Pharmacokinetics of synthetic atrial natriuretic peptides in normal men

The kinetics of atrial natriuretic peptides (ANP) and the kinetic profile of their effect on blood pressure and renal hemodynamic and electrolyte excretion were investigated in 20 salt-loaded healthy volunteers during and after constant rate infusion. At steady state, mean plasma concentrations of ANP were measured at 210, 430, and 2990 pg/ml and mean systemic clearance was 2.6, 2.5, and 1.7 L/min for ANP infusion rates of 0.5, 1, and 5 micrograms/min, respectively, which corresponds to the clearance rate of other vasoactive peptide hormones. The apparent volume of distribution averaged 17 L and the mean half-life was 4.5 minutes. ANP induced dose-related effects on systemic and renal hemodynamic, as well as urinary electrolyte excretion, albeit with a time lag between onset and full effect.     

Endothelin-1 impairs neutrophil respiratory burst and elimination of Escherichia coli in rabbits

OBJECTIVE: During systemic inflammation, elevated levels of endothelin (ET)-1 have been reported. The aim of this study was to investigate the effects of ET-1 on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissues. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: A total of 18 female chinchilla rabbits. INTERVENTIONS: To quantify the clearance process, defined numbers (10(8) colony-forming units) of E. coli were injected intravenously into anesthetized rabbits, 60 mins after onset of continuous 0.2 microg/kg/min ET-1 administration (n = 9) and after saline infusion (control group, n = 9), respectively. To evaluate potential effects of ET-1 on bacterial elimination and killing, blood clearance of E. coli and colonization of different organs were investigated. MEASUREMENTS: Variables monitored were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, blood gases, serum lactate concentrations, and nitrite and nitrate levels. The animals were killed 3 hrs after bacterial injection and tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS: Compared with the control group, ET-1 significantly impaired PMN respiratory burst (p < .05) and prolonged elimination of injected E. coli from the blood (p < .01), whereas phagocytosis functions remained unaltered. The reduced PMN burst activity after ET-1 was associated with a higher bacterial colonization of all organs (lung, p < .01; spleen, p < .05). Endothelin-1 induced increases in mean arterial pressure (p < .01) and serum lactate concentrations, whereas nitrite and nitrate levels remained unaltered. CONCLUSION: Endothelin-1 impairs respiratory burst and bacterial clearance from the blood and tissue. Thus, elevated levels of ET-1 during sepsis could induce organ hypoperfusion and cause disturbances in immune functions, increasing the risk of bacterial infections.     

Systemic hypertension induced by hepatic overexpression of human preproendothelin-1 in rats.

Endothelin-1 (ET-1) has been implicated in the regulation of vascular tone in various pathological conditions. To examine the effect of in vivo overexpression of the peptide in rats, we prepared recombinant adenovirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escherichia coli lacZ (Ad.betaGal), each driven by cytomegalovirus early promoter. Ad.ET-1 or Ad.betaGal was injected into the caudal vein of rats and the animals were studied under anesthesia 96 h later. Hepatic overexpression of the virus-derived human ET-1 mRNA was accompanied by a 13-fold elevation of liver ET-1 content in the Ad.ET-1 group. Circulating plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.betaGal group. Mean arterial blood pressure was increased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.betaGal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) receptor antagonist FR 139317 reduced the blood pressure to levels seen in the Ad.betaGal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.betaGal group. Intravenous infusion of the ET(B) receptor antagonist BQ-788 caused a small but significant increase in blood pressure in both groups. These findings demonstrate that endogenous overexpression of preproET-1, accompanied by an elevation of plasma ET-1 concentrations to the levels seen in pathophysiological states, can cause systemic hypertension through the activation of the ETA receptor.     

Reduction in hepatic endothelin-1 clearance in cirrhosis

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ET(B) receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49+/-0.04 fmol/ml (mean+/-S.E.M.) to 1.0+/-0.18 fmol/ml ( P <0.01). Liver ET-1 extraction was reduced from 81+/-1% (mean+/-S.E.M.) in controls to 50+/-6% in cirrhosis ( P <0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ET(B) receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ET(A) antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure ( r =-0.457; P <0.001) and the increase in ET-1 levels ( r =-0.462; P =0.002). Immunohistofluorescence with specific anti-(ET(B) receptor) antibodies revealed a preponderant distribution of ET(B) receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ET(B) receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.     

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained-release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t1/2 was 106 +/- 24 minutes in controls and increased gradually across the groups to 230 +/- 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 +/- 0.23 and 1.47 +/- 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% +/- 0.5% in controls to 93.5% +/- 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = -0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration-effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.     

Low dose infusion of atrial natriuretic peptide causes salt and water excretion in normal man

1. The effects of low dose infusion of atrial natriuretic peptide (ANP) were observed in double-blind, placebo-controlled study in six fluid-loaded volunteers. After baseline observations, hourly increments of 0.4, 2 and 10 pmol min-1 kg-1 were infused with continuous observation of heart rate, blood pressure and cardiac output. Plasma ANP, aldosterone, and catecholamines, and urinary volume and sodium excretion, were estimated at half-hourly intervals. 2. ANP infusion resulted in an increase of 35, 98 and 207% in urinary sodium excretion and of 10, 20 and 71% in urinary volume when compared with placebo. Plasma ANP was markedly elevated above placebo levels only during infusion of 10 pmol of ANP min-1 kg-1. 3. No change in heart rate of blood pressure was noted during the study, but a significant fall in stroke volume index was observed during active treatment. Plasma levels of aldosterone and catecholamines were not significantly different on the 2 treatment days. 4. The potent natriuretic and diuretic effects of this peptide at plasma concentrations not significantly elevated from physiological suggest a hormonal role for ANP in the homoeostasis of salt and water balance.     

老年高血压状态下左心室构型与左心房和左心室容积

背景：研究表明,左心房容积可反映左心室充盈压、心房结构重塑及神经激素的活动,左心房容积扩大是预测慢性心力衰竭不良预后的一个强有力的标志。目的：观察老年原发性高血压患者在不同左心室构型情况下左心房容积和左心室容积的变化。方法：采用超声心动图对129例老年原发性高血压患者（高血压组）和125名体检血压正常的老年人（对照组）的左心房容积和左心室容积相关指标进行测量,并依据Ganau标准对左心室几何构型进行分型;同时对老年高血压患者进行动态血压监测,依据血压节律进行分组比较。结果与结论：与对照组比较,高血压组左心房容积、左心房容积指数、左心室收缩末期容积、左心室舒张末期容积均明显增大（P〈0.05）;同时,在高血压组内,病程和动态血压昼夜节律对左心室几何构型的分布有影响,且左心室构型异常者上述指标较左心室构型正常者增大更明显（P〈0.05）。提示,老年原发性高血压患者病程和非杓型血压节律对左心室构型存在重要影响,左心房容积和左心室容积的变化与左心室构型的改变相伴随。     

B型钠尿肽和大内皮素1对心力衰竭患者的预后作用及其与心血管病关系的研究

目的研究B型钠尿肽(BNP)和内皮素1(EP-1)对心力衰竭患者的预后作用及其与心血管病关系。方法选择就诊的心力衰竭患者作为观察组,健康者作为对照组,采用酶联免疫分析法(ELISA)的方法检测外周血中BNP、EP-1的水平。结果心力衰竭患者外周血中BNP和EP-1明显高于健康者,并且心力衰竭的分期越高、病情越严重,患者外周血中BNP和EP-1的含量也越高;心力衰竭合并心房颤动的患者BNP和EP-1含量明显高于未合并房颤的患者,合并心肌梗死的患者BNP和EP-1含量也明显高于未合并心肌梗死的患者。结论 BNP和EP-1对心力衰竭的早期诊断、合并房颤和心梗的判断、预后的分析均有积极意义。     

Analysis of immunoglobulin G kinetics in the non-steady state

The effect of specific intravascular IgG depletion on IgG catabolism, generation, and intrabody transfer has been studied in rabbits. In contrast to previous studies, the radiolabeled IgG kinetics were analyzed in the non-steady state. A two-pool model was used to determine IgG distribution, catabolism, generation, and intrabody mass transfer after intravenous injection of 125I-IgG. Circulating IgG was then specifically removed by plasma perfusion through a Protein-A Sepharose column in an extracorporeal circuit. Based on the two-pool analysis, IgG catabolic clearance fell after IgG removal (1.0 ml/hr vs. 0.7 ml/hr), and mean generation rate was unchanged. Plasma levels rose 20 hours after IgG removal as a result equally of contributions from intrabody transfer and of generation. Model parameters from plasma 125I decay analysis overestimated plasma 125I levels in the first 24 hours after removal, although predicted endogenous levels corresponded well with experimental results over a 7-day period. Rapid intravenous infusion of a 7% body weight volume of saline solution during IgG removal resulted in 50% greater plasma levels of 125I-IgG 24 hours after removal. This indicated that an increased lymphatic flow had occurred, resulting in increased IgG transfer from the extravascular to the intravascular space. The two-pool model adequately describes circulating IgG levels after specific IgG removal. Catabolic clearance was found to be a function of IgG level, whereas generation does not appear to be similarly dependent. Both the two-pool model and saline infusion procedure may be applied directly to the planning and optimization of plasma exchange therapy regimens in human autoimmune disease.     

Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism.

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10-200 mg), and the effect of an infusion of a pharmacological dose [45 micrograms (90 micrograms in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean +/- SEM 22.0 +/- 6.2 pmol/l) compared with healthy control subjects (1.3 +/- 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P less than 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P less than 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 +/- 74 pmol/l, which is a level of atrial natriuretic peptide which would have 'swamped' all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin 1 impairs oxygen delivery in livers from LPS-primed animals

Endothelin 1 (ET-1) is a potent vasoactive peptide that acts at sinusoidal and extrasinusoidal sites in the liver. Sensitivity to ET-1 increases in LPS-primed animals and is associated with impaired liver microcirculation in these animals. We hypothesized that LPS priming leads to an exacerbation in the impaired oxygen delivery in response to intraportal infusion of ET-1. Rats were studied 24 h after LPS injection (1 mg/kg, i.p.). Surface PO2 was determined using a recently developed technology of O2 mapping. The baseline portal pressure was higher in LPS-primed animals (P < 0.05), and increased to'similar magnitude as sham animals after a 10-min infusion of ET-1. The resultant portal pressure remained elevated in LPS compared to sham animals. There was no significant difference in baseline mean arterial pressure, and no significant systemic response to ET-1 in either group. In contrast to the macrohemodynamic, the decrease in tissue surface PO2 in response to ET-1 infusion was potentiated by LPS treatment (increased from baseline levels 33.8+/-9 to 46.8+/-8.3 in sham; 42.3+/-9.1 to 69+/-6.5 gray scale units in LPS; P < 0.01, sham vs. LPS) at end of infusion of ET-1 for 10 min. This indicates tissue hypoxia in response to ET-1, which is exacerbated in livers from LPS-primed animals compared to sham. Frequency distribution analysis showed a shift in mode from lower intensity (higher PO2) to areas with higher fluorescent intensity ranges (lower PO2), indicating areas with shut down in perfusion in LPS-treated animals. In the whole liver, ET-1 suppressed oxygen consumption, and this response was potentiated by LPS pretreatment. We propose that ET-1 impairs oxygen delivery in the liver during endotoxemia, resulting in areas of focal hypoxia. This response is possibly due to potentiated action of ET-1 at both sinusoidal and extrasinusoidal sites in the liver during endotoxemia.     

Plasma concentrations of endothelial vasoactive substances in clinically healthy subjects. associations with urinary albumin excretion and ambulatory blood pressure

Elevated urinary albumin excretion (UAE) is a predictor of cardiovascular disease, and one possible explanation is that elevated UAE reflects a generalized vascular dysfunction. The present study tests whether the plasma concentrations of the two main endothelial vasoactive substances (nitric oxide and endothelin-1 [ET-1]) are changed in clinically healthy subjects with elevated UAE (>6.6 microg/ min-the 90th percentile in the background population) and to test associations between these concentrations and systemic blood pressure. Twenty-seven subjects with elevated UAE were compared with 46 matched controls with normoalbuminuria. Plasma concentration of ET-1 was measured using an ELISA method and plasma concentration of nitrate/nitrite using a photometric method. Twenty-four-hour blood pressure was measured using a portable recorder (TM-2421). No significant differences in the concentrations of nitrate/nitrite and ET-1 were found between the groups, e.g. 21 (10-105) vs. 18 (11 -152) (p=0.33) and 0.98 (0.58 1.95) vs. 1.10 (0.54 -1.50) (p = 0.27), respectively. However, plasma nitrate/nitrite was significantly positively correlated to systolic and diastolic blood pressure in subjects with normoalbuminuria but not in subjects with elevated UAE. In contrast, plasma ET-1 concentration was significantly positively correlated to systolic blood pressure only in subjects with elevated UAE. In conclusion, elevated UAE is not associated with changed plasma concentrations of endothelial vasoactive substances in clinically healthy subjects. However, nitrate/nitrite is positively correlated to BP only in subjects with normoalbuminuria, and ET-1 is positively correlated to BP only in subjects with elevated UAE.     

Multiple-dose amikacin kinetics in pediatric oncology patients.

Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr. This regimen is recommended but, due to patient variability, patients should be monitored. Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval. The data appeared consistent with and were analyzed according to 1-compartment model. An equation describing serum concentration with time for the multiple-dose case was fit to each patient's multiple-interval data with nonlinear regression. Half-life averaged 1.2 hr. volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg. The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels. Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapuetic concentrations were maintained.     

Exaggerated responsiveness of immunoreactive atrial natriuretic peptide to saline infusion in chronic renal failure

Plasma levels of immunoreactive alpha human atrial natriuretic peptide (IR-ANP) were measured in nine patients with chronic renal failure before and after removal of 1.3-3.7 litres of fluid by ultrafiltration and again during volume repletion with intravenous sodium chloride solution (150 mmol/l: saline). Baseline levels of IR-ANP were elevated but fell by 22% during ultrafiltration. Saline infusion induced a rapid and steep rise in IR-ANP levels which were 150% of baseline while body weight was still 2% below baseline. Changes in plasma renin, angiotensin II, aldosterone and vasopressin during the study were slight compared with the change in IR-ANP, but noradrenaline levels rose threefold during ultrafiltration. There was a significant positive relationship between arterial pressure and IR-ANP levels before and after ultrafiltration. These results lend support to the suggestion that atrial peptides are of physiological importance, especially in states of chronic fluid overload such as chronic renal failure.     

Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ET(A) receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60 min intra-arterial infusion of ET-1 (n=10) significantly blunted EDV in young healthy males (33 +/- 13% compared with 271 +/- 74% increase in FBF induced by 10 mug/min acetylcholine; P<0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60 min intra-arterial infusion of the selective ET(A) receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n=10; 109 +/- 45% compared with 255 +/- 101% increase in FBF induced by 10 microg/min acetylcholine; P<0.01), whereas no significant change was observed in healthy age-matched controls (n=9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ET(A) receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ET(A)-receptor-mediated mechanism.     

Differential effects of atrial natriuretic peptide and dopamine on urinary protein excretion in chronic glomerulonephritis.

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.     

Quantification and predictors of plasma volume expansion from mannitol treatment

Objective: To determine the effects of acute hypertonic mannitol infusion on intravascular volume expansion and to identify potential predictors of hypervolemia. Design: Measurements of plasma volume and volume regulatory hormones were performed in healthy volunteers before and over 90 min after acute infusion of 20 % mannitol solution in a therapeutic dose of 0.5 g/kg body weight, equalling an average infusion volume of 180 ml. Setting: Clinical research unit in an 800-bed teaching hospital in the eastern part of Switzerland. Participants: Eight normal male volunteers. Measurements and results: Baseline plasma volume was determined by the indocyanine green dye dilution technique. Serial plasma protein measurements were performed after mannitol infusion to calculate intravascular volume changes. Mannitol administration resulted in a plasma expansion that persisted for more than 90 min and peaked at 112 % of the baseline plasma volume 15 min after infusion. Concomitantly, an increase in systolic blood pressure and a fall in plasma sodium concentration occurred. Pharmacokinetic analyses of mannitol distribution and elimination revealed a close relation between plasma volume expansion and mannitol serum concentrations. While renin activity and aldosterone concentrations were suppressed proportionally to the intravascular volume increase, antidiuretic hormone was increased despite notable volume expansion and hyponatremia. Similarly, a rise in atrial natriuretic peptide was detected. Conclusions: Therapeutic doses of hypertonic mannitol cause substantial plasma volume expansion, resulting in increased blood pressure. Plasma volume expansion is related to mannitol serum concentrations and mannitol clearance determines the time required to restore normovolemia. ADH and ANP are potentially aggravating factors of mannitol-induced hyponatremia. Received: 27 January 1997 Accepted: 18 August 1997     

Concentration-time effects of quinidine disposition kinetics in rhesus monkeys.

The effects of dose and duration of drug administration (time) on the disposition kinetics of quinidine were investigated in unanesthetized rhesus monkeys. A specific thin-layer chromatography-fluorometric assay was developed for the determination of quinidine in plasma, blood and urine. After the monkeys receive an i.v. bolus dose of 3 to 7 mg/kg, quinidine distributes rapidly in the body (T 1/2alpha = 2 minutes). The half-life associated with elimination (T 1/2 beta) was 27 to 35 minutes and primarily involved metabolic transformation. The volume of distribution varied between 0.2 and 0.65 liters/kg and total clearance between 4.8 and 13 ml/min/kg. Similar estimates of T 1/2 beta, clearance and volume of distribution were obtained following constant infusions producing steady-state concentrations less than 6 microng/ml. Prolonged infusion of quinidine at rates producing plasma concentrations in the range of 6 to 13 microng/ml resulted in increases in the elimination half-life whereas drug clearance remained constant. This observation suggests an increased volume of distribution. Both concentration and time were demonstrated to be important in producing changes in quinidine disposition kinetics. The precise mechanism underlying this phenomenon remains unanswered.     

Elevated levels of brain natriuretic peptide in acute hypoxaemic chronic obstructive pulmonary disease.

1. Studies in vitro have recently shown that both atrial natriuretic peptide and brain natriuretic peptide have pulmonary vasorelaxant activity. The purpose of the present study was to evaluate for the first time whether plasma levels of brain natriuretic peptide are elevated in chronic obstructive pulmonary disease. Plasma levels of brain natriuretic peptide and atrial natriuretic peptide were therefore measured in 12 patients admitted with acute hypoxaemic chronic obstructive pulmonary disease [arterial partial pressure of O2, 6.2 +/- 0.4 kPa; arterial partial pressure of CO2, 6.9 +/- 0.1 kPa; forced expiratory volume in 1 s, 0.6 +/- 0.07 litre (27 +/- 3% of predicted)]. All but three patients had oedema on admission. 2. Plasma levels of both brain natriuretic peptide and atrial natriuretic peptide were elevated in patients with chronic obstructive pulmonary disease (31.4 +/- 4.1 pmol/l and 45.0 +/- 8.1 pmol/l, respectively) compared with healthy control subjects (1.7 +/- 0.8 pmol/l and 8.0 +/- 3.5 pmol/l, respectively). Thus, plasma levels of brain natriuretic peptide and atrial natriuretic peptide in patients with chronic obstructive pulmonary disease were increased by 18.5- and 5.6-fold respectively compared with healthy control subjects. 3. There was a significant inverse correlation between the plasma level of brain natriuretic peptide and the arterial partial pressure of O2 (r = -0.65, r2 = 0.42, P = 0.03), but not between the plasma atrial natriuretic peptide level and the arterial partial pressure of O2 (r2 = 0.07, not significant). The arterial partial pressure of CO2 did not correlate with the plasma level of either brain natriuretic peptide or atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between the renin-aldosterone system and atrial natriuretic polypeptide in rats

In order to examine the relationship between the renin-aldosterone system and atrial natriuretic polypeptide (ANP), we investigated the effects of alpha-human atrial natriuretic polypeptide (alpha-hANP) on the plasma concentrations of renin (PRC) and aldosterone (PAC), as well as the effects of captopril pretreatment on the natriuresis and blood pressure reduction induced by alpha-hANP in rats. Although alpha-hANP infused into conscious rats at 0.67 microgram min-1 kg-1 markedly increased the urinary excretion of sodium and decreased mean arterial pressure, its infusion did not change PRC; however, it significantly lowered PAC. Frusemide infusion at 20.8 micrograms min-1 kg-1 induced natriuresis comparable with that of alpha-hANP and it elevated both PRC and PAC, but mean arterial pressure was not altered. Pretreatment of rats with captopril did not have any significant influence on the acute natriuretic and hypotensive effects of alpha-hANP. Although the inhibitory effect of ANP on the renin-aldosterone system may be involved in the chronic modulation of body fluid volume and blood pressure, this effect does not seem to be directly involved in the acute natriuretic and hypotensive effects of the peptide.