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PubMed2004

Inhibition of cell growth, induction of apoptosis and mechanism of action of the novel platinum compound cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4'-6-diamidine-2'-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique. When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue. Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.

Animals↗
PubMed1982

Effect of procaine on potassium permeability of canine tracheal smooth muscle.

Procaine depolarized the cell membrane, and initiated oscillations and spike-like potentials in canine tracheal smooth muscle, at concentrations between 1 and 5 mM, while higher concentrations of this drug suppressed the spontaneous activities. Inhibitory effects of procaine on 86Rb-efflux were not evident in normal solution. In high K solution, procaine decreased the rate of 86Rb-efflux, in a dose dependent manner, and a Scatchard plot suggested two sites of action for procaine. The site with a higher affinity (KD = 0.26 mM) may directly regulate the K permeability and interact with procaine in a one to one manner. In high concentrations (greater than or equal to 10 mM), procaine interacted at another site and the tracheal smooth muscle which contracted in high K solution relaxed almost completely. Thus, the decrease in 86Rb-efflux by high concentrations of procaine may partly result from a decrease in intracellular Ca concentration. It is proposed that procaine has the dual effect by inhibiting the K conductance: (1) depolarization of cell membrane, (2) increase in membrane excitability. These actions would explain the spontaneous electrical activity induced by procaine in canine tracheal smooth muscle.

Animals↗
PubMed1989

Effect of the inhibition of dopamine uptake on the dopamine- and dimethyldopamine-induced-inhibition of the potassium-evoked release of [3H]acetylcholine from striatal slices.

1. Dimethyldopamine was eight times more potent than dopamine in activating the D2 receptor that inhibits the potassium-evoked release of [3H]acetylcholine from striatal slices. 2. Cocaine and mazindol produced an eight-fold shift in the concentration-response curve for dopamine, but not for dimethyldopamine. 3. The IC50 of dimethyldopamine for the inhibition of [3H]dopamine uptake was thirty times greater than that for dopamine. 4. Dopamine may be less potent than dimethyldopamine at the D2 receptor because dopamine has a higher affinity for the dopamine uptake system, resulting in its rapid removal from the vicinity of the receptor.

Acetylcholine↗
PubMed1996

The preparation and kinetic analysis of multiple forms of human erythrocyte acetylcholinesterase.

A method for preparing various forms of acetylcholinesterase (AChE) from human erythrocyte has been established and they have been characterized in terms of kinetic parameters such as K(m), rate constant (k), turnover number (kcat), specificity constant (ksp), Vmax, half-life (t1/2), IC50 and Ki for tetrabutylammonium hydroxide, procaine and physostigmine in the present study. The solubility experiments show that, there is one major form of AChE i.e. membrane bound AChE (MBAChE) and one minor form i.e. water soluble form (WSAChE). The MBAChE shows several subforms, and on the basis of percentage activity only three MBAChE forms have been selected for complete characterization by various kinetic parameters and found that these three forms of MBAChE demonstrate significant differences in their kinetic properties except IC50. This study supports the recommendation of the use of these kinetic parameters as a tool for the analysis of the multiple forms of the various enzymes in the biological systems.

Acetylcholinesterase↗
PubMed1983

Effects of agents that modulate potassium permeability on smooth muscle cells of the guinea-pig basilar artery.

1 Effects of various chemical agents, with known actions on K-permeability, on the membrane potential, membrane resistance and spike activity of smooth muscle cells of the guinea-pig basilar artery were investigated using the microelectrode method. The K-permeability suppressing agents procaine, tetraethylammonium (TEA), 4-aminopyridine (4-AP), and the K-permeability increasing agents acetylcholine (ACh), caffeine and 2-nicotinamidoethyl nitrate (2-NN) were used.2 The mean resting membrane potential of smooth muscle cells was -50.6 mV and was electrically quiescent. The maximum slope of the membrane depolarization produced by a ten fold increase in [K](o) plotted on a log scale was 42 mV. The contribution of the Na-K pump mechanism to the membrane potential was apparent, i.e. the maximum hyperpolarization induced by activation of the Na-K pump was -71 mV. This hyperpolarization ceased following application of ouabain. Reduction in the [Na](o) slightly hyperpolarized the membrane.3 TEA (1-10 mM) and procaine (0.3-10 mM) depolarized the membrane dose-dependently, and increased the membrane resistance. TEA markedly inhibited and procaine slightly inhibited rectification of the membrane.4 Caffeine had dual actions on the membrane potential, i.e. a low concentration (below 1 mM) hyperpolarized the membrane and reduced the membrane resistance, while increased concentrations (above 1 mM) transiently hyperpolarized, and then depolarized the membrane with an increase in the membrane resistance.5 ACh hyperpolarized the membrane dose-dependently (10(-7)-10(-5)M), and reduced the membrane resistance. The hyperpolarizing action of ACh did not persist and even in the presence of ACh, the membrane was repolarized to near the control level.6 2-NN (up to 10(-4)M) and 4-AP (up to 1 mM) did not modify the membrane potential or the membrane resistance.7 TEA (10 mM) generated a spike either spontaneously or by application of electrical stimulation and the spike was preceded or followed by slow oscillatory potential changes. These potential changes ceased with application of diltiazem (10(-5)M).8 Low concentrations of procaine (below 1 mM) accelerated but high concentrations (5-10 mM) inhibited the spike generation in the presence of 10 mM TEA. Low concentrations of caffeine (below 1 mM) inhibited the spike generation and higher concentrations (above 1 mM) of caffeine accelerated the spike generation in the presence of 10 mM TEA. ACh (10(-6)-10(-4)M) consistently inhibited the spike generation, with 10 mM TEA pretreatment.9 4-AP (1 mM) did not modify the membrane potential yet accelerated the spike generation, in the presence of 10 mM TEA. 2-NN (10(-4)M) had no effect on the spike evoked in the presence of 10 mM TEA.10 The results show that the low membrane potential in smooth muscle cells of the guinea-pig basilar artery is mainly due to the low permeability of the membrane to K ion, presumably due to the lack of a K channel sensitive to 2-NN and 4-AP. Similarities and differences between this vascular tissue and other regions are also discussed.

4-Aminopyridine↗
PubMed1984

The roles of stored calcium in contractions of cat tracheal smooth muscle produced by electrical stimulation, acetylcholine and high K+.

Effects of direct or indirect (nerve-mediated) muscle stimulation, acetylcholine (ACh), caffeine and procaine on the membrane and mechanical properties of smooth muscle cells of the cat trachea were investigated by means of double sucrose-gap and isometric tension recording methods. Outward current pulses (2 s in duration) applied to the muscle tissue in the presence of tetrodotoxin (10(-7)M), atropine (10(-6)M) and propranolol (10(-6)M) evoked no action potential (spike); however, when the depolarization exceeded 9 mV, a contraction was evoked. The spike and contraction evoked by outward current pulses in the presence of tetraethylammonium (TEA, 10 mM) were suppressed by treatment of the tissue with either Ca2+-free EGTA (2 mM) containing solution or Mn2+ (5 mM). In the presence of procaine (10 mM), outward current pulses evoked an action potential but no contraction. Field stimulation of short duration (50 microseconds) applied to the whole tissue produced an excitation of the intrinsic nerves and evoked excitatory junction potentials (e.j.ps), and when the amplitude of e.j.ps exceeded 4 mV, a twitch contraction occurred. E.j.p. was more effective in producing a contraction than was the membrane depolarization evoked by outward current pulses. Amplitudes of contractions evoked by exogenous ACh (10(-5)M) were much larger than those evoked by 128 mM-[K]0 or caffeine (10 mM), in normal Krebs solution. When the amplitudes of the contractions produced by 128 mM [K]0 were defined as a relative amplitude of 1.0, the mean amplitudes of contraction produced by ACh (10(-5)M) or caffeine were 2.5 +/- 0.20 or 1.2 +/- 0.26, respectively. In Ca2+-free EGTA (2 mM)-containing solution, the contraction induced by 128 mM-[K]0 was rapidly abolished, whereas the contractions evoked by caffeine (10 mM) or the initial phasic contraction produced by ACh (10(-5)M) were largely unaffected. When the amount of Ca2+ stored in the muscle cell was estimated from the amplitude of caffeine-induced contraction evoked in Ca2+-free solution, procaine (10 mM) applied simultaneously with Ca2+, after depletion of Ca2+ from the cells by means of caffeine, increased the amount of Ca2+ stored to 1.31 +/- 0.14 (n = 6) times the control value. However, ACh (10(-7)M) or excess concentrations of [K]0 applied with Ca2+ did not increase the amount of Ca2+ stored in the caffeine-sensitive intracellular compartment. 8 These results indicate that the amount of Ca2 + stored in the smooth muscle cells of the cat trachea may be larger than other visceral smooth muscle and plays an important role in the initiation of contraction, in response to endogenous or exogenous ACh.

Acetylcholine↗
PubMed1993

[Ca2+]i-sensitive, IP3-independent Ca2+ influx in smooth muscle of rat vas deferens revealed by procaine.

1. The actions of procaine (10 mM) on noradrenaline-induced effects on 45Ca-influx, 45Ca-efflux, 45Ca-content, total inositol phosphates, inositol-1,4,5-trisphosphate, and contractile status of the rat was deferens were examined. 2. Noradrenaline alone had no effect on 45Ca-influx or 45Ca-content, but released Ca2+ from intracellular stores as indicated by an increased 45Ca-efflux and increased total inositol phosphates, specifically inositol-1,4,5-trisphosphate, leading to contraction of the rat vas deferens. 3. Noradrenaline, in the presence of 10 mM procaine, increased 45Ca-influx and 45Ca-content. Procaine blocked the noradrenaline-induced 45Ca-efflux, the increase in total inositol phosphates, the increase in inositol-1,4,5-trisphosphate, and contraction. 4. The noradrenaline-induced increase in 45Ca influx which was observed in the presence of procaine was abolished by phentolamine and nifedipine but was not altered significantly by propranolol suggesting that, in the presence of procaine, noradrenaline activates dihydropyridine-sensitive calcium channels through alpha-adrenoceptors. 5. These findings indicate that, in the rat vas deferens, noradrenaline induces contraction by releasing intracellularly stored Ca2+. The effects of procaine appear to be due to its ability to block the release of Ca2+ from intracellular stores. Furthermore, the simultaneous increase in 45Ca influx and inhibition of inositol-1,4,5-trisphosphate formation in tissues treated with procaine plus noradrenaline indicates that Ca2+ influx is independent of inositol-1,4,5-trisphosphate formation.

Animals↗
PubMed1983

Electrical responses of smooth muscle cells of the mouse uterus to adenosine triphosphate.

Electrical responses of the smooth muscle cells to ATP were recorded in the longitudinal muscle of mouse myometrium, using intracellular micro-electrodes. ATP (greater than 10(-7) M) dose-dependently produced a biphasic change in the membrane potential, an initial hyperpolarization (20-30 sec) and then a depolarization. This effect of ATP was observed in all stages of gestation. The initial hyperpolarization was more quickly desensitized than the depolarization. Application of ATP for a short period (10 sec) produced only the initial hyperpolarization; the amplitude was dose-dependently increased. During the ATP-induced hyperpolarization and the depolarization, generation of spike potentials was suppressed and enhanced, respectively. Strong outward current restored the spike generation during hyperpolarization. During the ATP-induced hyperpolarization, the membrane resistance was decreased. The amplitude of the hyperpolarization was increased in low [K]0 solution and decreased in high [K]0 solutions. Pre-treatment with TEA (1 mM), procaine (1 mM), 4-aminopyridine (0.5 mM) or apamin (2 X 10(-7) M) did not, but TEA (5-10 mM) did suppress the ATP-induced hyperpolarization. Involvement of endogenous catecholamines, cyclic AMP, prostaglandins or acetylcholine in the ATP responses was ruled out. During the ATP-induced depolarization, the membrane resistance was reduced. In low [Na]0 solutions, the muscle membrane was depolarized and the amplitude of ATP-induced depolarization was reduced. In sodium-free solution, ATP produced only the initial hyperpolarization. It was concluded that the electrical responses of the smooth muscle cells of mouse myometrium to ATP consist of two components: an initial hyperpolarization with increase in the potassium conductance and a depolarization with increase in the sodium conductance.

4-Aminopyridine↗
PubMed1985

The influence of temperature and frequency of stimulation on the impairment of excitability of frog skeletal muscle by local anesthetics and alkyl amphipathic agents.

The potency of various types of alkyl amphipathic (cationic, anionic, and neutral) as well as tertiary amine local anesthetics in impairing the excitability of frog skeletal muscle was markedly enhanced by an increase in temperature from 20 to 30 degrees C. Enhancement of the local anesthetic effects of all types of agents was also produced by a decrease in temperature to 5 degrees C, but this effect was found to be frequency dependent. With abrupt increase or decrease in temperature, changes in excitability were rapid and unlikely to be the result of changes in the partition of the apolar portions of these molecules into the hydrophobic regions of the sarcolemma. These results are interpreted as indicating that both the presence of local anesthetics and alterations in temperature can influence the rates of potential-dependent changes in the conformation of membrane proteins that control the permeability of excitable sodium channels, possibly by modifying the fluidity of specific portions of their hydrophobic components or their immediate lipid environment. The accumulation of inactivation as the result of incomplete recovery from the effects of preceding depolarizations appears sufficient to explain the frequency-dependent effects produced by these agents.

1-Octanol↗
PubMed1985

Retarded recovery of excitability and twitches of frog toe muscles after K-induced depolarization (slow inactivation) in the presence of alkyl amphipaths.

Alkyl amphipaths resemble conventional local anesthetics in their ability to retard the recovery of excitability and twitch tension after depolarization at high Ko, an effect that is attributed to slow inactivation of potential-dependent sodium channels. The similar effect of low temperature offers an explanation for its ability to enhance the frequency-dependent effects of these agents.

1-Octanol↗
PubMed1978

Pulmonary absorption of drugs in the neonatal rat.

To compare the pulmonary absorption of drugs in newborn rats (3-27 days old) with that in adults, 0.01-0.1 ml of Krebs-Ringer phosphate solution (pH 7.4) containing a drug was administered to anesthetized animals by way of a catheter introduced through a tight-fitting tracheal cannula. After various times, lungs and trachea were removed and assayed for drug that remained. Semilogarithmic plots of percent drug remaining against time yielded a straight line for each compound. The lipid-soluble drugs procaine amide and sulfisoxazole were absorbed at similar rates in newborn and adult rats. In contrast, the lipid-insoluble drugs tetraethylammonium, p-aminohippuric acid, and mannitol were absorbed approximately 2 times more rapidly in younger rats (3-12 days) than in older animals (18 day, 27 day, or adult). The results suggested that the respiratory tract membranes of 3- to 12-day-old rats have a greater porosity than those of older animals.

Absorption↗