Frequency-dependent action potential prolongation in Aplysia pleural sensory neurones

The effects of repetitive activity on action-potential shape in Aplysia californica pleural sensory cells are described. Action potentials were evoked by intracellular current injection at frequencies between 7.41 and 0.2 Hz. In contrast to other molluscan neurons having brief action potentials, it was found that at these firing rates the normally brief action potential develops a prominent shoulder or plateau during the repolarization phase. Higher stimulus rates broaden the action potential more rapidly and to a greater extent than lower stimulus rates. Inactivation is slow relative to activation; effects of 3-s 6-Hz trains are detectable after 1 min rest. The amplitude of the plateau voltage reaches a maximum of 50-70 mV at the highest stimulus rates tested. Frequency-dependent increases in action-potential duration measured at half-amplitude normally range between 6 and 15 ms. Cadmium, at concentrations between 0.05 and 0.5 mM, antagonizes frequency-dependent broadening. The increases in duration induced by repetitive activity are more sensitive to cadmium than are the increases in plateau amplitude. Tetraethylammonium, at concentrations between 0.5 and 10 mM, slightly increases the duration and amplitude of single action potentials. During repetitive activity at high stimulus rates the maximum duration and rate of broadening are both increased but the amplitude of the plateau potential is not affected by these tetraethylammonium concentrations. Above 10 mM, tetraethylammonium greatly increases the duration and amplitude of single action potentials as well as the rates of action-potential duration and amplitude increase during repetitive activity. These high tetraethylammonium concentrations also cause the normally smoothly increasing duration and amplitude to reach a maximum value early in a train and then decline slowly during the remainder of the train. The consequences of frequency-dependent spike broadening in these neurons have not yet been investigated but it is clear from these data that repetitive activity in these cells will augment calcium entry and that this increased calcium entry has a complex but predictable dependence on the duration of, and firing rate within, an afferent volley. Because these cells are involved in important adaptive behaviour it is inferred that these behaviours will be complexly affected by the intensity and duration of the stimulation of the receptive fields of the pleural sensory neurons.     

The prolongation of the action potential in mammalian ventricular muscle at rest

The conventional microelectrode technique was used to investigate the effect of long periods of rest (>10 s) on the action potential duration of mammalian ventricular muscle. The action potential duration increased as the rest period increased. This prolongation of the action potential was the greatest and the slowest in rabbit ventricle, was smaller and more rapid in guinea-pig ventricle, and was practically absent in rat ventricle. The prolongation of the action potential at rest was suppressed with aminazine and strophanthin. Low sodium concentration, lanthanum ions, ruthenium red and acidosis failed to suppress the slow prolongation. It is concluded that the slow prolongation of the action potential at rest is related to changes in the intracellular calcium content induced by a mechanism different from Na/Ca exchange.     

Reflexogenic prolongation of respiratory pauses: A potential mode of action of antitussives

Four clinically effective antitussives and 37059 (1-Ethylaminoethyl-5-methoxy-benzocyclobutene), a substance with singular pharmacodynamic potencies on expiratory activity, are tested with a specified procedure for their potentialities to prolong the reflexogenic retardation of respiration induced in pigeons by a laryngeal stimulus. Compound 37059 was very effective. Clobutinole, codeine, normethadone and noscapine were not. The possible role of this difference for cough relief is discussed.     

Ionic mechanisms of desflurane on prolongation of action potential duration in rat ventricular myocytes

Purpose

Despite the fact that desflurane prolongs the QTC interval in humans, little is known about the mechanisms that underlie these actions. We investigated the effects of desflurane on action potential (AP) duration and underlying electrophysiological mechanisms in rat ventricular myocytes.

Materials and Methods

Rat ventricular myocytes were enzymatically isolated and studied at room temperature. AP was measured using a current clamp technique. The effects of 6% (0.78 mM) and 12% (1.23 mM) desflurane on transient outward K⁺ current (I_to), sustained outward current (I_sus), inward rectifier K⁺ current (I_KI), and L-type Ca²⁺ current were determined using a whole cell voltage clamp.

Results

Desflurane prolonged AP duration, while the amplitude and resting membrane potential remained unchanged. Desflurane at 0.78 mM and 1.23 mM significantly reduced the peak I_to by 20±8% and 32±7%, respectively, at +60 mV. Desflurane (1.23 mM) shifted the steady-state inactivation curve in a hyperpolarizing direction and accelerated inactivation of the current. While desflurane (1.23 mM) had no effects on I_sus and I_KI, it reduced the L-type Ca²⁺ current by 40±6% (p<0.05).

Conclusion

Clinically relevant concentrations of desflurane appear to prolong AP duration by suppressing I_to in rat ventricular myocytes.     

Mechanisms of action and potential therapeutic uses of thalidomide

Thalidomide was first introduced to the market in Germany under the brand name of Contergan in 1956, as a non-barbiturate hypnotic, advocated to ensure a good nights sleep and to prevent morning sickness in pregnancy. It was advertised for its prompt action, lack of hangover, and apparent safety. It has been banned from the market since 1963 after it caused the worldwide teratogenic disaster: babies exposed to thalidomide in utero during the first 34-50 days of pregnancy were born with severe life-threatening birth defects. Despite its unfortunate history, thalidomide has attracted scientific interest again because of its recently discovered action against inflammatory diseases and cancer. Its broad range of biological activities stems from its ability to moderate cytokine action in cancer and inflammatory diseases. Early studies examined its anxiolytic, mild hypnotic, antiemetic, and adjuvant analgesic properties. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy, being superior to Aspirin in controlling leprosy-associated fever. Recent research has shown promising results with thalidomide in patients with myeloma, myelodysplastic syndrome, a variety of infectious diseases, autoimmune diseases, cancer, and progressive body weight loss related to advanced cancer and AIDS. Here we review the history of its development, pharmacokinetics, metabolism, biologic effects, and the results of clinical trials conducted thus far. Further research in this field should be directed towards better understanding of thalidomide metabolism, its mechanism of action, and the development of less toxic and more active analogs.     

Coding system of therapeutic focus on action and insight

This study (a) used an established comprehensive process measure to uncover a latent pattern of therapeutic focus in cognitive-behavioral and psychodynamic-interpersonal sessions; (b) used these results to develop the coding system of Therapeutic Focus on Action and Insight, which makes it possible to evaluate therapists' relative emphasis on the Constructing Meaning and Facilitating Action domains of in-session focus; and (c) evaluated its reliability and validity.     

卡托普利对豚鼠心室细胞动作电位及外向延迟整流钾电流的作用(英)

目的：探讨卡托普利对豚鼠心肌细胞动作电位间期及延迟整流钾电流的作用。 方法: 采用内充3 mol/L KCl的玻璃微电极记录心肌动作电位。采用膜片钳全细胞技术，钳制电位-50 mV, 保持时间100 ms, 指令电位+40 mV, 记录外向延迟整流钾电流(Ik)最大峰电流。 结果: 与缺血组比较卡托普利组APD30、APD50及ERP显著延长，APD90无显著变化，缺血组Ik幅度显著增高而卡托普利组及卡托普利+缺血组显著降低。电流-电压关系曲线形状各组间无显著变化, 缺血组显著上移而卡托普利组及卡托普利+缺血组下移。 结论： 卡托普利具有的电生理作用是由于它降低外向延迟整流钾电流及延长APD30、APD50和ERP。     

Calcitonin gene-related peptide: release by capsaicin and prolongation of the action potential in the guinea-pig heart

The mechanisms underlying the stimulatory effects of capsaicin on the contractility of the guinea-pig heart were studied in vitro. Capsaicin (10(-7) to 10(-5) M) caused an increased overflow of immunoreactive material, suggesting release of calcitonin gene-related peptide (CGRP)-and neurokinin A (NKA)-like immunoreactivity (-LI), but not of neuropeptide Y (NPY)-LI from the isolated Langendorff-perfused whole heart. The capsaicin-induced release was calcium-dependent. During exposure to capsaicin, the heart rate was increased, while the contractile force was reduced. In addition to releasing CGRP and NKA-LI, potassium (60 mM) also increased the overflow of NPY-LI. The potassium-induced release of peptides was less calcium-dependent than the response to capsaicin. Considerably higher tissue levels of CGRP-LI were found in the atria (about 30 pmol g-1) than in the ventricles (about 10 pmol g-1). In experiments on the right atria using transmembrane action-potential recordings of myocytes, CGRP induced a prolongation of the action potential concomitantly with an increase in rate and contractile force, which was similar to the effect of noradrenaline. Furthermore, CGRP increased the contractile force and relaxation velocity of the electrically stimulated atria. Capsaicin (10(-7) M) also increased the duration of the atrial action potential. In conclusion, CGRP-like material is released by capsaicin from the isolated guinea-pig heart. Both CGRP and capsaicin prolong the plateau phase of the action potential of atrial myocytes. Therefore, the present data give further evidence that CGRP release from sensory nerves within the heart underlies the cardiostimulatory actions of capsaicin.     

CD28 superagonists: mode of action and therapeutic potential

Some CD28-specific monoclonal antibodies (mAbs) have the surprising property to activate T-cells without the need for TCR ligation. This review summarizes the differences between these "superagonistic" and conventional CD28-specific mAbs with regard to binding specificity and signalling properties. Furthermore, the dramatic effects of in vivo application of CD28 superagonists with regard to the induction of regulatory T-cells and polyclonal T-cell expansion in lymphopenic settings are discussed under the aspect of potential therapeutic applications.