the venous (EVC) and pulmonary (EPC) vascular beds as calculated from changes in central venous and diastolic pulmonary arterial blood pressure during haemorrhagia (-5 ml/kg) and hypervolaemia (+5 ml/kg).

Lack of nitric oxide sensitivity of carotid sinus baroreceptors activated by normal blood pressure stimuli in cats.

We examined the effects of inhibition of nitric oxide (NO) synthesis and local administration of NO-donors on baroreceptor activity in anaesthetized cats. Baroreceptor activity was assessed by measuring changes in the pulse synchronous carotid sinus nerve discharge in a modified blind sack preparation. Within physiological mean arterial blood pressure (BP) ranges (BP = 70-150 mmHg), neither abluminal (in a pool around the carotid sinus, n = 15) nor intravascular (via the A.

Convergence of visceral and somatic afferents on single neurones in the reticular formation of the lower brain stem in dogs.

The reticular formation of the lower brain stem contains neuronal circuits for the generation of sympathetic tone, respiratory rhythm, muscle tone and the control of vigilance. In anesthetized dogs single neurone activities were recorded in the medial two-thirds of the reticular formation to investigate the organizing principles of this multifunctional system. The results from 110 recordings demonstrate that single neurones receive information from somatosensory afferents of skin, joints and muscles together with afferents from baro-, chemo- and lung inflation and deflation receptors.

Carl Ludwig and the localization of the medullary vasomotor center: old and new concepts of the generation of sympathetic tone.

In Carl Ludwig's laboratories in Leipzig, P. Owsjannikow (1871) and C. Dittmar (1873) performed precise, histologically controlled lesioning experiments into the question of the location of the vasomotor center in the medulla oblongata.

Effects of nitric oxide on sympathetic baroreflex transmission in the nucleus tractus solitarii and caudal ventrolateral medulla in cats.

We have previously shown that nitric oxide (NO) attenuates baseline sympathetic tone in the rostral ventrolateral medulla (RVLM), while having no effects on baroreflex transmission in this region in cats. In the present study, we tested the effects of microinjections (500 nl) of NG-nitro-L-arginine (L-NNA, 0.3 mM) or the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10 microM) in the nucleus tractus solitarii (NTS) and in the caudal ventrolateral medulla (CVLM) which are the two other relays of the sympathetic baroreflex within the brainstem.

Effects of inhibitors of enzymatic and cellular pH-regulating systems on central sympathetic chemosensitivity.

Previous studies in cats using isolated NaCl-CO2 perfusion of the lower brainstem demonstrated an intrinsic chemosensitivity of sympathoexcitatory bulbospinal neurones within the rostroventrolateral medulla (RVLM). In the present experiments, the effects of inhibitors of enzymatic and cellular systems, known to be involved in pH regulation, were investigated. Isolated perfusion of the lower brainstem with CO2-enriched solutions was performed and preganglionic sympathetic nerve activity (SNA) was recorded.

Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide.

We examined possible functional roles for nitric oxide (NO) in the rostral ventrolateral medulla (RVLM), which is the final area for integration of sympathetic nerve activity (SNA) within the brain stem. Chloralose-anesthetized cats were completely baro- and chemoreceptor denervated, the RVLM was exposed for microinjections, and preganglionic SNA was recorded from the white ramus of the 3rd thoracic segment. Injections of NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, but not of NG-nitro-D-arginine, caused distinct increases in SNA and arterial blood pressure (BP).

The importance of baroreceptor afferents for the decrease in brain glucose utilization during stimulation of the rostroventrolateral medulla of the rat.

The rostroventrolateral medulla (RVLM) is the main integration center for the regulation of the sympathetic outflow. The present study had the aim of investigating the effects of stimulation of the RVLM on the glucose utilization of the brain. Local cerebral glucose utilization (LCGU) can be regarded as an indicator of the brain functional activity.

Changes in medullary extracellular pH, sympathetic and phrenic nerve activity during brainstem perfusion with CO2 enriched solutions.

Measurements are presented of sympathetic nerve activity (SNA), phrenic nerve activity (PNA), and local extracellular pH (ECF pH) within the rostral ventrolateral medulla (RVLM) in response to perfusions of the RVLM with CO2-enriched saline. Experiments were performed on cats anaesthetized with chloralose. The ventrolateral medullary surface was exposed, and a catheter was placed in the left vertebral artery from the axilla to allow perfusion of the RVLM.

Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo.

The objective of this study was to determine whether vasodilator effects of nitric oxide (NO) can be explained by the inhibition of vasoconstriction caused by peripheral sympathetic nerve activity (SNA) in vivo. For this purpose, we studied the effects of systemic inhibition of NO synthesis during experimental variation of SNA in anesthetized cats. Intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) in baroreceptor-intact animals (n = 6) caused increases in mean arterial blood pressure (MAP) from 105.

Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat.

The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP).

Somato-sympathetic reflex transmission in the ventrolateral medulla oblongata: spatial organization and receptor types.

Tonic sympathetic activity in vivo is continuously modulated by inhibitory and excitatory reflex mechanisms. We studied the properties of somato-sympathetic excitatory reflex transmission in the rostral ventrolateral medulla (RVLM) of baroreceptor-denervated and vagotomized chloralose-anesthetized cats. Electrical stimulation of the left intercostal nerve of the 4th thoracic segment (IC-T4) elicited an early spinal and a late supraspinal reflex in the ipsilateral white ramus T3 from which recordings were made.

Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity.

We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.