Non-competitive Interaction Research Articles

Hg2+-induced leakage of electrolytes and inhibition of NO3 ? utilization inNostoc calcicola

The effect of mercury (Hg2+) in the absence and presence of methylmercury (CH3Hg+), cadmium (Cd2+), copper (Cu2+), nickel (Ni2+) and calcium (Ca2+) on Nostoc calcicola Breb. has been studied in terms of electrolyte leakage, NO3 − uptake and in vivo nitrate reductase (NR) activity to discover any possible correlation among such parameters under Hg2+ stress. Leakage of electrolytes from Hg2+-treated cyanobacterial cells was directly proportional to Hg2+ concentrations and exposure time. In comparison to NO3 − uptake, an about 60-fold slower rate of NR activity was observed in the untreated cultures, the former being five times more Hg2+-sensitive. A non-competitive synergistic interaction of Hg2+ with CH3Hg+ or Cd2+ and antagonistic with that of Ni2+ or Ca2+ has been observed for both the processes of NO3 − utilization. The antagonistic interaction of Cu2+ with Hg2+ in terms of NO3 − uptake and synergistic with respect to NR activity, has been attributed to the dual bonding preference of Cu2+ for cellular ligands. These findings suggest that (a) a statistically significant correlation exists among such parameters; (b) Hg2+ predominantly attacks the cyanobacterial cell membrane; (c) Hg2+ inhibits NO3 − utilization; (d) the presence of other cations increases or decreases the inhibitory actions of Hg2+.

Non-competitive interaction between μ and δ-opioid receptor binding sites in homogenates from the rat neocortex

Non-competitive interaction between μ and δ-opioid receptor binding sites in homogenates from the rat neocortex

Antagonism in isolated equine digital vessels of contraction induced by epinephrine in the presence of hydrocortisone and an aqueous extract of black walnut (Juglans nigra).

Prazosin, isoxsuprine, and nifedipine were screened for ability to reverse contraction of isolated equine digital vascular strips produced by epinephrine (Epi) in the presence of hydrocortisone (Hc) and an aqueous extract of black walnut (Juglans nigra) (BW). Two arteries and two veins from each of three horses for each drug (n = 9) were maintained in isolated tissue baths in Krebs' bicarbonate buffer with 95% oxygen at 37 degrees C. Six-point Epi concentration-response (C-R) curves were obtained for each vessel in the presence of Hc, BW, and the appropriate vehicle. This was repeated for each vessel using one of two concentrations of one of the three test drugs. Each drug and concentration combination was tested on a total of three arteries and three veins. Prazosin produced a concentration-dependent shift of the Epi C-R curve to the right but the curve maintained the same maximum height and slope, which is consistent with competitive alpha 1 adrenergic blockade. Isoxsuprine exhibited similar behavior, although the precise mechanism of action for isoxsuprine is unknown. Conversely, nifedipine did not shift the curve but did depress maximum contraction, suggesting a non-competitive interaction consistent with its mechanism of calcium-channel blockade.

The effects of ethanol on the structural stability of acetylcholine receptor and the activity of various molecular forms of acetylcholinesterase

The actions of ethanol on the structural stability of acetylcholine receptor (AchR)-enriched membrane vesicles and the activity of various molecular forms of acetylcholinesterase (AchE) were investigated, using the receptor and the enzyme isolated from the electric organ of Torpedo californica. In the presence of ethanol up to 200 mM, the thermogram of AchR-enriched membranes exhibited no significant decrease in the temperature ( t d) of receptor transition at 57°C, but a decrease in the enthalpy change ( ΔH d) indicated a slight ethanol-induced structural perturbation. The presence of 12.5 nmol α-bungarotoxin also caused a decrease in ΔH d. A complete loss of the receptor transition was observed at a higher concentration 500 nmol of α-bungarotoxin and no recovery of the transition was found with the addition of 200 mM ethanol. The results suggested a noncompetitive interaction of ethanol with the receptor. In the presence of 200–1000 mM ethanol, the activity of two soluble forms of AchE, a higher (117 S) aggregate and a lower (10 S) aggregate was not significantly affected. Comparing the activity of these two aggregates over a wide concentration range of ethanol (200–2000 mM) revealed no obvious difference in the level of ethanol effect between them. However, after removal of ethanol, the higher aggregate form of AchE exhibited a greater recoverability of the activity, suggesting a possible slightly greater structure-functional stability for it. Studies of soluble AchE and membrane-bound AchE showed that the presence of 200 or 600 mM ethanol caused a greater level of inhibition in membrane-bound enzyme than in soluble enzyme, possible due to a disruption of protein-lipid interaction needed to maintain the conformation of membrane-bound AchE. Interestingly, at a much higher concentration of ethanol (2.0 M), membrane-bound AchE became more resistant to ethanol than did the soluble forms of AchE. In this case, the effective concentration of ethanol felt by the enzyme was expected to be less for membrane-bound AchE, owing to ethanol's solubility in lipids.

Effect of Alcohols and Their Interaction with Ethylene on the Ripening of Epidermal Pericarp Discs of Tomato Fruit

Ethanol concentrations that were induced in pericarp discs of mature-green tomato fruit (Lycopersicon esculentum Mill, cv Castlemart) either by anaerobic metabolism or by exposure to ethanol vapor inhibited ripening without increasing the rate of ion leakage. Inhibition of ripening (i.e. lycopene synthesis) of excised tomato pericarp tissue by ethanol vapor was reversed by increasing concentrations of the plant hormone ethylene. A Lineweaver-Burk plot indicated noncompetitive interaction between ethanol and ethylene. Methanol and n-propanol also inhibited lycopene synthesis without significantly increasing ion leakage. The similar inhibitory effects of methanol, ethanol, and n-propanol at concentrations which did not stimulate ion leakage, and the relationship between activity and lipophilia of the alcohols suggest that their mode of action was through disruption of membranes associated with ethylene action.

Effect of atrial natriuretic factor (ANF) on nicotinic acetylcholine receptor channels in bovine chromaffin cells

Bovine chromaffin cells have binding sites for rat atrial natriuretic factor (ANF), as demonstrated autoradiographically by using the 125I-labelled peptide. Patch-clamp recording revealed that ANF reduces acetylcholine (ACh)-induced membrane currents in chromaffin cells at physiological membrane potentials. The effect was dose-dependent with the IC50 value being 5.2 microM ANF and the Hill coefficient close to 1. The channel block was absent at positive membrane potentials, indicating a non-competitive interaction of ANF with the open ACh receptor channel. Fragments of ANF had a much less pronounced action, which is possible due to their structure and molecular charge being different to ANF. The block of nicotinic ACh receptor channels may enable ANF to control the secretion of catecholamines from adrenal chromaffin cells.

Competitive vs. noncompetitive styles: Which is most valued in courtship?

Although competitiveness has been stereotypically associated with masculinity and noncompetitiveness with femininity, recent research (M. R. Laner, “Competition in Courtship,” Family Relations, 1986, Vol. 32, pp. 275–279) has shown very high rates of certain kinds of competitive behaviors experienced by courtship partners of both sexes. This study was designed to test (1) whether competitive or noncompetitive interaction is the preferred mode, and (2) whether competitive tactics are clearly distinguishable from noncompetitive tactics. Findings indicate that noncompetitive styles are preferred by majorities of both women and men. For the most part, respondents of both sexes are able to distinguish between competitive and noncompetitive behaviors. Discussion focuses on the differential outcomes of competition and cooperation, and on why persons behave differently from the mode they claim to prefer.

Characteristics of acidic, basic and neutral amino acid transport in the perfused rat hindlimb.

1. We have employed a paired-tracer isotope dilution technique in a perfused rat hindlimb preparation to obtain information on the kinetics of transport across the sarcolemmal membranes of acidic, neutral and basic amino acids. 2. We have defined the characteristics of the saturable transport of amino acids normally regarded as paradigm substrates for the A, ASC, L, y+(basic) and the dicarboxylic amino acid transport systems. Their maximal transport capacities (Vmax, nmol min-1 (g muscle)-1 and substrate concentrations for half-maximal transport (Km, mM) of representative amino acid substrates are as follows: 2-aminoisobutyrate (AIB), Vmax = 15 +/- 7, Km = 1.26 +/- 0.6; alanine, Vmax = 332 +/- 53, Km = 3.9 +/- 0.9; serine, Vmax = 410 +/- 61, Km 3.4 +/- 0.5; leucine, Vmax = 2800 +/- 420, Km = 20 +/- 2; lysine, Vmax = 136 +/- 46, Km = 2.1 +/- 1.3; glutamate, Vmax = 86 +/- 6, Km = 1.05 +/- 0.05; proline, Vmax = 196 +/- 48, Km = 4.1 +/- 0.6. 3. Glycine uptake was faster than expected on the basis of diffusion but was not saturable and showed uptake that could be best described by a first-order rate constant of 0.07 +/- 0.003 min-1. 4. We have attempted to discriminate kinetically between possible routes of entry for an amino acid on the basis of competitive and non-competitive interaction between substrates potentially sharing common routes. On this basis, the major routes of alanine entry appear to be via the ASC and L systems with the A system playing a quantitatively minor role. Glutamate and aspartate appear to be transported exclusively by a dicarboxylate amino acid carrier. The branched-chain amino acids (BCAA) and the aromatic amino acid, phenylalanine, are almost equivalent substrates for an L-like system. 5. Insulin had no detectable effect on the uptake of paradigm substrates for ASC, L, y+, the dicarboxylic amino acid or glycine transport systems. 6. Transport of serine and lysine was Na+ dependent. Lysine transport apparently occurred with a stoichiometry of 2 Na+: 1 lysine. With the exception of alanine, whose transport was partially Na+ dependent, all other amino acids examined in the present study were transported in a Na+-independent manner.

Inhibition of endothelial cell proliferation by type β-transforming growth factor: Interactions with acidic and basic fibroblast growth factors

TGFβ is a potent (ED 50 ∼10 −11 M) inhibitor of the proliferative activities of both acidic and basic FGF on vascular and capillary endothelial cells in vitro . The inhibition of cell growth is dose-dependent and characteristic of a non-competitive interaction. The results demonstrate that TGFβ and FGF can interact at the cellular level to modulate growth and suggest that many of the biological activities of FGF observed in vitro and in vivo (ie angiogenesis, cell growth, cell differentiation) may be regulated by the presence of TGFβ and related proteins (ie inhibin) in the local cellular milieu. The possible identity of TGFβ with the inhibitors of endothelial cell growth detected in in vitro assays of crude extracts is discussed.

S protein modulates the heparin-catalyzed inhibition of thrombin by antithrombin III. Evidence for a direct interaction of S protein with heparin.

The interference of S protein with the heparin-catalyzed inhibition of thrombin by antithrombin III was studied in a purified system and in plasma. The effect of S protein to counteract heparin activity was documented by kinetic analysis of the initial phase of the inhibition reaction. Addition of S protein induced a concentration-dependent reduction of the inhibition rate, reflected in a decrease of the apparent pseudo-first-order rate constant by a factor of 5-8 in the presence of a twofold molar excess of S protein over antithrombin III. A non-competitive interaction of S protein with the thrombin--antithrombin-III--heparin inhibition reaction with Ki = 0.6 microM was found. While the association constant of thrombin--antithrombin III in the presence of 0.05 U/ml heparin amounted to 2.5 X 10(8) M-1, an approximately 200-fold decrease of this value was observed in the presence of S protein. The fast formation of the covalent complex between thrombin and antithrombin III in the presence of heparin was impaired as a result of the presence of S protein, as was shown by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. In the absence of heparin the inhibition of thrombin by antithrombin III alone was not influenced by S protein. The heparin-counteracting activity of S protein was found to be mainly expressed in the range of 0.01-0.1 U/ml heparin, thereby shifting the point of 50% inhibition of thrombin from 0.003 U/ml to 0.1 U/ml heparin with a second-order rate constant of k2 = 1.4 X 10(6) M-1. A direct interaction of S protein with heparin was demonstrated by crossed immunoelectrophoresis with purified proteins as well as in plasma and serum. The analysis of plasma and serum by crossed immunoelectrophoresis against rabbit anti-(human S protein) serum revealed an additional cathodal peak in the serum sample, resulting from the interaction of S protein with serum components. These findings not only indicate a direct interaction of S protein with heparin in the onset of the inhibition of thrombin by antithrombin-III--heparin, but also a contribution of S protein during enzyme-inhibitor complex formation.

Interaction of non-steroidal antiestrogens with dopamine receptor binding

The ability of various estrogen antagonists and agonists to compete with [ 3H] spiroperidol, [ 3H]domperidone, [ 3H]dihydroalprenolol, [ 3H]dihydroergocryptine, [ 3H]dopamine or [ 3H]5-hydroxytryptamine for binding to membrane preparations from rat brain tissue was tested. The non-steroidal triphenylethylene-type antiestrogens with an amine side chain—enclomiphene, nitromifene, tamoxifen and zuclomiphene—were found to be competitive inhibitors of [ 3H]spiroperidol ( K d = 0.12 nM; Aaax = 101 fmol/ mg protein) and [ 3H]domperidone ( K d = 0.62 nM; B max = 86 fmol/ mg protein) binding to striatal membranes. The K i values ranged from 4–12μM. Estradiol-17β( K i = 480 μM) or diethylstilbestrol ( K i = 63 μM) were much less effective inhibitors exhibiting noncompetitive interaction with the in vitro binding of [ 3H]spiroperidol. The pharmacological relevance of the antiestrogen interactions with dopamine receptor binding is discussed with respect to adverse effects of the in vivo administered compounds such as nausea and vomiting.

Non-competitive interaction between normorphine and calcium on the release of noradrenaline

The interaction between calcium and magnesium or normorphine was studied on the electrically evoked outflow of previously incorporated [ 3H]noradrenaline in the isolated mouse vas deferens. The stimulation-evoked outflow of [ 3H]noradrenaline increased with increasing concentrations of Ca 2+ ions in the medium. Mg 2+ counteracted the effect of Ca 2+ in a manenr compatible with competitive antagonism. In contrast, normorphine interfered with the effect of Ca 2+ non-competitively, thus suggesting that its mode of action differed from that of Mg 2+.

In vitro binding of gibberellin A 4 to extracts of cucumber measured by using DEAE-cellulose filters

A rapid method for assaying [(3)H]gibberellin A(4) bound to a soluble protein from cucumber hypocotyls by using DEAE-cellulose filter discs is described. The binding is saturable, reversible with unlabeled gibberellin A(4), and has a half-life of association under nonequilibrium conditions at 0-4 degrees C of 6-7 min. By using this assay, the dissociation constant (K(d)) was estimated to be 70 nM and the number of binding sites, 0.4 pmol mg(-1) of soluble protein or 0.69 pmol g(-1) (fresh weight) of hypocotyls. The speed and reliability of the assay make it invaluable for kinetic studies involving competitors. Thus, it has been possible to show that gibberellins that are biologically active in a cucumber bioassay compete for binding to the same protein and their calculated affinity constants bear a direct relationship to their known activities in the cucumber bioassay. Gibberellins that are inactive in this bioassay and other plant hormones, such as indoleacetic acid, abscisic acid, and kinetin, show a noncompetitive interaction.

Fluctuation analysis of short-circuit current in a warm-blooded sodium-retaining epithelium: site current, density, and interaction with triamterene.

Density and conductance of the Na-site in hen coprodeum were studied by employing fluctuation analysis of short-circuit current at sodium concentrations from 26 to 130 mM. Fluctuations of current in the frequency range 2-800 Hz were induced by triamterene, a reversible blocker of conducting epithelial Na-sites. At 130 mM Na the site density was 5.8 +/- 1.0 micrometer-2 and the site conductance was 4 pS. This conductance is equal to that of the frog skin (W. Van Driessche and B. Lindemann, 1979, Nature (London) 282:519-520). Extrapolation of site density to zero sodium renders a total of 38 +/- 28 sites micrometer-2, which is compared with other estimates for the coprodeum. The site-triamterene association and dissociation constants were 9.5 +/- 0.4 rad sec-1 micrometer-1 and 255 +/- 20 rad sec-1 and they were independent of external sodium concentration. An analysis of the affinity constant for triamterene based on the DC-short-circuit current was found to be unrelated to the external sodium concentration and identical to that obtained from fluctuation analysis indicating a noncompetitive interaction between sodium and triamterene. Due to the oxygen demand of the epithelium we have developed an experimental method using short data processing times. A new analytical approach using integration of the power density spectrum proved necessary because of low signal-to-noise ratios.

A quantitative analysis of the Na+-dependence of Vmax of the fast action potential in mammalian ventricular myocardium. Saturation characteristics and the modulation of a drug-induced INa blockade by [Na+]o.

In microelectrode experiments on papillary muscles of guinea pigs, the quantitative dependence of\(\dot V_{{\text{max}}} \) of the fast action potential, taken as a measure of INa, on external Na+ concentration has been analyzed under different experimental conditions including the presence of antiarrhythmic drugs such as lidocaine, procaine and propafenone. 1. External Na+ concentration changes between 225 mmol/l and 45 mmol/l led to a non-linear response of\(\dot V_{{\text{max}}} \) in that the\(\dot V_{{\text{max}}} \) changes obtained experimentally were significantly smaller than predicted theoretically from a linear dependence of\(\dot V_{{\text{max}}} \) on [Na+]o. 2. Each individual\(\dot V_{{\text{max}}} \) relationship exhibited saturation characteristics. In Lineweaver-Burk plots,\(\dot V_{{\text{max}}} \) correlated extremely well to 1/[Na+]o with correlation coefficients between 0.995 and 0.999. In 16 experiments, the apparentKm for Na+ varied within a range from 170 to 455 mmol/l. Values of 450 V/s–900 V/s were calculated for the saturated\(\dot V_{{\text{max}}} \) (at an infinitely large [Na+]o). 3. The apparentKm for Na+ rose from 232.0±24.7 mmol/l to 544.0±50.2 mmol/l when the K+ concentration of the medium was increased from 5.4 to 10 mmol/l and, thus, resting potential declined from −90.5±2.5 mV to −76.1±1.8 mV. 4. Alkalization (pH 9.0) of the medium lowered the apparentKm for Na+ and, simultaneously, reduced the saturated\(\dot V_{{\text{max}}} \). This typical shift of the straight relating\(\dot V_{{\text{max}}} \) to 1/[Na+]o in the Lineweaver-Burk plot excludes a competitive interaction between Na+ and H+ ions. 5. Lidocaine (5×10−5–2×10−4 mol/l), procaine (2×10−4 mol/l) and propafenone (0.5–3×10−5 mol/l) depressed\(\dot V_{{\text{max}}} \) the stronger the lower [Na+]o was. The changes of the\(\dot V_{{\text{max}}} \) relationship induced by these drugs indicated neither a competitive nor a non-competitive interaction of these compounds with Na+. 6. As tested with propafenone, external Na+ changes modulated the tonic and the phasic block of\(\dot V_{{\text{max}}} \). The Na+ sensitivity of both types of block differed considerably. In a Na+-poor (50 mmol/l) medium, the apparentKm for the tonic block declined from 5×10−5 to 1.4×10−5 mol/l and the apparentKm for the phasic block from 3.8×10−5 to 2.3×10−5 mol/l. 7. Na+ is not the sole cation that determines the strength of a drug-induced blockade of\(\dot V_{{\text{max}}} \) as it can be substituted by the permeant Li+. 8. In the presence of drugs like propafenone which are capable of shifting the steady state inactivation (h∞) of INa to more negative potentials, the voltage-dependence ofh∞ can be modified by external Na+ variations. Na+ withdrawal led to a considerable shift in the hyperpolarizing direction.

Hemicholinium 3-bromo mustard: A new high affinity inhibitor of sodium-dependent high affinity choline uptake

A newly synthesised mustard analog of hemicholinium 3. the trivial name of which is hemicholinium 3-bromo mustard, was evaluated as an inhibitor of the sodium-dependent high affinity choline uptake system. When synaptosomes prepared from rat striatum were incubated for ten minutes with a low concentration (10 nm) of the cyclised bi-ethylenimine form of hemicholinium 3-bromo mustard, the sodium-dependent high affinity choline uptake activity was reduced by more than 80° o. The inhibition profile produced by the bi-ethylenimine ion was consistent with mixed kinetics, in that both the V max and K m of the sodium-dependent high affinity choline uptake system were lowered in the presence of the compound in a non-parallel fashion. The reduction in V max was investigated further to establish if it resulted from a reversible non-competitive interaction or whether it was of a more enduring nature. Synaptosomes pretreated with low concentrations of the bi-ethylenimine form of hemicholinium 3-bromo mustard (25 nM) were thoroughly washed free of inhibitor and subsequently incubated at 37 C for up to 15 minutes before assaying the uptake activity. Under these conditions part of the inhibition effected by the mustard was found to persist and remain unchanged throughout the incubation period. The results are consistent with the bi-ethylenimine form of hemicholinium 3-bromo mustard effecting, possibly via alkylation of sites involved in the high affinity reversible binding of hemicholinium 3, a potent and enduring inhibition of the sodium-dependent high affinity choline uptake system.

On the action of the anticonvulsant 5,5-diphenylhydantoin and the convulsant picrotoxin in crayfish stretch receptor.

1. The effects of the anticonvulsant drug 5,5-diphenylhydantoin (DPH) and the convulsant drug picrotoxin (PTX) on various membrane properties and GABA-ergic inhibition were investigated in the slowly adapting neurone of the isolated crayfish stretch receptor. The soma was penetrated with two micro-electrodes to allow accurate determination of membrane conductances. 2. Neither DPH nor PTX at 10(-4) M had any significant effect on parameters of the anti- or orthodromic action potential or on the amplitude and duration of post-tetanic hyperpolarization. This suggests that the pharmacological properties of the two drugs are unlikely to be mediated by effects on cationic movements in this preparation. 3. DPH increased the amplitude and duration of the inhibitory post-synaptic potential (i.p.s.p.) within the range 10(-9) to 10(-4) M. The response to ionophoretically applied GABA was similarly prolonged. 4. PTX decreased the amplitude of the i.p.s.p. and prolonged its rising phase within the range 10(-8) to 10(-4) M. The response to ionophoretically applied GABA was similarly depressed. 5. A slow component of fluctuations in the resting potential was accentuated by DPH at 10(-4) M and eliminated by PTX 10(-4) M. This may reflect effects on the random opening and closing of inhibitory channels. 6. We conclude that the action of both drugs is post-synaptic and suggest that DPH decreases the probability of closing, and PTX the probability of opening, of the transmitter-activated channels. 7. The lack of any structural similarity between the two drugs suggests that they modify post-synaptic inhibition at separate sites. These sites appear to be interdependent since analysis of the shift in the DPH dose-response curve by PTX and vice versa, showed neither truly non-competitive nor competitive interaction.

Interactions of cholecystokinin (CCK-PZ) and gastrin on motor activity of isolated guinea-pig antrum and fundus.

Pressure responses to cholecystokinin (CCK-PZ, approximately 500 U/mg) and gastrin (human synthetic gastrin) were investigated in isolated guinea-pig antral and fundal pouches. Both drugs stimulated motor activity, in the antrum mainly by increasing amplitudes and rhythmic activity, in the fundus by increasing basal tension. Antral responses to gastrin were markedly smaller than to CCK-PZ, while the differences were less pronounced in the fundus. Prestimulation with gastrin, being an agonist by itself, significantly reduced the antral responses to submaximal doses of CCK-PZ, while no inhibition was found in the fundus. When pre-exposed to gastrin, the antral dose-response curve to CCK-PZ was flattened, with reduced maximal response, simulating a non-competitive interaction. It seems that gastrin behaves like a partial agonist to CCK-PZ on guinea-pig antral smooth muscle.

Interference of gestagens and androgens with rat uterine oestrogen receptors.

The inhibitory effect of some gestagens and calusterone on the binding of oestradiol-17beta to its specific uterine receptors has been investigated in intact rats. Progesterone, medrogestone, clogestone, medroxyprogesterone acetate and calusterone reduce the specific oestradiol-receptor interaction in vitro; this effect is dose-dependent and does not differ significantly from one drug to the other. A more relevant decrease in the amount of oestradiol-17beta bound to specific receptors has been observed with calusterone. Progesterone, clogestone, medrogestone, medroxyprogesterone acetate and calusterone given orally induce a marked decrease (between 30 and 70% depending on the dose) in the binding capacity of oestradiol-17beta to specific uterine receptors in vivo. Results from a Scatchard plot analysis suggest that the interference with the binding of oestradiol-17beta caused by both progestogens and calusterone is due to a non-competitive interaction.

Effect of cimetidine on pentagastrin-stimulated gastric secretion in healthy man.

Two series of experiments were carried out in three healthy volunteers. In one series increasing doses of cimetidine were tested on a constant background stimulation with 0.15 microgram-kg-1h-1 of pentagastrin. In the other series of experiments increasing doses of pentagastrin were given either alone or in combination with a fixed dose of cimetidine (1.2 mg-kg-1h-1). Pentagastrin and cimetidine were given as continuous intravenous infusions, the various doses tested on separate days. The inhibition of acid output in response to pentagastrin stimulation increased almost linearly with the log dose of cimetidine. Fifty per cent inhibition of the response to 0.15 microgram-kg-1h-1 of pentagastrin was achieved by about 0.6 mg-kg-1h-1 of cimetidine. 2.4 mg-kg-1h-1 of cimetidine gave on average 90% inhibition. The inhibition caused by cimetidine decreased to a minimum of 57% and could not be overcome by increasing the doses of pentagastrin. The results suggest a mixture of competitive and noncompetitive interaction. The effect of cimetidine on pepsin secretion was less regular. Generally, pepsin output was less inhibited than acid output.