Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake

Summary Plasma levels of -human atrial natriuretic peptide (hANP) were measured in 17 patients with primary hypertension (11 females, 6 males, aged 22–61; blood pressure systolic 154±7 mmHg, diastolic 92±4 mmHg) and in 9 normotensive controls (4 males, 5 females, aged 20–71; blood pressure systolic 117±4 mmHg, diastolic 76±2 mmHg) during unrestricted sodium diet, at the 4th day of a low sodium intake (40–60 mEq/day) and at the 6th day of sodium loading (280–320 mEq/day) both after an overnight rest and after 4 h of upright posture. In the controls, plasma levels of hANP at 8:00 a.m. were lowered from 73±11 to 49±7 pg/ml during low sodium diet and increased to 128±37 pg/ml after high salt intake. Plasma ANP levels were significantly lower after 4 h of upright posture during unrestricted, low and high sodium intake. In the hypertensive group, plasma ANP levels were elevated during unrestricted diet (203±43 pg/ml), during the low sodium period (139±31 pg/ml), and after high sodium intake (267±63 pg/ml) compared to the controls. All levels were lowered by upright posture. The absolute decrease was more pronounced compared to the normotensives, the relative decline was similar in both groups. In the hypertensives, plasma ANP levels significantly correlate with systolic and diastolic blood pressure (r=0.468,r=0.448,P<0.05) and with urinary aldosterone during unrestricted diet (r=0.536,P<0.05). There was an inverse correlation between plasma ANP levels and plasma renin concentration during low and high sodium intake (r=–0.469,r=–0.496,P<0.05).These studies demonstrate raised circulating plasma ANP levels in patients with essential hypertension. The modulation of ANP by different sodium intake and by upright posture is maintained similar to the changes in plasma ANP in normotensive controls. Raised ANP levels in the hypertensives are correlated with low renin secretion and high aldosterone excretion. High ANP levels, therefore, might indicate sodium retention in essential hypertension.Abbreviation ANP atrial natriuretic peptide Supported by a grant from Ministerium für Wissenschaft und Forschung, NRW     

Effects of atrial natriuretic peptide on systemic and renal hemodynamics and renal excretory function in patients with chronic renal failure

Summary We examined the effects of 60 min-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m² and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6±9.1 vs 13.6±1.9 pmol/l,p<0.05; cGMP: 14.3±2.9 vs 6.6±1.1 pmol/ml,p<0.05). During ANP infusion, peak levels of cGMP were higher in CRF than in C (27.5±3.2 vs. 17.3±1.3 pmol/ml,p<0.05). During ANP infusion, GFR increased in CRF by 70.7±4.2% from 34.5±6.8 to 57.4±9.9 ml/min/1.73m² (p<0.001) as compared to 16.2±1.4% in C (p<0.001 vs CRF). RBF increased in CRF by 43.6±6.4% and in C by 3.1±1.2% (p<0.01). Basal urinary sodium excretion (U_NaV) was slightly lower in CRF than in C but rose to the same level in both groups during ANP infusion. In CRF, as opposed to C, U_NaV remained elevated above baseline after the end of the infusion. The effect of ANP on fractional sodium excretion (FE_Na), however, was more pronounced in C. Basal FE_Na was higher in CRF (12.8±2.5% vs 2.4±1.5% in C,p<0.001), FE_Na remained elevated at 180% over baseline in C sixty minutes after cessation of ANP infusion, while it had returned to baseline in CRF. During ANP infusion, CI increased in CRF after 30 min from 2.91±0.08 to 3.12±0.091/min/m² (p<0.001) and in C from 3.20±0.11 to 3.39±0.13 l/min/m² (p< 0.05). Mean arterial BP was higher in CRF and its decrease was greater than in C (21.1±2.7% vs 9.1±1.0%,p<0.001). In patients with CRF GFR, RPF, and CI remained significantly elevated and BP was still significantly decreased 60 min after ANP infusion. Total peripheral vascular resistance (TPR) was elevated in CRF and declined during ANP infusion in both CRF and C. The decline of TPR was sustained and more pronounced in CRF than in C. Renal vascular resistance (RVR) was high in CRF and dropped by nearly 50% during ANP infusion, whereas only a moderate decline in RVR during ANP application was observed in C. Thus, exogenous ANP had greater and prolonged effects on systemic hemodynamics and renal function in CRF than in C. They may be due to higher levels of ANP following ANP infusion and appear to be mediated by a more sustained formation of the second messenger cGMP.Abbreviations ANP atrial natriuretic peptide - CRF chronic renal failure; - GFR glomerular filtration rate - FF filtration fraction - ERPF effective renal plasma flow - ERBF effective renal blood flow - BP blood pressure - MAP mean arterial blood pressure - HR heart rate - SV stroke volume - CO cardiac output - CI cardiac index - TPR total peripheral resistance - RVR renal vascular resistance - U_NaV urinary sodium excretion - FE_Na fractional sodium excretion - PRA plasma renin activity - ECFV extracellular fluid volume - PAH paminohippuric acid Dedicated to Prof. Dr. med. F. Krück on the occasion of his 70th birthday     

Effect of chemical sympathectomy on coronary flow and cardiovascular adjustment to exercise in dogs

Summary The exercise capacity and the increase of coronary and systemic hemodynamics under treadmill exercise were studied in 5 dogs, chemically sympathectomized with 6-hydroxy-dopamine.Completeness of adrenergic denervation was verified by stimulation of the right stellate ganglion, by intravenous administration of tyramine, and by demonstration of supersensitivity to exogenous norepinephrine.These dogs demonstrated a retarded adaptation of hemodynamics to a sudden start of exercise. A fall in mean arterial pressure below 45 mmHg within 10 to 15 sec lead to collapse. After a recovery period of 60–90 sec, moderate treadmill exercise could be continued; steady state attainment of hemodynamic parameters was considerably delayed.A steady state of exercise with an O₂-consumption (vO₂) of 29.6±2.6 ml/min · kg and a cardiac outupt (CO) of 307±16 ml/min · kg was tolerated for at least 20 min.An increase of vO₂ up to 42.0±1.7 ml/min · kg and of CO up to 357±13 ml/min · kg under exercise was tolerated for 5 min with steady state, maximal heart rate being 160±4 min^–1 at this level of exercise.Mean arterial pressure and total peripheral resistance were significantly reduced at rest and during steady state of exercise as compared to controls prior to sympathectomy identical vO₂, whereas CO remained unchanged.The significant fall in left circumflex coronary flow was proportional to the decline in external heart work due to sympathectomy both at rest and under exercise.Supported by Deutsche Forschungsgemeinschaft.     

Concomitant increase in plasma atrial natriuretic peptide and cyclic GMP during volume loading

Summary To investigate the effects of fluid expansion on endogenous atrial natriuretic peptide (ANP) and cyclic 3,5-guanosine monophosphate (cGMP), four male volunteers were studied before, during and after intravasal volume loading. Volume expansion was performed by intravenous infusion of 2,000 ml isotonic saline solution within 30 min. Mean plasma ANP levels increased 2.5-fold from 31.2 pg/ml to 81.7 pg/ml 40 min after the start of infusion. Plasma cGMP levels paralleled the rise in ANP, shwoing a mean cGMP increment from 2.7 pmol/ml to a maximum of 8.2 pmol/ml. Both ANP and cGMP levels were back to basal levels 120 min after termination of the infusion. Stimulation of endogenous ANP release by volume loading suggests that ANP is involved in the regulation of fluid homeostasis in man. The parallel rise in plasma cGMP levels supports the idea that cGMP is a mediator for the effects of ANP.Abbreviations ANP atrial natriuretic peptid - cGMP cyclic 3,5-guanosine monophosphate - PRA plasma renin activity     

Erhöhtes atriales natriuretisches Peptid (ANP) bei essentieller Hypertonie — Abhängigkeit vom rechtsatrialen Druckverhalten

Summary The role of atrial natriuretic peptide (ANP) in the pathogenesis of essential hypertension has not yet entirely been clarified. We investigated whether the increase of ANP in essential hypertension may be explained by elevated right atrial pressures and/or a different relationship between right atrial pressures and ANP secretion. Patients with stable essential hypertension undergoing right and left heart catheterization because of suspected coronary heart disease had significantly higher ANP levels than normotensives: 58.7±6.7 pg/ml in hypertensives versus 42.0±4.1 pg/ml in normotensives (p<0,01). Matching hypertensives with normotensives at identical levels of left ventricular enddiastolic pressure revealed significantly higher mean pulmonary artery pressures in hypertensives. Right atrial diastolic pressure (v-wave) after matching for LVEDP was 4.8±0.5 mm Hg in hypertensives and 3.1±0.2 mm Hg in normotensives (p<0.05). In addition, at any given mean right atrial pressure hypertensives showed higher ANP levels than normotensives. These results demonstrate that hypertensives exhibit raised pressures in the pulmonary artery independent of left ventricular pressure load. The elevation in right atrial pressures and the steeper relationship between these pressures and ANP are a suitable explanation for raised ANP levels in hypertension. ANP in essential hypertension may represent a counterregulation against elevated pulmonary resistance.

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Abkürzungsverzeichnis ANP Atriales natriuretisches Peptid - LVEDP Left ventricular enddiastolic pressure (Linksventrikulärer enddiastolischer Druck) - RAO Right anterior oblique (Aufnahmetechnik von rechter schräger Bildröhrenposition aus) - SEM Standard estimate of the mean (Standardabweichung dividiert durch die Wurzel aus der Fallzahl) - HT Hypertoniker - NT Normotoniker Mit Unterstützung der Deutschen Forschungsgemeinschaft     

Renal response to central volume expansion induced by water immersion (WI) in heart transplant patients

This work was aimed to assess the secretion of volume related hormones in heart transplant patients (HTP) and their relationship to excretory renal function studied under bed rest and water immersion conditions. Fractional sodium (FENa%) and potassium (FEK%) clearance, plasma renin activity (PRA), plasma aldosterone (Ald), vasopressin (AVP) and atrial natriuretic peptide (ANP) were estimated in six HTP with moderate renal failure (C creat = 69 +/- 6.9 ml/min) and in 10 healthy subjects (N) (C creat = 110 +/- 2.0 ml/min). All HTP were treated with cyclosporine A and azathioprine. In HTP basal AVP (6.18 +/- 0.92 pg/ml) and ANP (138.17 +/- 14.69 pg/ml) levels were significantly higher than in normals (2.07 +/- 0.11 pg/ml and 74.10 +/- 7.10 pg/ml, respectively). HTP were also characterized by increased FENa% and FEK% both under bed rest (DI) and water immersion (WI) conditions. As abnormalities of excretory renal function in HTP were not significantly related to the plasma endocrine profiles factors other than PRA, Ald, AVP and ANP seemed to be also involved in their pathogenesis.     

Concentration effect relationships of infused histamine in normal volunteers

Histamine was infused in six normal volunteers at rates of 16, 32, 64 and 96 ng/kg/min increasing at 5-min intervals followed by 128 ng/kg/min for 45 min. Heart rate increased, diastolic blood pressure decreased and skin temperature increased in a dose-dependent fashion. Mean heart rate increased by 15.6±5.7 beats/min, mean diastolic pressure fell by 8.8±3.2 mmHg and mean skin temperature increased by 1.2±0.3°C at the highest infusion rate. Mean plasma histamine rose from a basal level of 0.20±0.03 ng/ml to 1.97±0.25 ng/ml at the end of the highest infusion rate. The threshold infusion rate for physiological effects was 64–96 ng/kg/min corresponding to 0.77–0.97 ng/ml. Salivary flow was stimulated by 21% after 30 min at the highest dose infusion (P=0.05). Plasma adrenaline increased 132% but plasma noradrenaline was unchanged.There was a linear decline in heart rate after terminating the histamine infusion with a half time of 82 sec. The half life of infused histamine in the plasma was 102 sec. The clearance of histamine from the plasma was 6.1±0.2 l/min or 83 ml/kg/min.These concentration effect relationships in normals throw doubt on some of the high endogenous plasma histamine values in the literature.     

Elevated serum interleukin-6 levels in patients with acute hepatitis

To study the mechanisms of hepatocyte injury, we examined serum interleukin-6 (IL-6) level in acute hepatitis patients. Based on their clinical features, these patients were divided into three groups, acute hepatitis (AH), severe acute hepatitis, and fulminant hepatic failure (FHF). The present study demonstrated that, in association with their clinical status, their serum IL-6 levels were gradually increased (16.5±14.5 pg/ml in AH, 26.3±19.0 pg/ml in severe AH, and 470.2±261.4 pg/ml in FHF; control level, 5.2±0.6 pg/ml). Furthermore, we found that a significant correlation between serum IL-6 level and prothrombin time existed in these patients and that the elevated serum IL-6 returned to a normal range after recovery from their hepatocyte injury. Thus, our study demonstrates that the serum IL-6 level is a possible marker for identifying the clinical status in acute hepatitis and that this cytokine may have some roles in hepatocyte injury.     

Heterologous Radioimmunoassay of Atrial Natriuretic Polypeptide in Dog and Rabbit Plasma

Abstract

Atrial natriuretic peptide (ANP) was measured in plasma of dogs and rabbits by radioimmunoassay (RIA) using a commercially available anti α-ANP serum and compared to our measurements of ANP in rats and humans. Plasma concentration of ANP in dog coronary sinus (234.9 ± 41.0 pg/ml) was significantly greater than in systemic arterial blood (81.2 ± 8.4 pg/ml). Gel filtration of dog coronary sinus plasma resulted in an ANP peak with the elution volume (V_e) of synthetic atriopeptin III (AIII) and a minor peak eluting with the void volume (V_o). Rabbit systemic arterial plasma ANP was 53.3 ± 4.3 pg/ml and yielded one peak, with a V_e of AIII. Ion exchange chromatography of dog and rabbit atrial extracts (AE) resulted in a major ANP region which resembled AIII. Gel filtration of AE showed larger molecular species as well as AIII. Dilutions of dog and rabbit plasma and AE were parallel with the AIII standard in radioimmunoassay.     

Tyrosine loading in patients with hepatic cirrhosis: Lack of effect on plasma catecholamines

Summary Plasma norepinephrine concentrations are often elevated in patients with hepatic cirrhosis in relation to the stage of disease and possibly in response to a decrease in effective arterial blood volume. Since tyrosine, the precursor for catecholamines, is said to influence the rate of catecholamine biosynthesis within the central nervous system and peripheral sympathetic structures, we tested whether basal hypertyrosinemia and increased plasma tyrosine levels after oral loading with l-tyrosine are associated with elevated plasma catecholamine concentrations. Baseline norepinephrine (NE) and epinephrine (E) were significantly higher in 17 patients with decompensated cirrhosis, as compared with 11 healthy controls (NE: 809±108 pg/ml vs 295±16 pg/ml; E: 69±9 pg/ml vs 36±8 pg/ml). No significant correlation between the basal plasma tyrosine and norepinephrine level could be demonstrated in patients with cirrhosis (r=0.04). Oral tyrosine loading (100 mg/kg b.w.) administered in six equal doses did not change the level of catecholamines, whereas plasma tyrosine increased two- to three-fold. Even a large single dose (14 g l-tyrosine) failed to alter plasma catecholamines in six cirrhotic patients with marked ascites. We therefore conclude that the enhanced availability of tyrosine in cirrhotics does not influence catecholamine biosynthesis in peripheral sympathetic neurons.Abbreviations D dopamine - E epinephrine - NE norepinephrine - Tyr tyrosine     

Heterologous radioimmunoassay of atrial natriuretic polypeptide in dog and rabbit plasma

Atrial natriuretic peptide (ANP) was measured in plasma of dogs and rabbits by radioimmunoassay (RIA) using a commercially available anti alpha-ANP serum and compared to our measurements of ANP in rats and humans. Plasma concentration of ANP in dog coronary sinus (234.9 +/- 41.0 pg/ml) was significantly greater than in systemic arterial blood (81.2 +/- 8.4 pg/ml). Gel filtration of dog coronary sinus plasma resulted in an ANP peak with the elution volume (Ve) of synthetic atriopeptin III (AIII) and a minor peak eluting with the void volume (Vo). Rabbit systemic arterial plasma ANP was 53.3 +/- 4.3 pg/ml and yielded one peak, with a Ve of AIII. Ion exchange chromatography of dog and rabbit atrial extracts (AE) resulted in a major ANP region which resembled AIII. Gel filtration of AE showed larger molecular species as well as AIII. Dilutions of dog and rabbit plasma and AE were parallel with the AIII standard in radioimmunoassay.     

Alterations of vasoconstrictor and sodium-regulating hormone systems in vascularly decompensated liver cirrhosis

Plasma levels of atrial natriuretic peptide (ANP), aldosterone (PA), vasopressin (AVP), and the plasma renin activity (PRA) were examined in 15 vascularly decompensated patients suffering from liver cirrhosis, before and after administration of albumin and after a subsequent administration of furosemide. The initial ANP level was lower in 9 patients (group "A") and higher in 6 patients (group "B") than in healthy controls (Group "A": 19.5 +/- 3.0 fmol/ml; group "B": 36.7 +/- 3.9 fmol/ml; control: 25.8 +/- 2.4 fmol/ml). The initial PRA (4.4 +/- 1.0 ng AngI/ml/h) and AVP (8.5 +/- 1.5 pg/ml) activity in group "A" increased significantly compared to group "B" (PRA: 0.44 +/- 0.09; AVP: 4.1 +/- 0.5), indicating an intravascular volume depletion in group "A". Albumin infusion raised the urine and sodium excretion and the plasma concentration of ANP in group "A" but lowered in plasma levels of renin and vasopressin. The same parameters were not changed by albumin in group "B". Furosemide equally raised the urine flow rate and sodium excretion in both groups. Plasma ANP level depends on the intravascular volume, and the secondary change in its plasma concentration plays a considerable role in the retention of fluid and electrolytes in patients with cirrhosis. The increased intravascular volume in these patients depletes the fluid and electrolyte retention via the increase in ANP level.     

Atrial natriuretic peptide response to physical exercise is inhibited by an antagonist of the opioid receptors

It was been shown that physical exercise increases plasma atrial natriuretic peptide (ANP) level. This effect was attributed to the hemodynamic changes of exercise which could increase atrial volume and result in ANP secretion. On the other hand, it was evidenced that morphine and opiate peptides greatly stimulate ANP release. To evaluate to what extent the endogenous opioid secretion during exercise induces the ANP release, six healthy volunteers male trained subjects were submitted to two maximal exercise tests with and without (placebo) opiate receptors blockade by naltrexone (50 mg per os). Blood samples were drawn before (rest) and after maximal exercise in order to measure by radioimmunological methods human atrial natriuretic peptide (alpha-h-ANP), beta-endorphin, plasma aldosterone (ALD), plasma renin activity (PRA) and corticotrophin (ACTH). Expired gas was collected during exercise to measure oxygen consumption. Subjects reached the same value of maximal oxygen consumption (VO2 max) at the end of exercise whatever treatment. Plasma ANP level at rest decreases slightly after administration of naltrexone (32.8 +/- 6.3 pg/ml with placebo versus 21.3 +/- 4.6 pg/ml with naltrexone) but the response to physical exercise was significantly reduced by naltrexone (73.3 +/- 14.9 pg/ml with placebo versus 46.9 +/- 8.6 pg/ml with naltrexone) (p less than 0.05). There was no statistical difference according to the treatment between the plasma levels of beta-endorphin, PRA and ACTH at rest as well as at the end of a maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Die sympathische Aktivität bei terminaler Niereninsuffizienz und Nierentransplantation

Summary Blood pressure as well as noradrenaline, creatinine and electrolytes in blood and urine were compared in normal controls (n=25), patients with chronic renal failure (n=39), patients with continuous ambulatory peritoneal dialysis (CAPD) (n=28) and haemodialysis patients before and after renal transplantation (n=63). The average blood pressures of the control group and the CAPD patients were lower than those of the renal failure patients without and with haemodialysis. After renal transplantation elevated blood pressure normalised in 18% within the following 6 months. In all groups of patients with renal failure the mean noradrenaline plasma concentration was increased more than three-fold of normal values: 1,470 pg/ml in patients with chronic renal failure, 1,366 pg/ml in CAPD patients and 1,284 pg/ml in patients with haemodialysis. No correlation was found between these elevated noradrenaline plasma levels and blood pressure. However, there was a significant correlation between noradrenaline excretion and sodium excretion. Compared to the controls, the urine excretion of noradrenaline was significantly lower in patients with chronic renal failure and almost zero in patients with dialysis treatment. Two days after renal transplantation the mean noradrenaline urine excretion increased to 15.7±1.8 µg/day and 4 days after transplantation the noradrenaline plasma concentration decreased to 592±155 pg/ml. Nine months after renal transplantation the creatinine clearance was 76 ml/min and the mean noradrenaline plasma concentration 438±153 pg/ml. It is concluded that in chronic renal failure the level of noradrenaline plasma concentration is dependant on renal function.

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Abkürzungen CAPD continuous ambulatory peritoneal dialysis Zum 60. Geburtstag von Herrn Prof. Dr. W. Kaufmann     

Cerebrospinal fluid profile of amyloid β42 (Aβ42), hTau and ubiquitin in North Indian Alzheimer's disease patients

Alzheimer's disease (AD) is the most common form of dementia, and is characterized by the degeneration of neurons and their synapses, and a higher number of amyloid plaques and neurofibrillary tangles (NFTs) compared with that found in non-demented individuals. Amyloid-β-peptides (Aβ) are major components of amyloid plaques in AD brain whereas NFTs are composed of Tau and associated with ubiquitin. The aim of the present study was to analyze the levels of Aβ42, hTau (total Tau) and ubiquitin in CSF of North Indian population. CSF Aβ42, Tau and ubiquitin were measured in CSF of AD patients as well as controls using ELISA assays. Here we report low Aβ42 levels in AD patients (324.24 ± 76.38 pg/ml) as compared to those in non-AD (NAD) (668.34 ± 43.13 pg/ml), neurological controls (NCs) (727.28 ± 46.49 pg/ml) and healthy controls (HCs) (976.47 ± 124.46 pg/ml). In contrast, hTau and ubiquitin levels were significantly high (568.65 ± 48.89 pg/ml and 36.82 ± 4.34 ng/ml, respectively) in AD patients compared to those in NAD, NC and HC. The hTau levels were 267.37 ± 36.64 pg/ml, 167.34 ± 44.27 pg/ml and 107.62 ± 24.27 pg/ml in NAD, NC and HC, respectively. Similarly, ubiquitin levels were 23.57 ± 2.32 ng/ml, 19.76 ± 3.64 ng/ml and 13.24 ± 4.56 ng/ml in NAD, NC and HC, respectively. In conclusion, low Aβ42 and high Tau–ubiquitin levels were found in North Indian AD patients.     

Involvement of endogenous adenosine in ischaemic preconditioning in swine

Adenosine release and the subsequent activation of adenosine receptors are involved in ischaemic preconditioning in dogs and rabbits. In the present study, we investigated whether adenosine also mediates ischaemic preconditioning in swine. Swine were used since, due to the lack of an innate collateral circulation, infarct development in this species most closely resembles that observed in humans. In 36 enflurane-anaesthetized swine the impact of increased adenosine breakdown with exogenous porcine adenosine deaminase (5 IU/ml blood/min) on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres) and infarct size (IS, triphenyl tetrazolium chloride staining following 90 min ischaemia and 120 min reperfusion) were analysed. Low-flow ischaemia for 90 min at an ENDO of 0.09±0.04 (mean±SD) ml/min/g caused an IS of 13.2±9.7% (n=8) of the area at risk. Ischaemic preconditioning by a cycle of 10 min low-flow ischaemia followed by 15 min reperfusion prior to the 90-min ischaemic period (ENDO=0.06±0.03 ml/min/g) reduced IS to 2.6±3.0% (n=11, P<0.05). The interstitial adenosine concentration (microdialysis) increased from 1.60±0.87 nmol/ml to above 10 M during ischaemia; with intracoronary adenosine deaminase, the interstitial adenosine concentration fell from 1.65±0.23 to 0.12±0.07 nmol/ml and did not increase during ischaemia. Adenosine deaminase per se did not alter IS after 90 min ischaemia (n=7, ENDO=0.08±0.04 ml/min/g, IS=12.1±6.9%) but abolished the beneficial effect of ischaemic preconditioning (n=10, ENDO=0.06±0.03 ml/min/g, IS=8.8±5.8%). For any given ENDO, IS was significantly reduced in the ischaemic preconditioned group compared with the other three groups. Global and regional myocardial function were comparable among all groups of swine. We conclude that endogenous adenosine mediates ischaemic preconditioning also in swine.     

Atrial natriuretic excretion in patients with obstructive sleep apnea syndrome (OSAS)

During obstructive sleep apneas stimuli, that may increase excretion of atrial natriuretic peptide (ANP) occur. The aim of the study was the evaluation whether in patients with OSAS levels of ANP are significantly different in relation to sleep or wakefulness and in relation to disturbances of ventilation during sleep and wakefulness. The material of the study consisted of 34 patients with OSAS (age 25-65 years). There were no differences in the levels of ANP late in the evening, during sleep and early in the morning. There were 2 groups of the patients: with low (< 70 pg/ml, mean at 21 p.m. 9.7 +/- 8.7 pg/ml, at. 2 a.m. 12.5 +/- 9.3 pg/ml, at 6 a.m. 14.4 +/- 15.1 pg/ml) and high (> 70 pg/ml, mean at 21 p.m. 148.6 +/- 232.9 pg/ml, at 2 a.m. 119.5 +/- 45.5 pg/ml, at 6 a.m. 164.9 +/- 161 pg/ml) ANP levels. As compared with patients with low ANP levels, patients with high ANP levels were older and more obese, more frequently had concomitant COPD, lower VC and FEV1, higher daytime PaCO2 and lower PaO2; most of them had peripheral edema. In patients with high ANP levels there was more profound mean arterial blood desaturation during sleep apnoeas than in patients with low ANP levels (SaO2 75 +/- 8% vs 81 +/- 4%, p < 0.001), although apnea index and mean apnea duration were similar in both groups. CONCLUSIONS: In patients with OSAS the daytime and sleep levels of ANP are similar. High levels of ANP can be found in OSAS patients with impaired daytime ventilation and gas exchange, and profound arterial oxygen desaturation during sleep apnoeas.     

Digoxin and digitoxin elimination in man by charcoal hemoperfusion

Summary Since there is no widely used causal means of reducing the severity of massive digitalis intoxication the capability of hemoperfusion with coated activated charcoal to remove toxicologically relevant amounts of digoxin and digitoxin was evaluated in vitro and in man. At a blood flow rate of 100 ml/min the digoxin clearance by hemoperfusion in vitro was 51±8 ml/min in comparison to 24.3±11.3 ml/min by hemodialysis. The average hemoperfusion clearance of digitoxin was 31.7±13.4 ml/min, whereas almost no digitoxin was removed by hemodialysis. These clearance values point to the ability of hemoperfusion of eliminating digitalis glycosides from the blood. They do not clarify the essential question whether it is possible to lower the toxic concentrations in the tissues.In two patients being on hemoperfusion for other reasons, 0.5 mg digoxin were injected intravenously as a bolus 1 h prior to the beginning of hemoperfusion and 0.125 mg/h were infused continuously over 4h simultaneously with hemoperfusion. By an average digoxin clearance of 77 ml/min, only 5 and 4.5% of the dose given were removed by this procedure. In 2 patients receiving digitoxin under the same trial conditions an average of 24% of the digitoxin load were eliminated by 4 to 6 h hemoperfusion period although the clearance values obtained were below the clearance for digoxin.The lack of effectiveness in eliminating toxicological relevant amounts of digoxin is due to the quite high distribution volume which results in high tissue concentrations and low blood concentrations of the drug. On the other hand the effective removal of digitoxin is due to the appreciably smaller distribution volume and suggests that hemoperfusion may be a valuable method of rapid reversal of advanced digitoxin toxicity in man.Supported by a grant of Deutsche Forschungsgemeinschaft     

Kinetics and cardiac effects of propranolol in humans

Summary Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (±SE) kinetic variables for IV propranolol were: elimination half-life (t1/2), 5.3 (±0.6) h; volume of distribution, 2.3 (±0.3) l/kg; total clearance, 4.9 (±0.3) ml/min/kg; predicted extraction ratio, 0.23 (±0.02). After single oral doses, t1/2 (3.8±0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60±0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47±5 ng/ml) tended to be less than those predicted based on the single oral dose (61±5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).Supported in part by Grant Oc 10/6-3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-34223 from the United States Public Health Service