Biomedical subjects

P Du Souich

Publications and source records attributed to P Du Souich.

At least 19 recordsLinked to original sources

PubMed2004

Effect of hypoxia on cytochrome P450 activity and expression.

In the last three decades, numerous reports have shown that patients with chronic pulmonary disease and with heart failure with hypoxemia cleared drugs at a lower rate than healthy volunteers. As a consequence decreased clearance, drug toxicity is frequent in these patients. The reduction in drug clearance is due to a decrease in activity of cytochrome P450 isoforms, partly associated to the hypoxemia. With in vivo animal models, acute moderate hypoxia (PaO2 of around 35-50 mm Hg) reduces the clearance of drugs biotransformed by CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2E1, although hypoxia does not affect the clearance of drugs biotransformed by CYP3A6. Ex vivo and in vitro experiments demonstrate that hypoxia down-regulates CYP1A1, CYP1A2, CYP2B6, CYP2C9 and CYP2C19, decrease preceded by a reduction in activity. On the other hand, acute moderate hypoxia up-regulates CYP3A6. The changes in protein expression are preceded by modifications in the mRNA coding for the proteins. The effect of hypoxia on hepatic cytochrome P450 is carried out by serum mediators, e.g. interferon-gamma, interleukin-1beta, and interleukin-2 are responsible for the decrease in activity and in expression of cytochrome P450 isoforms, and erythropoietin accounts for the increase in CYP3A6. Probably several mechanisms underlie and contribute to the decrease in activity and down-regulation of cytochrome P450 isoforms by hypoxia, e.g. reducing potentiation factors, inducing repressor elements and activating negative regulatory elements. The up-regulation of CYP3A6 implies a PTK- and p42/44MAPK-dependent stabilization/activation, nuclear translocation of HIF-1 and AP-1, binding to CYP3A6 promoter, and transactivation of the gene to induce CYP3A6 expression.

Animals↗

PubMed2003

The effect of a strongly basic alkaloidal fraction of Rhazya stricta, a traditional medicinal plant, on cytochrome P450-mediated metabolism of theophylline in mice.

The strongly basic alkaloidal fraction of the traditional medicinal plant Rhazya stricta (RS) was given orally to mice, in a single dose of 10 mg/kg (group 1) or, twice daily for 3 days at the same dose (group 2). A third group (control) received normal saline. Liver homogenates from all animals were used to assess the microsomal activity of cytochrome P450 and its isoforms as well as its catalytic activity (using theophylline as a substrate). RS alkaloidal fraction had no significant effect on the total amount of microsomal cytochrome P450, but it caused a significant increase in the cytochrome P450 isoforms CYPs 1A1 and 1A2. It also significantly increased the concentrations of some metabolites of theophylline. These results suggest that RS has the potential to interact with other drugs that are biotransformed by cytochrome P450, when given concomitantly with it.

Administration, Oral↗

PubMed2001

Permeability of the peptidic GH secretagogues hexarelin and EP 51389, across rat jejunum.

The intestinal permeability of hexarelin and EP 51389, two growth hormone releasing hexa- and tri- peptide analogues, was assessed in vitro with side-by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P-gp) was evaluated by rhodamine 123 accumulation on monolayers of CH(R)C5 cells with increasing concentrations of EP 51389. Hexarelin and EP 51389 permeability were found to be < 1%. Permeability coefficients (P(app)) were 18.87 +/- 2.86 (x10(-7) cm/s) and 5.87 +/- 0.45 (x10(-7) cm/s) for hexarelin and EP 51389, respectively. Bidirectional studies revealed that hexarelin transport was similar in both directions. EDTA did not influence hexarelin permeability. Permeability was predominantly secretory for EP 51389 as P(app) in the BL-to-AP direction [32.56 +/- 6.11 (x10(-7) cm/s)] was greater than AP-to-BL. Confirming involvement of a secretory transport system, chlorpromazine inhibited EP 51389 transport across the jejunum. EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine in CH(R)C5 cells. These results suggest that: 1) the intestinal permeability of hexarelin and EP 51389 is poor; 2) the passage of hexarelin is mainly via a transcellular passive pathway since the contribution of paracellular permeability to the overall permeability is rather low; 3) P-gp may act as a potential barrier for the intestinal absorption of EP 51389.

Animals↗

PubMed1999

Cytochrome P-450 content and activity after cold storage of rat hepatocytes in university of wisconsin and sodium-lactobionate-sucrose solutions.

We compared the capacity of University of Wisconsin (UW) and of sodium-lactobionate-sucrose (SLS) hypothermic preservation solutions to maintain the integrity of the hepatic cytochrome P-450-dependent mono-oxygenase system. Isolated rat hepatocytes were stored for 0, 10, 24, and 48 hours in UW or SLS solution and were subsequently cultured shortly at 37 degrees C. Cell viability declined slightly but significantly in a time-dependent manner during cold preservation in either UW or SLS solution, and warm culture exacerbated this effect. Total cytochrome P-450 declined gradually after cold preservation and warm culture to reach values of 70% and 52% of unstored controls in cells preserved for 24 and 48 hours in cold UW solution, respectively. Storage in cold SLS solution yielded a similar decrease to 79% and 59% of unstored controls for the equivalent preservation times. Cytochrome P-450 activity was assessed by the metabolism of theophylline after various cold preservation times in UW or SLS solutions. Production of the major metabolite 1,3-dimethyluric acid was not significantly affected by extended cold preservation periods in either UW or SLS solutions. Similarly, the amount of residual theophylline remained stable in all groups, suggesting that alternative metabolic routes were not modified. These studies show that cold preservation in SLS solution is as effective as that in UW solution in terms of cell viability, cytochrome P-450 content, and activity toward theophylline. In addition, the significant reduction in cytochrome P-450 in conjunction with unaffected theophylline disposition suggests that certain cytochrome P-450 isoforms are specifically damaged by cold preservation and rewarming.

Adenosine↗

PubMed1997

Hepatic extraction of hexarelin, a new peptidic GH secretagogue, in the isolated perfused rat liver.

PURPOSE: To assess the hepatic extraction of hexarelin (HEX), a novel peptidyl GH secretagogue, in the isolated perfused rat model and document the in vitro binding of HEX to plasma proteins using plasma from rats, dogs, pigs, and humans. METHODS: Rat liver was perfused in situ using a recirculating system. The recirculating perfusate consisted of a Krebs Henseleit buffer containing 20% (v/v) prewashed bovine red blood cells, 1% albumin, and lg/L dextrose. Three HEX concentrations of 5, 50, and 500 ng/ml were examined. In vitro plasma binding was determined by the ultrafiltration method. RESULTS: The disappearance rate constant (K), half-life (t1/2), clearance (Cl), and hepatic extraction ratio (E) were: K = 0.013-0.014 min-1, t1/2 = 45-55 min, Cl = 0.345-0.401 ml/min/g liver, and E = 19-21% for the different concentrations of HEX. A linear increase in AUC (270-24334 min pmol/ml) was observed with increasing concentrations. Binding of HEX to plasma proteins of rats, dogs, pigs, and humans was 68.7 +/- 0.8%, 78.7 +/- 0.6%, 67.3 +/- 0.7%, and 65.2 +/- 0.6% respectively. Plasma binding was concentration-independent in the range between 0.003-3 microM for the four species examined. CONCLUSIONS: These results show that 1) the hepatic extraction of HEX is low, 2) the hepatic clearance is concentration independent up to 500 ng HEX/ml of perfusate, and 3) the plasma protein binding of HEX is significant over the dose range studied. HEX exhibits a low hepatic extraction ratio, allowing us to predict that its hepatic clearance may be limited upon HEX protein binding.

Animals↗

PubMed1997

In vivo, ex vivo, and in vitro effects of L-NAME and L-arginine on the metabolism of theophylline in the rabbit.

It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg i.v.) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 microM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.

Animals↗

PubMed1996

Arginine vasopressin disposition in the conscious rabbit.

To characterize the urinary kinetics of AVP, and the influence of regional blood flow on the metabolic degradation of AVP, multiple doses of AVP were administered to conscious rabbits. AVP systemic clearance (ClT) was not influenced by changes in dose, in spite of a decrease in AVP urinary clearance following the highest dose. Hepatic blood flow was inversely associated with AVP concentrations, and despite a decrease in hepatic plasma flow of 37% (p < 0.05), following the high dose of AVP, ClT remained unchanged. These results indicate that AVP plasma kinetics are first order and plasma flow independent, and urinary kinetics are zero order.

Animals↗

PubMed1996

Single-dose pharmacokinetics of ampicillin and tobramycin administered by hypodermoclysis in young and older healthy volunteers.

1. To test the feasibility of administering antibiotics by subcutaneous infusion to the elderly, we compared the pharmacokinetics of tobramycin (single dose of 80 mg) given by hypodermoclysis (HDC) with the kinetics of the antibiotic injected intravenously (i.v.) in 10 young (< 50 years old) and 10 elderly (> 65 years old) healthy volunteers. Similar studies were performed with ampicillin (single dose of 1 g) in 12 young and 10 older healthy volunteers. 2. Compared with the i.v. route, HDC delayed the time to reach the maximal plasma concentration (tmax) of tobramycin in young volunteers: 32 +/- 6 (s.d.) min vs 88 +/- 46, P < 0.005, and older volunteers: 27 +/- 4 min vs 89 +/- 15, P < 0.005. Administration of the antibiotics by HDC was well tolerated. The plasma concentration of tobramycin 30 min after the end of infusion (C60) was lower (P < 0.05) following HDC than after the i.v. route in both young, 2.2 +/- 0.7 vs 3.5 +/- 0.8 micrograms ml-1, and elderly subjects, 2.2 +/- 0.8 vs 3.8 +/- 0.9. micrograms ml-1. 3. The area under the curve (AUC) of tobramycin given by HDC was slightly smaller than when given i.v., i.e. in young subjects: 740 +/- 225 (s.d.) vs 893 +/- 223 micrograms ml-1 min, NS, and in the elderly: 980 +/- 228 vs 1056 +/- 315 micrograms ml-1 min, NS. 4. When ampicillin was administered by HDC, the tmax was also delayed in young volunteers: 45 +/- 18 vs 23 +/- 6 min, and in the elderly: 49 +/- 18 vs 27 +/- 4 min, P < 0.005, the AUC was greater by HDC than i.v. in the young volunteers: 4527 +/- 1658 micrograms ml-1 min vs 3810 +/- 1033 micrograms ml-1 min and in the elderly: 6795 +/- 2094 micrograms ml-1 min vs 4217 +/- 1518 micrograms ml-1 min, and the C60 was higher by HDC in the young: 27 +/- 7 vs 24 +/- 9 micrograms ml-1, and in the elderly: 32 +/- 9 vs 23 +/- 11 micrograms ml-1, P < 0.05. 5. In conclusion, HDC delays the entry of the antibiotic into the systemic circulation, but did not affect the amount available. HDC was well tolerated and could become an adequate method for antibiotic administration to the elderly.

Administration, Cutaneous↗

PubMed1995

Plasma concentrations and effects of salbutamol administered orally to patients with cystic fibrosis.

1. To test whether cystic fibrosis (CF) altered the kinetics and dynamics of oral salbutamol, 11 patients with CF (19-33 years old; five females; FEV1: 37 +/- 12% of predicted value) and 10 healthy volunteers (20-41 years old; five females; FEV1: 99 +/- 14% of predicted value) received orally 4 mg salbutamol. 2. The estimated pharmacokinetic parameters of salbutamol in patients with CF were identical to those in healthy subjects. For instance, peak plasma concentrations of salbutamol were 10.5 +/- 2.6 (mean +/- s.d.) and 10.2 +/- 2.9 ng ml-1 (NS), and the area under salbutamol plasma concentrations as a function of time (AUC (0, 7 h)) was 43.0 +/- 9.3 ng ml-1 h and 43.3 +/- 12.7 ng ml-1 h (NS) in CF patients and in healthy subjects, respectively. Since on a mg kg-1 dose basis, CF patients received a dose 28% greater than healthy subjects, this lack of differences implies a decrease in the amount of salbutamol absorbed, or alternatively, an increase in both clearance and volume of distribution of salbutamol. 3. Salbutamol did not elicit bronchodilation in CF patients, but increased heart rate from 77 +/- 2 to 103 +/- 3 beats min-1 (P < 0.05). 4. Salbutamol decreased plasma potassium concentrations from 4.5 +/- 0.1 to 3.8 +/- 0.1 mmol l-1 in the CF group (P < 0.05) and from 4.1 +/- 0.2 to 3.4 +/- 0.1 mmol l-1 in the controls (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

Acute moderate hypoxia in conscious rabbits: effect on hepatic cytochrome P450 and on reactive oxygen species.

This study aimed to document whether acute moderate hypoxia modifies the amount and activity of hepatic cytochrome P450 and in addition, induces changes in the production or the ability to neutralize oxygen reactive species (ORS). Rabbits were exposed to a low partial pressure of oxygen (12%) for 8 or 24 h, killed, and the amount and activity of cytochrome P450, lipid peroxidation, microsomal chemiluminescence and enzymatic scavenger activity were assessed in the liver. After 8 h of hypoxia, total amount but not the activity of cytochrome P450 was decreased, although after 24 h of hypoxia, both the amount and the activity of cytochrome P450 were decreased. Hypoxia for 8 h increased the activity of glutathione peroxidase. However, after 24 h of hypoxia, lipid peroxidation, microsomal chemiluminescence and superoxide dismutase activity were increased, while hepatic glutathione and glutathione peroxidase activity were reduced, modifications that suggest an enhanced presence of ORS. In in-vitro studies, an ORS generating system reduced the activity of cytochrome P450 and enhanced lipid peroxidation of hepatic microsomal membranes, supporting the view that ORS can impair cytochrome P450. The results of the present study show that hypoxia induces changes in the amount and activity of cytochrome P450, as well as in the production or the ability to neutralize ORS, and that these changes are time-dependent.

Acute Disease↗

PubMed1995

Influence of hypoxia and hypercapnia on the kinetics and hypokaliaemic effect of salbutamol in the rabbit.

1. The aims were to document the influence of moderate hypoxia or hypercapnia on salbutamol kinetics and its hypokaliaemic effect, following its administration through the intravenous (60 micrograms/kg), intratracheal (60 micrograms/kg), and oral (2400 micrograms/kg) routes (n = 5). In control animals, PaO2 was around 85 mmHg and PaCO2 20 mmHg; in hypoxic animals PaO2 was around 40 mmHg and in the hypercapnic rabbit PaCO2 was 50 mmHg. 2. Following the intravenous administration of salbutamol, the apparent volume of distribution increased two-fold (p < 0.05) in animals with hypoxia and hypercapnia. Consequently, its half life was enhanced (p < 0.05). Given via the trachea, salbutamol bioavailability was decreased by hypoxia. 3. When salbutamol was given orally, hypoxia or hypercapnia increased the area under salbutamol plasma concentration as a function of time (p < 0.05). 4. In control animals, the salbutamol hypokaliaemic effect was greater when administered orally than through the other routes. Compared with control animals, the experimental conditions reduced the hypokaliaemic effect of salbutamol only when given orally. 5. It is concluded that salbutamol kinetics and dynamics can be altered by hypoxia and hypercapnia.

Administration, Oral↗

PubMed1995

Presystemic elimination of morphine in anesthetized rabbits. Contribution of the intestine, liver, and lungs.

To assess the role of the intestine and the lung in the first-pass uptake of morphine relative to that of the liver, five groups of 6-7 New Zealand rabbits were used. A control group of conscious rabbits received 2 mg/kg of morphine iv. The remaining groups included anesthetized rabbits who received morphine into the aortic cross (2 mg/kg), the jugular vein (2 mg/kg), the portal vein (14 mg/kg), or into the duodenum (20 mg/kg). Multiple blood samples were withdrawn for 3 hr from the abdominal aorta, and morphine and morphine-6-glucuronide were assayed by HPLC. Anesthesia and surgery decreased morphine presystemic clearance from 264 +/- 14 to 194 +/- 12 ml/min/kg (p < 0.05). When morphine was injected into the aortic cross, the area under morphine plasma concentration-time curve (AUCM 0-->infinity) normalized by the dose was 7.81 +/- 0.56 10(-3) kg min/ml, a value that decreased to 5.26 +/- 0.36 (p < 0.05), 2.50 +/- 0.35 (p < 0.05), and 0.87 +/- 0.10 (p < 0.05) 10(-3) kg min/ml when morphine was injected before the lung, liver, or intestine, respectively. The extraction ratio of morphine by the lung, liver, and intestine was 0.33, 0.52, and 0.65, respectively. Compared with the aortic route, the AUCM6G 0-->infinity normalized by the dose ratio tended to be greater (p > 0.05) when morphine was injected into the jugular and portal veins, suggesting that morphine-6-glucuronide is not the major product result of morphine first-pass uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1995

Contribution of the small intestine to the first-pass uptake and systemic clearance of propranolol in rabbits.

Epithelial cells of the intestine enclose isozymes able to metabolize propranolol, raising the possibility that the gut contributes with the liver to the first-pass uptake and systemic clearance of propranolol. To assess the role of the liver in the first-pass uptake, propranolol was injected into the jugular vein and a mesenteric vein of anesthetized New Zealand rabbits, and blood samples were drawn from the abdominal aorta, or it was injected into the intestine and samples were drawn simultaneously from the portal vein and the abdominal aorta. Extraction of propranolol by the liver was estimated to be 96-97%. To assess the intestinal extraction of oral propranolol, a porto-cava transposition was conducted in two groups of animals, and propranolol was injected into the first 30 cm of the small intestine or into the jugular vein and samples were withdrawn from the abdominal aorta; propranolol extraction by the intestine was 43%. To document the contribution of the intestine in the systemic clearance of propranolol, propranolol was injected into the jugular vein and blood samples were drawn simultaneously from the abdominal aorta (before the gut) and from the portal vein (after the gut); propranolol extraction from the systemic circulation by the intestine was 24%. Only the liver generated detectable amounts of conjugated metabolites of propranolol. In the in vitro studies, it was shown that propranolol was rapidly metabolized by the liver, yielding 4-hydroxypropranolol and conjugates of propranolol; propranolol metabolism in the proximal small intestine was slower and yielded only 4-hydroxypropranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1994

Pharmacokinetics and pharmacodynamics of a slow-release formulation of diltiazem after the administration of a single and repeated doses to healthy volunteers.

Diltiazem is a calcium antagonist used in angina pectoris and hypertension. There is little information concerning the slow-release (SR) formulation in the literature. The pharmacokinetics of diltiazem SR (120 mg) have been assessed over a 36h period in healthy volunteers after single- (SD) and multiple-dose (MD) administrations. Cmax, AUC0-36, and AUC0-infinity were significantly increased at steady state compared to the extrapolated SD values, suggesting accumulation of the drug. Renal and cardiovascular parameters have also been assessed at intervals of 3-6h during baseline (B) and following single and multiple doses of diltiazem SR. Diuresis over a 24 h period was increased, but not significantly, by the administration of diltiazem SR i.e. 1782 ml (MD) and 1915 ml (SD), versus 1626 ml (B). Natriuresis and creatinine clearance were slightly decreased by diltiazem SR, compared to B values; this might be due to the relatively short period over which steady state was maintained (five days) and the effects of norepinephrine and angiotensine II on renal vasculature and the pharmacokinetics of diltiazem SR. No increase in the systolic blood pressure occurred after the administration of diltiazem SR; diastolic blood pressure and PR interval were decreased and increased respectively by diltiazem SR. These results do not appear to be clinically significant. Finally, no relation was found between the pharmacokinetics and pharmacodynamics of diltiazem. This may be attributed to the absence of clinically significant effects in healthy volunteers, the presence of active metabolites, the pharmacokinetics of the SR formulation and/or the accumulation of the drug at steady state.

Adult↗

PubMed1994

Influence of chronic hypoxia on salbutamol tissular concentrations and on respiratory resistance in anesthetized rabbits.

Salbutamol is a potent beta 2-adrenoceptor agonist given to patients with bronchial asthma who are frequently hypoxemic. The aims of this study were to document the influence of chronic hypoxia on salbutamol tissue concentrations and on salbutamol effect on total respiratory resistance. To this purpose, salbutamol (60 micrograms/kg) was administered intravenously to four groups of six rabbits exposed to four experimental conditions: (1) control rabbits breathing air, (2) histamine-induced bronchoconstriction in rabbits breathing air, (3) animals with chronic hypoxia, (4) histamine-induced bronchoconstriction in animals with chronic hypoxia. The area under salbutamol plasma concentration time curve (0 to 45 min) was not affected by these experimental conditions. Compared with control rabbits breathing air, following histamine-induced bronchoconstriction, salbutamol concentrations rose by 40 to 50% in lung and heart (p < 0.05). Hypoxia did not affect salbutamol distribution in these organs; however, in hypoxic animals, histamine-induced bronchoconstriction increased salbutamol concentrations only in the heart (p < 0.05), without affecting those in the lung. Compared with rabbits breathing air and with histamine-induced bronchoconstriction, the effect of salbutamol was reduced in rabbits under chronic hypoxia and histamine-induced bronchoconstriction (p < 0.05). We conclude that chronic hypoxia reduces salbutamol effect on pulmonary resistance, possibly by decreasing salbutamol lung concentrations.

Airway Resistance↗

PubMed1992

Pharmacodynamics as a tool to assess the bioequivalence of non-systemically available drugs: size of the sample required.

Bioequivalence studies of drugs which are not systematically available must rely on the measure of the pharmacological response. Detection of a difference between two such preparations is often hampered by the need to include an elevated number of subjects. The number of subjects can be reduced whenever: (a) the characteristics of the subjects are well defined, (b) the selection of the baseline target effect is done rigorously, (c) the target effect can be quantified reliably, (d) the effect is measured when less variability is expected, e.g. at steady state, (e) the effect is measured repeatedly, and (f) when possible, the predicted maximal effect (Emax) and the concentration to elicit 50% of Emax are estimated. A simple equation has been derived to estimate the number of subjects needed in these bioequivalence studies.

Cohort Studies↗

PubMed1991

Effect of salbutamol on gastroesophageal reflux in healthy volunteers and patients with asthma.

The aim of this work was to establish whether beta-adrenergic agonists promote or increase gastroesophageal reflux in patients with asthma. Ten healthy individuals and eight patients with asthma were studied on 2 different days. One day they received a placebo, and the other day they received 4 mg of salbutamol by mouth. Complete measurements of esophageal manometry were performed before and every 30 minutes for 210 minutes after the administration of the drugs. Esophageal pH was measured continuously for the duration of the experiment. The results demonstrate that (1) salbutamol had no effect on the lower esophageal sphincter pressure gradient, the peak esophageal contraction pressure, or the number and duration of reflux episodes in patients with asthma and normal individuals, and (2) patients with asthma have a resting lower esophageal sphincter pressure higher than healthy subjects. We conclude that the administration of salbutamol does not affect esophageal function.

Adolescent↗

PubMed1991

High salt intake-induced changes in atrial natriuretic factor kinetics are mediated by clearance receptors.

We have reported a paradoxical plasma atrial natriuretic factor (ANF) decline following prolonged high salt intake that was attributed to an increased tissue uptake of circulating ANF, leading to its augmented distribution volume (Vas) and metabolic clearance rate (MCR) as compared with control rats on a standard diet. To explore this phenomenon further, we evaluated possible chronic salt-loading-induced changes in ANF clearance (C-ANF) receptors, which appear to play a major role in ANF removal from the circulation. We studied changes in plasma [125I]ANF(1-28) and its pharmacokinetics after preoccupation of C-ANF receptors by its specific ligand, C-ANF(4-23), in high-salt-treated rats and their controls. Following C-ANF(4-23) administration, we detected significantly higher circulating [125I]ANF levels throughout the study period (8 min) in high-salt-fed rats compared with the controls (280-470% vs 100-215% increase of basal values, P less than 0.05). C-ANF(4-23) infusion caused a significantly greater decrease of the metabolic clearance rate and distribution volume of [125I]ANF in high-salt-fed rats than in control animals (74 +/- 6% vs 41 +/- 6% and 75 +/- 4% vs 50 +/- 5% of basal values, respectively; P less than 0.05). These data suggest that a prolonged high salt diet may increase the availability of C-ANF receptors and, through this mechanism, may negatively modulate plasma ANF concentrations. C-ANF receptors may thus fulfill a regulatory function on circulating ANF during prolonged salt loading in rats.

Analysis of Variance↗