Time Course Of Blockade Research Articles

Time course of action of antagonists of mitochondrial Ca uptake in intact ventricular myocytes.

Mitochondrial Ca uptake is important for ATP production and intracellular Ca buffering. Several agents are often used to interfere with mitochondrial Ca transport, but the use of these agents in intact cells is complicated by lack of knowledge about how rapidly these agents gain access to intracellular mitochondria. We have developed a novel method to assess the time course with which extracellularly applied inhibitors gain access to mitochondria in intact ventricular myocytes preloaded with the fluorescent Ca indicator indo-1-AM. Cell contraction (assessed as the normalized change in cell length delta L(n)) was employed as an index of the cytosolic [Ca] ([Ca](c)), and was compared with the indo-l ratio R(n), which reflects both mitochondrial [Ca] ([Ca](m)) and [Ca](c). Upon abrupt plasma membrane damage in control cells, the delay ( t(k)) between the rise in L(n)and R(n) was <10 s (reflecting the time lag between the change in [Ca](c) and that in [Ca](m)). Exposure of cells to 50 microM ruthenium red (RR) increased t(k) as a monotonic function of preincubation time. In contrast, 10 microM Ru360, a selective and more potent Ca uniporter blocker ( K(i) approximately 0.2 nM) reached a comparable maximal t(k) after only 10 min, making it practical to use in intact cells. Carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) and carbonylcyanide m-chlorophenylhydrazone (CCCP) produced smaller maximal effects on t(k), but did so almost immediately. These results are the first quantitative data on the time course of blockade of mitochondrial Ca uptake by the four most widely used mitochondrial Ca uptake antagonists in single ventricular myocytes.

Different effects on different muscles: Clinical implications

N 'EUROMUSCULAR blocking agents must be regarded as having multiple sites of action. The main action of these drugs is competitive blockade at the nicotinic receptor of the neuromuscular junction, but these receptors are found at every muscle in the body. Although all postsynaptic nicotinic receptors are structurally the same throughout the body, muscles vary with respect to blood supply, size of fibers, and architecture of their junctional apparatus. As a result, time course of neuromuscular blockade after a bolus dose of a neuromuscular blocking agent varies from one muscle to the next. It would be tedious to learn and remember the characteristics of all the muscles of the body. In practice, one needs to focus on those having clinical relevance (ie, the muscles of the respiratory system). In addition, it is important to understand the relationship between the muscles used for monitoring and those that are clinically important. The data available on the time course of blockade at the respiratory muscles (diaphragm, intercostals, abdominal muscles), those of the larynx, and upper airway, are remarkably consistent if one considers the confounding effect of dose on onset time, maximum effect, and duration. Because it is impractical to monitor these muscles in clinical practice, surrogate muscle groups have been identified. The most commonly used are those of the hand, foot, and eyebrow. Instead of taking the traditional approach of listing results coming from all muscles using all possible methods of measurement, a discussion of the possible patterns of onset, maximum blockade, and duration will be made, and the influence of dose on these patterns will be presented. Then the

No Substitute for the Intravenous Route

No Substitute for the Intravenous Route

Pharmacodynamics and pharmacokinetics of tolfenamicacid in ruminating calves: Evaluation in models of acute inflammation

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan) in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TX)B2 and inflammatory exudate prostaglandin (PG)E2 were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8 mgkg-1 tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB2 synthesis and the duration of inhibition was dose-related. A dose of 2 mgkg-1 tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE2 synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short tmax (0.94-2.04 h), a high estimated Vdarea (1.79-3.20 Lkg-1), an estimated t1/2 beta of 8.01-13.50 h and Cl beta of 0.142-0.175 Lkg-1h-1. The actions of tolfenamic acid in inhibiting PGE2 synthesis and in attenuating two of the cardinal signs of inflammation (heat and swelling) suggest that a dosage of 2 mgkg-1 administered intramuscularly should be effective clinically as an anti-inflammatory agent.

Action of botulinum toxin on transmission from sympathetic nerves to the vas deferens.

Botulinum toxin (Type A) depressed or abolished transmission from postganglionic nerves to smooth muscle of isolated preparations of guinea-pig and mouse vas deferens. The time course of blockade was 2 to 6 times slower than that observed with the same concentration of the same batch of toxin on the rat diaphragm. Spontaneous excitatory junction potentials were still observed after 7 h exposure, indicating that the smooth muscle membrane was still able to respond to noradrenaline. Depression of transmission is probably due to a presynaptic action of unknown nature.