Interaction of epicutaneously applied lipids with stratum corneum depends on the presence of either emulsifiers or hydrogenated phosphatidylcholine.

The barrier function of the stratum corneum (SC) significantly determines the interaction of epicutaneously applied substances with the skin organ. Although the exact molecular processes are still unclear, it is undoubted that the intercellular lipid composition and order of the SC is significantly involved in this interaction. Topically substituted phases, especially those of lipophilic composition, seem to interact very intensely with lipid membranes; they can be integrated, form separate phases, or even permeate through the SC into the viable skin. The latter is not desired, especially in barrier-protective preparations with a lipophilic phase. The present paper investigates the penetration behavior of topically applied, DiI-labeled lipids into human ex vivo skin depending on the phase organization of different o/w emulsifiers compared to emulsifier-free preparations containing hydrogenated phosphatidylcholine by means of fluorescence indication. Results are presented for intact and defined damaged epidermal barrier. In addition, the washout effect based on skin samples treated by artificial watering after lipid incubation, and the influence of the phase transition temperature of the SC membrane were studied. The results show that in intact and damaged skin, the penetration depth of the lipids increases directly proportionally with the hydrophilic-lipophilic balance (HLB value), while the washout effect and the HLB value proved to be inversely related. An increase in penetration depth with higher HLB values was also apparent when the phase transition temperature of the physiological membranes was exceeded. Altogether, the results clearly demonstrate that the characteristics of the emulsifying phase of a preparation significantly determine the interaction of a substituted lipophilic phase with the SC. Especially bipolar lipids, like phosphatidylcholines, showed intradermal dispersion patterns which hint at an especially intense interaction with physiological membranes.

Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).

BACKGROUND: For long-term management of atopic eczema, the use of skin care creams is recommended, but effectiveness of this treatment is not well established. OBJECTIVE: The objective of this study was to yield data on the skin care properties of a cream with a unique lamellar matrix containing N-palmitoylethanolamine (PEA) and to assess quality-of-life variables in patients with mild to moderate atopic eczema. SETTING: In this multinational, multicentre, observational, non-controlled, prospective cohort study, patients between 2 and 70 years of age were enrolled. All patients were supplied with the study product sufficient for treatment over the entire study period. Outcome was followed in periods between 3 and 7 days and 4 and 6 weeks after study start. Data were gathered from doctor reports and patient self-assessments via patient questionnaires. RESULTS: Data from 2456 patients entered the database. The mean examination intervals were 6 days for the 3- to 7-day period and 38 days for the 4- to 6-week period. At study end, intensities of erythema, pruritus, excoriation, scaling, lichenification and dryness were significantly reduced with a combined score reduction of 58.6% in the entire population (57.7% in adults > 12 years and 60.5% in children

Antihypertensive effect of 0.1-Hz blood pressure oscillations to the kidney.

BACKGROUND: Physiological blood pressure (BP) fluctuations with frequencies >0.1 Hz can override renal blood flow autoregulation. The influence of such immediate changes in renal perfusion pressure (RPP) on daily BP regulation, eg, via shear stress-stimulated liberation of renal endothelial NO, however, is unknown. Thus, we studied the effects of such RPP oscillations on renal function and on systemic BP during the onset of renal hypertension. METHODS AND RESULTS: Seven beagles (randomly assigned to each of the following protocols) were chronically instrumented for the measurement of systemic BP, RPP, and renal excretory function. An inflatable cuff was used to reduce and to oscillate RPP over 24 hours in the freely moving dog. Reducing RPP to 87+/-2 mm Hg diminished excretion of sodium and water and doubled plasma renin activity (PRA, n=7, P<0. 01) but had no significant effect on urinary nitrate excretion (n=6), a marker of NO generation. Superimposing 0.1-Hz oscillations (+/-10 mm Hg) onto the reduced RPP blunted hypertension, returned fluid excretion almost to control levels, and doubled renal sodium elimination. Nitrate excretion peaked at 8 hours, only to return to control values shortly thereafter. PRA, conversely, was significantly reduced during the last third of the experimental protocols. CONCLUSIONS: BP fluctuations transiently stimulate NO liberation and induce a reduction in PRA, which enhances 24-hour sodium and water excretion and markedly attenuates the acute development of renovascular hypertension.

ACE inhibition facilitates sodium and water excretion during PEEP in conscious volume-expanded dogs.

Increased activity of the renin-angiotensin system may be involved in sodium and water retention during controlled mechanical ventilation (CMV) with positive end-expiratory pressure (PEEP). We therefore evaluated renal, hemodynamic, and hormonal effects of an acute angiotensin-converting enzyme inhibition (ACEI) during PEEP and extracellular volume expansion in five trained chronically tracheotomized dogs. Three protocols were performed: control, 4 h spontaneous breathing with continuous positive mean airway pressure (Paw) of 4 cmH2O (CPAP 4); CMV 20, CPAP for 1st h, CMV with 20 cmH2O Paw for 2 h (2nd and 3rd h), and 1 h of CPAP (4th h); and CMV20-ACEI, ACEI (Ramipril, 2 mg/kg body wt) followed by the same protocol as in CMV 20. During control, sodium excretion (UNaV) and urine volume (V) increased continuously to 56.2 +/- 2.7 (SE) mumol.min-1.kg body wt-1 and 482 +/- 23 microliters.min-1.kg body wt-1, respectively. UNaV and V increased less during PEEP in CMV 20 and CMV 20-ACEI. However, significantly more sodium and water were retained in CMV 20 than in CMV 20-ACEI (2.3 +/- 0.3 vs. 1.0 +/- 0.3 mmol/kg body wt, and 20 +/- 3 vs. 11 +/- 2 ml/kg body wt) because of a decrease of glomerular filtration rate and fractional UNaV in CMV 20. Heart rate did not change in control, CMV 20, or CMV 20-ACEI. Mean arterial pressure increased during control by 13 mmHg, did not change during CMV 20, and was decreased by 7 mmHg in CMV 20-ACEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of catheter-related infections by a new, catheter-restricted antibiotic filling technique.

Catheter-related infections pose a hazard to both humans and laboratory animals. The aim of this study was to develop a technique preventing bacterial colonization of intravascular catheters. In 27 dogs a total of 70 catheters were implanted. On an average catheters were used for 207 days. Three protocols were compared: (1) flushing the catheters with a heparinized solution; (2) filling only the catheter lumen with alpha-chymotrypsin solution (225 units/ml); (3) filling only the catheter lumen with a solution containing a mixture of the aminoglycoside antibiotic gentamicin (20 mg/ml) and chymotrypsin (225 units/ml). Catheter fillings were always withdrawn before catheter use. Catheter exit sites were all treated with povidone iodine ointment once a day. Body temperatures and weights were recorded, bacteriological and electron microscopical examinations of catheters performed. Without gentamicin filling all catheters were colonized after a few weeks. The dogs showed clinical signs of chronic bacteraemia. Gentamicin filling eradicated colonization. No further bacteraemia was observed. We conclude that filling only the catheter lumen with a concentrated solution of chymotrypsin and gentamicin, combined with measures to prevent infections via the subcutaneous catheter tunnel, is an effective and safe technique to prevent catheter-related infections.

[Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus]. / Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus.

BACKGROUND: Chronic, therapy-resistant pruritus often fails to respond to standard measures so new therapeutic approaches are needed. Recently, the expression of cannabinoid receptors on cutaneous sensory nerve fibers was described, so cannabinoid agonists seem a rational therapeutic option for pruritus. PATIENTS: In an open application observation 22 patients with prurigo, lichen simplex and pruritus applied an emollient cream containing N-palmitoyl ethanolamine (PEA). RESULTS: In 14/22 patients a good antipruritic effect could be documented. The average reduction in itch was 86.4%. The therapy was well-tolerated by all patients; neither burning burn nor contact dermatitis was observed. CONCLUSIONS: Topical cannabinoid agonists represent an new effective and well-tolerated therapy for refractory itching of various origins. Creams with a higher concentration may be even more effective with broader indications.

Arterial blood gas tensions and acid-base status of Wistar rats during thiopental and halothane anesthesia.

Arterial blood gas tensions and acid-base status of spontaneously-breathing, unanesthetized Wister rats were compared with values obtained during 4 hr of thiopental and 6 hr of halothane (1%) anesthesia. During thiopental anesthesia, marked respiratory depression occurred (PaCO-2:57.0 plus or minus 10.0 MM Hg, PaO-2:70.4 plus or minus 11.2 MM Hg). Thirty-six percent of the rats died. During inhalation of room air and 1% halothane, PaO-2 decreased also, whereas PaO-2 did not change. Twenty-seven percent of the original number of rats died. Lowered arterial oxygen tension may have caused death; no rats died during inhalation of oxygen and 1% halothane. This technic insured sufficient analgesia for surgical procedures without marked alterations of the acid base status and is recommended for long-term anesthesia of small laboratory animals like rats.

The control of sodium metabolism to maintain osmo- and volumehomeostasis.

Chronically instrumented female beagles were maintained in standardized environmental and dietary conditions allowing careful examination of the mechanisms governing sodium homeostasis. The experimental increase in left atrial pressure (obtained by a reversible mitral stenosis) is accompanied by an increase in sodium excretion (atrial natriuresis, AN). AN served as an experimental manoeuvre from which the mechanisms governing sodium homeostasis could be elucidated. The results allow the following conclusions: (1) The 'signals' arising from distension of the left atrium (e.g. expansion of the extracellular fluid volume) appear not to be a necessary prerequisite for the maintenance of sodium homeostasis. (2) The control mechanisms seem to be very sensitive to changes in total body sodium (TBS). A small reduction in TBS abolishes sodium eliminating processes e.g. saline diuresis, osmotic diuresis, AN. (3) It is probable that a natriuretic factor exists for sodium elimination. In summary, total body sodium appears to be controlled by a series of 'redundant' mechanisms which guarantee an appropriate strategy for the comfort and ultimate survival of the organism. At the moment it is impossible to quantitate the contributions made by the various mechanisms in the control of sodium metabolism.

Atrial natriuresis under the condition of a constant renal perfusion pressure: experiments on conscious dogs.

An experimental elevation of left atrial pressure (eLAP) by means of a reversible mitral stenosis is accompanied with an increase in sodium excretion (UNaV) and arterial blood pressure (by about 20 mm Hg, 2.7 kPa), and by a decrease in plasma renin activity. It is well established that an increase in renal perfusion pressure (Pren) can augment UNaV. Therefore the present study was undertaken to examine whether the eLAP-induced natriuresis was caused by the increased Pren. -Four female beagle dogs were kept under controlled environmental conditions. They received a sodium rich diet (14.5 mmol/Na/kg/d). The dogs were chronically instrumented: purse string around the mitral annulus, catheter in the left atrium, carotid loop, pneumatic cuff above the renal arteries, pressure transducer below the renal arteries. Pren was kept constant by means of a digital servofeedback control circuit. The dogs served as their own controls (13 experiments without and 15 experiments with a controlled renal perfusion pressure were performed). After eLAP(+1.0 kPa), UNaV rose from 4.1 +/- 2.6 to 10.3 +/- 3.9 mumol Na/min/kg. If Pren was kept constant, the corresponding values were 4.2 +/- 2.8 and 9.3 +/- 2.9 mumol/min/kg. These data clearly indicate that the atrial natriuresis is not mediated by an augmentation of renal perfusion pressure. Therefore these results support the hypothesis that atrial natriuresis probably is due to en eLAP-induced suppression of the renin-angiotensin-system or other natriuretic mechanisms.

Renal sodium handling in intact and renal denervated dogs.

The ability to retain sodium was investigated in six conscious dogs before and after surgical renal denervation. Dietary sodium and water intake were kept constant (2.5 mmol Na X kg-1 bw X day-1 and 91 ml water X kg-1 bw X day-1). Balance experiments were performed from 6 days before to 8 days after having produced a sodium deficit of 6.4 +/- 0.4 (intact dogs) and 5.8 +/- 0.2 (renal denervated dogs) mmol Na X kg-1 bw by means of a peritoneal dialysis (PD). Having the same sodium excretion before PD, intact and renal denervated dogs demonstrated a similar striking decrease of sodium excretion and a similar increase of plasma renin activity after PD until the amount of sodium lost had been replenished (4th day after PD). In intact and renal denervated dogs plasma sodium concentration (PNa) decreased and renal water excretion increased on the first day after PD, indicating a homeostatic response to the fall of PNa. After dietary sodium restriction (from 2.5 to 0.5 mmol Na X kg-1 bw X day-1) a similar striking decrease of renal sodium excretion occurred in intact and renal denervated dogs. It therefore is concluded that in conscious dogs the presence of the renal nerves is not essential in order to maintain body sodium homeostasis after an acute sodium loss or after dietary sodium restriction.

Diurnal pattern of sodium excretion in dogs with and without chronically reduced renal perfusion pressure.

In 5 conscious dogs the diurnal patterns of urinary sodium excretion (UNaV) were investigated, initially during 1 control day and, thereafter, during 4 days of servo-controlled reduction of renal perfusion pressure (rRPP). The individual dog's mean arterial blood pressure was reduced to 80% of the blood pressure on the control day. This value was always found to be below the threshold for the pressure-dependent renin release. During the entire study period urine was collected in 4-hour intervals and blood samples were taken every 4 h. The dogs were kept on a standardized high sodium and high water intake and were fed once daily at 8.30 h. On the control day, UNaV, urinary flow rate (UV), fractional lithium excretion (FELi) and fractional sodium excretion (FENa) had similar diurnal patterns. They peaked 4-8 h after food intake and decreased to low values during the night. On day 1 of rRPP, UNaV and FENa were maintained at very low levels in all collection periods, whereas the patterns of UV and FELi were unaltered compared with the patterns on the control day. On days 2-4 of rRPP, a clear-cut maximum in the patterns of UNaV and FENa recurred, comparable with the patterns on the control day. However, compared with the control day this maximum was shifted by 4 h towards the night. In contrast, the patterns of UV and FELi remained unchanged compared with the control day. The results indicate that UNaV has a typical time course in conscious, sodium- and water-replete dogs fed once daily. Endogenous stimulation of sodium reabsorption by means of rRPP results in a characteristic 4-hour shift of UNaV and FENa towards the night during rRPP days 2-4. This delay in UNaV seems to be evoked by processes in the distal tubule.

An attempt to quantitate the contribution of antidiuretic hormone to the diuresis of left atrial distension in conscious dogs.

In order to quantitate the contribution of the antidiuretic hormone (ADH) to the diuresis of left atrial distension 52 experiments have been performed in 12 conscious, chronically instrumented beagle dogs. Left atrial pressure was increased by a reversible mitral stenosis by about 10 cm H2O (1.0 kPa) for 60 min. Plasma ADH concentration (range between 1.3 and 6.0 pg . ml-1) (radioimmunoassay) decreased in every experiment, the average decrease being about 50%. An i.v. infusion of vasopressin (0.05 mU . min-1 . kg-1) abolished the diuretic effect of left atrial distension or decreased the urine volume below control values; natriuresis was not affected. The magnitude of the vasopressin effect was dependent on the concurrent sodium excretion: when sodium excretion was low during left atrial distension, vasopressin was more effective in reducing the urine volume than when sodium excretion was high. It is concluded that the diuresis of left atrial distension is mediated (a) by a suppression of ADH and (b) by factors controlling sodium excretion, the contribution of these two mechanisms being dependent on the concurrent sodium excretion.

Left atrial distension and intrarenal blood flow distribution in conscious dogs.

Measurements were made with radioactive microspheres of the distribution of renal blood flow in conscious dogs during left atrial distension. Urine volume, sodium excretion, mean arterial blood pressure and heart rate increased during the 60 min period of left atrial distension (increase in left atrial pressure by about 1.0 kPa). Total renal blood flow and cardiac output (electromagnetic flowmeters) did not change. The perfusion rates of four renal zones did not change. Striated muscle blood flow (M. psoas) fell markedly.--Stimulation of left atrial receptors in conscious dogs is followed by an increase in renal and skeletal muscle resistance. The diuresis and natriuresis during left atrial distension is not accompanied by a detectable redistribution of renal cortical blood flow.

Is arterial blood pressure a powerful factor in sodium excretion?

The control of sodium balance is very complex. Many different factors act together in the regulation of renal sodium excretion. Some investigators suggest that arterial blood pressure has a direct effect on urinary excretion of sodium and water. They report that whenever arterial pressure increases, urinary excretion of sodium and water also increases. This phenomenon is called pressure diuresis and natriuresis. It has been stated that an increase in arterial pressure of about 30% can increase urinary output as much as three-fold or more. Many studies, especially in the isolated, perfused kidney, support this idea. However, it is not clear how important this mechanism is under physiological conditions.

Effect of high sodium and high water intake on 24 h-potassium balance in dogs.

The influence of different amounts of oral sodium intake combined with high oral water intake on potassium excretion and plasma potassium concentration (PK) was evaluated. Female beagle dogs (11-16 kg) were divided into 2 groups: 1. Normal Sodium and high Water Intake (NSWI): 2.5 mmol Na, 3.55 mmol K, 91 ml H2O, and 277 kJ per kg body mass and 24 h (31 24 h-balance studies with 11 dogs). 2. High Sodium and high Water Intake (HSWI): Same diet as NSWI but 14.5 mmol Na x kg body mass-1 x 24 h-1 (55 24 h-balance studies with 21 dogs). The 24 h-balance studies were performed after different periods of time after onset of the respective diet (dogs in metabolic cages). Plasma sodium concentration (PNa) on NSWI was 148.4 +/- 2.6 mmol x 1(-1), whereas it was lower on HSWI (145.9 +/- 2.4 mmol x 1(-1). The lower plasma aldosterone concentration (PAC) on HSWI (24 +/- 8 pg x ml-1) compared to NSWI (67 +/- 38 pg x ml-1) may account for the lower PNa on HSWI. 24 h-sodium excretion was 93.6 +/- 6.5% of intake (%i) on HSWI and 91.5 +/- 20.7% i on NSWI. 24 h-water excretion was not different between both groups (81 +/- 7% i). PK was 3.93 +/- 0.25 mmol x 1(-1) on NSWI regardless of the time the dogs were on NSWI.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhythmicity of urinary sodium excretion, mean arterial blood pressure, and heart rate in conscious dogs.

The existence of urinary excretion rhythms in dogs, which is a matter of controversy, was investigated under strictly controlled intake and environmental conditions. In seven conscious dogs, 14.5 mmol Na, 3.55 mmol K, and 91 ml H2O.kg body wt-1.24 h-1 were either administered with food at 8:30 A.M. or were continuously infused at 2 consecutive days. During these 3 days, automatized 20-min urine collections, mean arterial blood pressure (MABP), and heart rate (HR) recordings were performed without disturbing the dogs. Fundamental and partial periodicities, the noise component of urinary sodium excretion (UNaV), MABP, and HR were analyzed using a method derived from Fourier and Cosinor analysis. Oral intake (OI) leads to powerful 24-h periodicities in all dogs and seems to synchronize UNaV. UNaV on OI peaked between 1 and 3 P.M. Under the infusion regimen, signs of nonstationary rhythms and desynchronization predominated. UNaV under the infusion regimen could be separated into two components: a rather constant component continuously excreted and superimposed to this an oscillating component. No direct coupling between UNaV and MABP periodicities could be demonstrated. On OI, an increase in HR seems to advance the peak UNaV in the postprandial period. HR and MABP signals were both superimposed with noise. We conclude that UNaV rhythms are present in dogs. They are considerably more pronounced on OI.

[Water diuresis during methohexitone anaesthesia. Studies in chronically instrumented dogs (author's transl)]. / Wasserdiurese während Methohexitalnarkose. Untersuchungen an chronisch instrumentierten Hunden.

Seven chronically prepared dogs (electromagnetic flow transducers around the pulmonary and left renal artery, left atrial catheter) maintained on a controlled sodium and water intake were studied. About 20 h after the last intake of food and water, the effects of i.v. methohexitone (initial dose: 6.10 +/- 0.84 mg/kg bw; sustaining infusion: 0.34 +/- 0.10 mg/min.kg bw) on renal excretion of sodium, potassium, urea and water as well as on several haemodynamic values were investigated over a period of 60 min (MP) after a control period (CP) of 60 min in the unanaesthetized state. In 18 of 19 experiments water diuresis (U/Posm less than 1) was observed between 20 and 40 min after starting the administration of methohexitone. Urine volume increased from 44 +/- 21 microliter/min.kg bw (CP) to 104 +/- 62 microliter/min.kg bw (MP).I.v. administration of arginine-vasopressin (ADH) completely abolished water diuresis. During MP, there was a decrease in cardiac output (-11%), stroke volume (-36%) and left atrial pressure (-27%), heart rate increased (+ 43%). Mean arterial blood pressure and renal blood flow did not change. It is assumed-as plasma osmolality did not change-that the central release of antidiuretic hormone is suppressed by methohexitone.

Pressure-dependent renin release: effects of sodium intake and changes of total body sodium.

The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2-4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (-3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.

Mechanisms compensating Na and water retention induced by long-term reduction of renal perfusion pressure.

Endogenous downregulation of plasma aldosterone (Aldo) concentration, despite increased plasma renin activity (PRA), has been suggested to compensate Na and water retention, which is induced by long-term reduction of renal perfusion pressure (rRPP). To determine whether fixed plasma Aldo concentration would prevent equilibration of 24-h Na and water balances during rRPP, chronically instrumented, freely moving beagle dogs were kept under standardized conditions (daily intake 5.5 mmol Na/kg body wt) and studied for 4 consecutive days under the following conditions: control without rRPP (protocol 1) and rRPP + infusion of Aldo (rRPP + Aldo, protocol 2). Because Aldo administration reduces PRA and, thereby, angiotensin II (ANG II) levels ANG II was additionally infused in protocol 3 (rRPP + ANG II + Aldo). During rRPP + Aldo, 24-h Na balances were never equilibrated. Daily Na retention was approximately 3.5 mmol/kg body wt on day 1 and decreased to approximately 1.6 mmol/kg body wt on day 4; 24-h water balances changed in a similar manner. PRA decreased stepwise. On all rRPP + ANG II + Aldo days, Na and water retentions were more extensive than during rRPP + Aldo. Daily Na retention decreased from approximately 4.4 mmol/kg body wt on day 1 to approximately 3.0 mmol/kg body wt on day 4. Plasma atrial natriuretic peptide increased during both protocols. It is concluded that 1) endogenous downregulation of components of the renin-angiotensin-aldosterone system is a pivotal compensatory mechanism to reduce Na and water retention and 2) natriuretic and diuretic factors seem to be of minor potency, because not even the sum of all could counterbalances the Na- and water-retaining effects of Aldo and ANG II.