Pharmacokinetics of the local anesthetic ropivacaine after transversus abdominis plane block in healthy volunteers.

PURPOSE: The transversus abdominis plane (TAP) block is a regional anesthetic technique used for pain control following abdominal surgical procedures. While a minimum of systemic side effects is usually expected after local anesthesia, it is unknown to which extent systemic absorption and redistribution to the abdominal wall contributes to the effects of anesthetics. The aim of this study was to determine concentration-time profiles of ropivacaine after the injection of 150 mg of ropivacaine into the lateral abdominal wall in various compartments. METHODS: The microdialysis technique was used to measure ropivacaine in plasma as well as at abdominal wall sites cranial from the injection site (below the 12th rip) and caudal from the injection site (cranial from the iliac crest) and in the skeletal muscle tissue of the contra lateral thigh of eight healthy volunteers. RESULTS: The mean exposure to ropivacaine measured as the area under the concentration-time curve was significantly higher at the two abdominal sites (240.9 ± 409.1  and 86.18 ± 133.50 µg h/mL, respectively) than in plasma (5.1 ± 1.0 µg h/mL) or in peripheral tissue (1.1 ± 1.2 µg h/mL). While the high mean concentrations of ropivacaine measured at the abdominal wall sites support the topical concept of the TAP block, the observed variability was striking. CONCLUSIONS: While the systemic pharmacokinetics was comparable between subjects, the local distribution of ropivacaine was highly variable after TAP block.

[Coxibs: cyclooxygenase-2 inhibitors]. / Coxibe: Hemmer der Cyclooxygenase-2.

The oxygenating enzyme cyclooxygenase (COX) catalysis the conversion of arachidonic acid to proinflammatory prostaglandins. For many years it was thought that COX is a single enzyme that is present constitutively in most tissues. But in the late 80ies COX activity was found to be increased in inflammatory states with cytokines and bacterial lipopolysaccharides as inducing agents. The expression of the induced COX is inhibited by glucocorticoids which is not the case with the COX known up to then. According to these findings COX exists in two forms, the aminoacid sequences of which are known. The expression of COX-1 is not or only poorly regulated, the prostaglandins produced by it are responsible for the protection of the gastric mucosa, maintenance of normal kidney function and platelet aggregation. COX-2, in contrast, is highly regulated, the prostaglandins produced by this isoenzyme are involved in inflammation, fever and pain but also in the regulation of kidney function. Conventional non-steroidal antiinflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2. The analgesic, antipyretic and antiinflammatory effects of these agents are accounted for by COX-2 inhibition, whereas the toxic effects on the stomach as well as the inhibition of platelet aggregation are attributed to COX-1 inhibition. In search for selective blockers of COX-2, celecoxib and rofecoxib were developed which have an analgetic and antirheumatic potency similar to that of conventional NSAIDs but are associated with significantly fewer adverse gastroduodenal events. The renal toxicity of the selective COX-2 inhibitors is not better than that of the non-selective NSAIDs.

Analgesic effects of caudal and intramuscular S(+)-ketamine in children.

BACKGROUND: Previous studies suggest that caudal administration of ketamine cause effective analgesia. The purpose of the current study was to compare the clinical effectiveness and plasma concentrations of S(+)-ketamine after caudal or intramuscular administration in children to distinguish between local and systemic analgesia. METHODS: After induction of general anesthesia, 42 patients, aged 1 to 7 yr, scheduled to undergo inguinal hernia repair randomly received a caudal (caudal group) or intramuscular (intramuscular group) injection of 1 mg/kg S(+)-ketamine. Intraoperatively, heart rate (HR), mean arterial pressure (MAP) and arterial oxygen saturation were measured. Postoperative measurements included duration of analgesia, a four-point sedation score, and hemodynamic and respiratory monitoring for 6 h in the recovery room. Analgesic requirements in the recovery room were assessed by an independent blinded observer using an observational pain/discomfort scale (OPS). Plasma samples for determination of ketamine concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, and 180 min after injection of S(+)-ketamine. RESULTS: A significantly longer duration of analgesia (P < 0.001) was observed after caudal administration (528 min [220-1,440 min]; median [range]) when compared with intramuscular administration (108 min [62-1,440 min]) of S(+)-ketamine. Plasma levels of ketamine were significantly lower from 10 to 45 min after caudal administration than after intramuscular injection. CONCLUSION: Caudal S(+)-ketamine provides good intra- and postoperative analgesia in children. Despite similar plasma concentrations during most of the postoperative observation period, caudal S(+)-ketamine provided more effective analgesia than did intramuscular S(+)-ketamine, indicating a local analgesic effect.

[Adverse effects of psychotropic drugs in the elderly]. / Unerwünschte Wirkung von Psychopharmaka im Alter.

As in other organs, homeostatic mechanisms become insufficient in the aging brain, in part because of reduced activity of various neurotransmitter systems. Counter-regulatory processes are therefore reduced and reactions to drugs may be increased. Aside from these pharmacodynamic mechanisms, the increased toxicity of psychotropic agents in the elderly may be a result of pharmacokinetic changes. The total clearance of a number of drugs is reduced in old age, hence steady-state plasma concentrations of these compounds will be increased when conventional doses are used. Because of these changes, the central nervous system is especially vulnerable in elderly. With tranquilizers and hypnotics, sedation is increased and cognitive function may decrease. The risk of falls and injuries is enhanced with all psychoactive drugs. In addition, response to agents with anticholinergic properties (classical antidepressants and neuroleptics) is increased in old age and is accompanied by peripheral symptoms such as urinary retention, obstipation, tachycardia and visual disturbances. In the central nervous system there may be impairment of intellectual capabilities, agitation, and ultimately delirium. Further, the undesirable cardiac effects of tricyclic antidepressants should be noted. The selective serotonin reuptake inhibitors (SSRI) and moclobemide have an advantageous pharmacological profile compared to older antidepressants. Of the neuroleptics, the benefit-risk relation of the newer atypical agents appears to be more favorable than that of classical neuroleptics.

Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects.

AIMS: The prevalence of hyperuricaemia and gout increases with age as does the incidence of adverse effects to allopurinol, the major uric acid lowering drug. The present study was performed to compare the disposition and effects of allopurinol and its active metabolite oxipurinol in elderly and young subjects without major health problems. METHODS: Ten elderly (age range 71-93 years) and nine young subjects (24-35 years) received an oral dose of 200 mg allopurinol in an open, single dose, cross sectional design. Four of these individuals were additionally dosed with 200 mg allopurinol intravenously. Plasma and urine concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid were measured by h. p.l.c. RESULTS: Total clearance of allopurinol was not different in elderly (15.7+/-3.8 ml min-1 kg-1, mean+/-s.e. mean) and young subjects (15.7+/-2.1), whereas total clearance of oxipurinol was significantly reduced in the aged (0.24+/-0.03) compared with young controls (0.37+/-0.05) as was the distribution volume of oxipurinol (0.60+/-0.09 and 0.84+/-0.07 l kg-1, respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by metabolism. Fractional peroral bioavailability of allopurinol was 0.81+/-0.16 (n=4, two elderly and two young subjects). Although maximal plasma concentrations of oxipurinol were significantly higher in elderly (5. 63+/-0.83 microgram ml-1 ) than in young persons (3.75+/-0.25) as was the area under the oxipurinol plasma concentration-time curve, AUC (260+/-46 and 166+/-23 microgram ml-1 h, respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly than young subjects (time-dependent decrease of plasma uric acid 83+/-30 microgram ml-1 h in elderly compared with 176+/-21 in young controls). Oxipurinol increased the renal clearance of xanthine, suggesting inhibition of tubular xanthine reabsorption by oxipurinol. CONCLUSIONS: Although allopurinol elimination is not reduced in the aged, that of its active metabolite oxipurinol is because of an age-dependent decline in renal function. Xanthine oxidase inhibition by oxipurinol appears to be reduced in old age. In addition to its uricostatic action, oxipurinol has a xanthinuric effect which is also diminished in the elderly.

[Increased rate of spontaneous version in breech presentation by Indian bridge? A prospective, randomized study]. / Erhöhung der Rate von Spontanwendungen bei Beckenendlagen durch die Indische Brücke? Eine prospektive, randomisierte Studie.

BACKGROUND: The effectiveness of Indian version to convert fetuses from breech to vertex presentation was evaluated. METHODS: One hundred and nine pregnant women presenting between 30 and 32 weeks of gestation with singleton breech infants were included in our prospective randomized open study making an interim analysis recruitment to estimate the sample sizes after one year. The spontaneous version rate of fetuses in breech presentation was compared with the version rate in women performing Indian version. Indian version is a maternal positioning exercise that consists of raising the pelvis, abduction of the thighs, and relaxed abdominal breathing. Clinical parameters that could influence the result were assessed. RESULTS: In primiparous women, the version rate was 70% in the Indian version group and 63% in the comparison group. In multiparous women, 89% Indian versions and 87% spontaneous versions were observed. Parity was the only clinical parameter found to be related to outcome. CONCLUSION: Indian version does not significantly improve the rate of spontaneous version of breech to vertex presentation.

Membrane phospholipid composition affects function of potassium channels from rabbit colon epithelium.

We tested the effects of membrane phospholipids on the function of high-conductance, Ca(2+)-activated K(+) channels from the basolateral cell membrane of rabbit distal colon epithelium by reconstituting these channels into planar bilayers consisting of different 1:1 mixtures of phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI). At low ambient K(+) concentrations single-channel conductance is higher in PE/PS and PE/PI bilayers than in PE/PC bilayers. At high K(+) concentrations this difference in channel conductance is abolished. Introducing the negatively charged SDS into PE/PC bilayers increases channel conductance, whereas the positively charged dodecyltrimethylammonium has the opposite effect. All these findings are consistent with modulation of channel current by the charge of the lipid membrane surrounding the channel. But the K(+) that permeates the channel senses only a small fraction of the full membrane surface potential of the charged phospholipid bilayers, equivalent to separation of the conduction pathway from the charged phospholipid head groups by 20 A. This distance appears to insulate the channel entrance from the bilayer surface potential, suggesting large dimensions of the channel-forming protein. In addition, in PE/PC and PE/PI bilayers, but not in PE/PS bilayers, the open-state probability of the channel decreases with time ("channel rundown"), indicating that phospholipid properties other than surface charge are required to maintain channel fluctuations.

Drug dosage in the elderly. Is it rational?

Pharmacotherapy in the elderly requires an understanding of the age-dependent changes in function and composition of the body. Aging is characterised by a progressive loss of functional capacities of most if not all organs, a reduction in response to receptor stimulation and homeostatic mechanisms, and a loss of water content and an increase of fat content in the body. The most important pharmacokinetic change in old age is a decrease in the excretory capacity of the kidney; in this regard, the elderly should be considered as renally insufficient patients. The decline in the rate of drug metabolism with advancing age is less marked. In addition, the volume of distribution and the oral bioavailability of drugs may be changed in the elderly compared with younger individuals. Average dosage adjustments for the aged can be derived from simple equations and mean pharmacokinetic parameters from older and younger adults. However, these average dose adjustment factors neglect the large variation in the decline in organ functions among the elderly. Individual dose adjustment factors can be obtained from the drug clearance in a particular patient, where clearance/fractional bioavailability (CL/f) may be calculated from the area under the plasma concentration-time curve (AUC) of the drug in question. Using pharmacokinetic guidelines for dose adjustments, the same plasma drug concentrations result in elderly as in younger adults. However, we are frequently confronted with pharmacodynamic changes in old age which alter the sensitivity to drugs, irrespective of changes in drug disposition. For instance, the sensitivity of the cardiovascular system to beta-adrenergic agonists and antagonists decreases in old age and the incidence of orthostatic episodes in response to drugs that lower blood pressure is increased. The CNS is especially vulnerable in the elderly; agents that affect brain function (anaesthetics, opioids, anticonvulsants, psychotropic drugs) must be used very cautiously in this age group. The increased responsiveness to drugs in the elderly renders the measurement of drug plasma concentrations an attractive method to monitor pharmacotherapy in this age group. Sensitive technology to quantitatively determine plasma drug concentrations is available. However, optimal therapeutic plasma concentrations have not been established for most drugs in the elderly. Investigations concerning drug pharmacokinetic-pharmacodynamic relationships in the aged are an important area of future work in clinical pharmacology.

Topical anesthesia with pH-adjusted versus standard lidocaine 4% for clear corneal cataract surgery.

PURPOSE: To evaluate and compare the efficacy of a sodium-bicarbonate-adjusted preparation of lidocaine 4% (pH = 7.2) and standard lidocaine (pH = 5.2) for topical anesthesia in clear corneal cataract surgery. SETTING: Department of Ophthalmology, University of Vienna, Austria. METHODS: In a prospective, randomized, double-blind clinical trial, clear corneal cataract surgery was performed under topical anesthesia in 44 eyes of 34 patients. In 22 eyes, pH-adjusted lidocaine 4% was administered; in the other 22, standard lidocaine 4%. Aqueous and serum concentrations of lidocaine were measured by high-performance liquid chromatography and ultraviolet detection. Subjective pain was assessed using a visual analog scale of no pain (0%) to worst imaginable pain (100%). On the first postoperative day, visual acuity, intraocular pressure, and corneal staining with fluorescein were examined. RESULTS: In the pH-adjusted lidocaine group, significantly higher lidocaine concentrations were found in the aqueous humor (15.06 microg/mL +/- 8.2 [SD] versus 4.75 +/- 3.5 microg/mL; P < .0001). In all samples (n = 8), serum lidocaine concentrations were below a minimum detectable level of 0.02 microg/mL. Subjective pain ratings were similar in the pH-adjusted and standard lidocaine groups (mean 9.73 +/- 10.4% and 10.0 +/- 15.4%, respectively). There was no significant between-group difference in intraoperative and postoperative outcomes. CONCLUSIONS: In this study, pH-adjusted lidocaine 4% was a safe, effective topical anesthetic for clear corneal surgery and had minimal local and systemic toxicity. Administration of pH-adjusted lidocaine 4% resulted in significantly higher aqueous humor lidocaine concentrations than administration of standard lidocaine 4%.

Inhibition of high-conductance, calcium-activated potassium channels of rabbit colon epithelium by magnesium.

High-conductance, Ca(2+)-activated K+ channels from the basolateral membrane of rabbit distal colon epithelial cells were reconstituted into planar phospholipid bilayers to examine the effect of Mg2+ on the single-channel properties. Mg2+ decreases channel current and conductance in a concentration-dependent manner from both the cytoplasmic and the extracellular side of the channel. In contrast to other K+ channels, Mg2+ does not cause rectification of current through colonic Ca(2+)-activated K+ channels. In addition, cytoplasmic Mg2+ decreases the reversal potential of the channel. The Mg(2+)-induced decrease in channel conductance is relieved by high K+ concentrations, indicating competitive interaction between K+ and Mg2+. The monovalent organic cation choline also decreases channel conductance and reversal potential, suggesting that the effect is unspecific. The inhibition of channel current by Mg2+ and choline most likely is a result of electrostatic screening of negative charges located superficially in the channel entrance. But in addition to charge, other properties appear to be necessary for channel inhibition, as Na+ and Ba2+ are no (or only weak) inhibitors. Mg2+ and possibly other cations may play a role in the regulation of current through these channels.

Pharmacokinetics and pharmacodynamics of the diuretic bumetanide in the elderly.

In a cross-sectional study of the pharmacokinetics and pharmacodynamics of peroral and intravenous bumetanide (0.5 mg, single dose), total and renal clearance of the diuretic was significantly lower in elderly persons than in young adults, resulting in higher bumetanide plasma levels in the aged. Nonrenal clearance, bioavailability, and the volume of distribution were not significantly changed. Together with the decreased delivery into the urine the diuretic and natriuretic effect of bumetanide was reduced in the elderly. Renal clearance of bumetanide was linearly related with creatinine clearance, hence the decreases in bumetanide clearance and diuretic efficacy in the elderly are attributed to the age-dependent decline in renal function. The bumetanide concentration in urine and the fractional sodium excretion were not different in the two age groups, suggesting that the decrease in diuretic response in the elderly is a result of a reduction in the number of functioning nephrons, whereas the response of the remaining nephrons to bumetanide is unaltered.

[Geriatric pharmacology. Pharmacokinetics and pharmacodynamics in the elderly. Problems with geriatric and nootropic drugs]. / Geriatrische Pharmakologie. Pharmakokinetik und Pharmakodynamik im Alter. Problematik der Geriatrika und Nootropika.

The reasons for the increased frequency of adverse drug reactions in the elderly are a decrease in drug elimination, primarily via the kidneys, on the one hand and a decrease in adaptive counterregulatory mechanisms on the other hand that attenuate drug effects in younger subjects. Because of the decreased functional reserve in the aged drugs may adversely affect preexisting chronic diseases. Generally, the possibility that clinical symptoms in the elderly are drug-related has to be considered. Abrupt changes in dosage should be avoided. The indication of drug therapy should be reevaluated periodically. However, advanced age is no reason to withhold necessary medication. The compliance with or adherence to drug therapy may be improved by giving clear, written instructions, simplifying the dosage schedule and reducing the number of drugs, for instance by using combination drugs. Elderly patients are particularly vulnerable to the sedative effects of psychotropic drugs, resulting in cognitive impairment and motor incoordination with an increased risk of falls and hip fracture. There is no rational basis for the use of geriatric drugs that claim to stop or slow the aging process. Also the available evidence does not support the therapeutic value of so-called nootropic or cerebroactive drugs to improve mental function in the elderly.

[Incidence of ovarian hyperstimulation syndrome in in-vitro-fertilization treatment over a period of 11 years]. / Beobachtungen zum Auftreten des ovariellen Uberstimulationssyndroms bei der Behandlung mit In-vitro-Fertilisation in einem Zeitraum von 11 Jahren.

A total of 2915 cycles of controlled ovarian hyperstimulation (COH) were performed from 1981 to 1992 in an in-vitro fertilization--embryo transfer (IVFET) programme at our institute. In 325 (11.2%) cycles an ovarian hyperstimulation syndrome (OHSS) developed. It was defined if more than 10 follicles with a size of > 15 mm were found on the day of follicle puncture. OHSS was found to be more frequent in the 3rd quarter of the years. Soltriol or melatonin may play a role in this context. Additionally, we were able to confirm some risk factors that were previously reported to be associated with the OHSS: use of gonadotropin-releasing hormone agonist (GnRHa) protocols, and young age (< 35 years). The pregnancy rate was found to be higher among OHSS cases.

Neurogenic chloride secretion induced by scorpion venom and veratrine in rabbit colon.

In earlier reconstitution experiments the venom of the scorpion Leiurus quinquestriatus, LQV, was shown to block Ca(2+)-activated high-conductance K+ channels from the basolateral cell membrane of rabbit colonocytes (Turnheim K, Costantin J, Chan S, Schultz SG (1989) J Membrane Biol 112:247-254). These LQV-sensitive K+ channels do not seem to be involved in active Na+ transport across rabbit colon, as absorptive Na+ fluxes were not significantly affected by serosal addition of LQV to isolated epithelia of rabbit descending colon. While Na+ absorption was not changed, LQV and veratrine caused electrogenic Cl- secretion in this tissue by a neural (tetrodotoxin sensitive) mechanism. The secretory effect of LQV was partly inhibited by atropine, suggesting the involvement of m-cholinoceptors, and by a VIP-antagonist. In contrast to the neurogenic secretion in the small intestine of guinea pig, rat and cat, 5-hydroxytryptamine (5-HT) does not seem to be involved in neurogenic secretion in rabbit colon, as 1) several 5-HT receptor antagonists did not inhibit the LQV effect with the exception of high concentrations of tropisetron, 2) exogenous 5-HT had no secretory effect, and 3) there was no significant release of 5-HT from the tissue during neurogenic secretion. The inhibitory effect of tropisetron on intestinal Cl- secretion seems to be unrelated to its property as a 5-HT3 receptor antagonist.

Epithelial sodium transport: basic autoregulatory mechanisms.

The epithelial cell is equipped with autoregulatory mechanisms that coordinate the rates of apical Na+ entry and basolateral Na+ extrusion, so that intracellular Na+ activity is maintained relatively constant when the rate of active Na+ transport changes. The increase of basolateral Na+ extrusion via the ouabain-inhibitable Na+,K(+)-ATPase during Na+ transport stimulation appears to be a result of both an increase in the number of operative Na+,K(+)-ATPase units in the basolateral cell membrane and in the Na+ turnover per Na+,K(+)-ATPase unit. Further, it is possible that the number of epithelial cells, which are involved in active Na+ transport, changes when the rate of Na+ transport is altered. Not only apical Na+ entry and basolateral Na+ extrusion are coupled, the basolateral membrane K+ conductance also changes in parallel with the rate of basolateral Na+ extrusion ("pump-leak parallelism"). These regulatory mechanisms serve to prevent inordinate changes in intracellular ion composition, transmembrane electrical potential difference, and cell volume. The cellular events taking place during stimulation of active transport resemble the changes during osmotic cell swelling. Hence, it is possible that cell volume changes are responsible for the coordination of apical and basolateral membrane properties.

Pharmacokinetics of indomethacin in the elderly.

In a cross-sectional study the pharmacokinetics of indomethacin were studied in old and young adults without manifest organ failure. Total clearance of indomethacin after a single oral dose of 50mg was 0.8 ml/min/kg in elderly individuals (mean 79.5 +/- 1.3 years) compared with 1.4 ml/min/kg in younger individuals (mean 36.9 +/- 3.0 years). The apparent elimination rate constant averaged 0.23 h-1 in the aged and 0.32 h-1 in the young people. Oral bioavailability was close to 1 in the young but 0.77 in the elderly. The apparent volume of distribution was similar in each group. Based on these results it is suggested that the maintenance dose of indomethacin be reduced by 25% in the elderly.

Endothelin-1 stimulates chloride and potassium secretion in rabbit descending colon.

The vasoactive peptide endothelin-1 (ET-1) which is present in high concentrations in the colon, causes concentration-dependent electrogenic Cl- secretion in rabbit descending colon. This effect is half-maximal at 0.11 mumol/l. Like other secretagogues, ET-1 also stimulates K+ secretion. The secretory effect of ET-1 is associated with increased release of prostaglandin E2 from the serosal surface of the mucosa. ET-1-induced Cl- secretion is completely inhibited by the loop diuretic bumetanide and by indomethacin and quinacrine, inhibitors of prostaglandin synthesis. Neuronal mechanisms do not seem to be involved, as tetrodotoxin did not affect the secretory response to ET-1 significantly. On the other hand, neither the catalytic activity nor the transport function of the Na+/K(+)-ATPase of rabbit colon epithelium is affected by endothelin-1 (ET-1) in concentrations up to 10 mumol/l. It is concluded that ET-1 causes Cl- and K+ secretion by stimulating phospholipase A2 and release of prostaglandins, whereas Na+ transport is not altered.

Vanadium-induced Cl(-)-secretion in rabbit descending colon is mediated by prostaglandins.

Vanadium in the 4+ (vanadyl-ion) and 5+ (vanadate-ion) oxidation state stimulates furosemide-sensitive electrogenic Cl- secretion in isolated epithelia of rabbit descending colon. This effect is associated with an increased release of prostaglandin E2 from the tissue. Inhibitors of phospholipase A2 or cyclooxygenase abolish both vanadium-induced release of prostaglandin E2 and Cl- secretion. Neuronal mechanisms are not likely to be involved, as tetrodotoxin does not affect the vanadate induced Cl- secretion. Although vanadate is known to inhibit Na+,K(+)-ATPase activity, no inhibition of active Na+ transport was observed in intact colonic epithelia suggesting a rapid intracellular reduction of vanadate ions to vanadyl ions which have no inhibitory effect on the Na+,K(+)-ATPase. The present findings therefore indicate that vanadate stimulated colonic Cl- secretion involves intracellular conversion of vanadate to vanadyl and release of prostaglandin E2.

Sodium-dependent nucleoside transport in rabbit intestinal epithelium.

Cellular uptake of formycin B, a poorly metabolized analog of inosine, by the isolated epithelium of rabbit jejunum is three times higher in the presence of Na+ than without this cation. The Na(+)-dependent nucleoside transport system is located in the apical membrane of the enterocytes and is capable of uphill transport, as shown for formycin B and adenosine with brush border membrane vesicles. According to present and earlier evidence, nucleoside transport across the basolateral membrane appears to have the properties of facilitated diffusion. Na(+)-dependent formycin B transport activity in intestinal epithelium decreases from jejunum to ileum and is absent in descending colon. As with Na(+)-coupled cotransport systems for other organic solutes, apical entry of formycin B is driven by the electrochemical Na+ gradient into the cell. In contrast to the facilitated diffusion system for nucleosides, Na(+)-dependent formycin B transport is not inhibited by nitrobenzylthioinosine, but both carrier systems are sensitive to inhibitors of D-glucose transport. Natural purine nucleosides and uridine are strong inhibitors of Na(+)-dependent formycin B transport. Transepithelial flux measurements substantiated that the Na(+)-dependent transport mechanism for formycin B functions as an absorptive system.

Intrinsic regulation of apical sodium entry in epithelia.

In the past 30 years the basic features of Na+ absorption by epithelia have been unraveled and generally accepted cell models have been established. However, these cell models of transepithelial Na+ transport represent, for the most part, a static view of cell function, i.e., all transport parameters are assumed to be in a steady state. Today the focus is on the dynamic properties of epithelia, the non-steady-state condition, and the adaptation to environmental or transport changes. This review deals with mechanisms intrinsic to the epithelium that regulate apical membrane Na+ permeability in response to changes in transport load and ambient conditions. Together with parallel autoregulatory events concerning the basolateral K+ conductance, the described mechanisms controlling apical membrane Na+ permeability serve to maintain the intracellular ionic composition within the limits that are compatible with cell function and survival. Extraepithelial factors that influence epithelial Na+ transport such as mineralocorticoids and glucocorticoids, ADH, catecholamines, and other neurotransmitters are discussed elsewhere. Apical membrane Na+ permeability appears to be determined by several intrinsic or autoregulatory mechanisms. The PmNa of epithelia with channel-mediated apical Na+ entry is downregulated by increases in the Na+ concentration of the apical bathing solution (self-inhibition) and by procedures that inhibit basolateral Na+ extrusion (feedback inhibition). The underlying mechanisms of both regulatory systems are unclear. With the use of current-noise (fluctuation) analysis, on the one hand, and single-channel recordings, on the other hand, conflicting results were obtained concerning the saturability of single-channel conductance with increasing external Na+ concentrations. Results from Na(+)-uptake studies in apical membrane vesicles from amiloride-sensitive epithelia render it unlikely that cell Na+ itself is the mediator of feedback inhibition. Both self-inhibition and feedback inhibition of PmNa are prevented by titrating superficial sulfhydryl groups in the apical membrane. Elevations of cell Ca2+ decrease apical Na+ entry, possibly via an indirect mechanism involving protein kinase C. The PmNa is markedly dependent on cell metabolism and pHc; inhibition of ATP supply and lowering cell pH reduce PmNa. Additionally, PmNa may be altered by exocytotic expansion and endocytotic retrieval of the apical membrane area or by insertion of channel proteins into the apical membrane without increasing the apical membrane area. The diversity of regulatory systems may insure the high degree of flexibility and plasticity of epithelia in their response to environmental changes.