Download Advances in General and Cellular Pharmacology: Volume 1 by Francis M. Weld, J. Thomas Bigger Jr. (auth.), Toshio PDF

By Francis M. Weld, J. Thomas Bigger Jr. (auth.), Toshio Narahashi, C. Paul Bianchi (eds.)

Knowledge of the mechanism of motion of substances at mobile, subcellular, or molecular degrees is of significant significance not just in giving the root of inter­ pretation of the systemic motion of gear but additionally in bettering current medicinal drugs; in designing new sorts of medicines; and in giving the foundation of healing functions. Classical pharmacology, about the motion of substances at built-in degrees, doesn't inevitably provide enough info as to the mechanism of motion of substances. quite a few refined suggestions using the equipment of physics, chemistry, biophysics, biochemistry, and body structure needs to be synthesized to appreciate the mechanism of motion. basically because the final decade, besides the fact that, have those recommendations been totally utilized to pharma­ cological investigations. it truly is of maximum value to gain new size of pharmacological learn has certainly emerged due to this type of multidisciplinary method; this technique is encompassed quite often and mobile pharmacology. Such contemporary reports of drug activities have resulted in a few very important findings. convinced chemical compounds and medication have been discovered to own hugely particular activities on mobile features, so they are broadly getting used as strong instruments for the research of a number of physiological and pharmacological prob­ lems. Our wisdom of the mobile mechanisms of drug motion has supplied the root for reading the systemic results of the medicine and perception into the molecular mechanism involved.

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However, under adverse circumstances, such as digitalis intoxication or hypoxia, sodium may accumulate in cells, causing a signficant decrease in the driving force for sodium across the membrane [see equations (7) and (8b)]; this state would tend to oppose normal automaticity. Outside the physiologic range, reduction ofthe external sodium concentration may have significant effects on either normal or abnormal automaticity. In sodium-poor or sodium-free solutions, iK2 is greatly reduced in cardiac Purkinje fibers (Deck and Trautwein, 1964; McAllister and Noble, 1966).

4. Chloride Studies in cardiac Purkinje fibers show that the chloride ion provides background current at diastolic and plateau values oftransmembrane voltage and a brief current transient in the initial portion of the action potential. The distribution of chloride ions in cardiac muscle is thought to be passive and determined by membrane voltage (Carmeliet, 1961; Hutter and Noble, 1961) so that, in fibers which have been at rest for long periods oftime, the chloride equilibrium potential, VCI> should be equal to Vm • In cardiac muscle which is repeatedly activated, VCl will assume a value between the plateau and diastolic voltages, about - 50 mV (Hutter and Noble, 1961).

Catecholamines can also influence phase 4 depolarization in cardiac Purkinje fibers by their effects on membrane ion pumping. Norepinephrine increases 42K influx in Purkinje fibers, an effect attributed to stimulation of a membrane Na + -K + pump (Vas salle and Barnabei, 1971). Trautwein and Schmidt (1960) showed that catecholamines could increase resting transmembrane voltage in canine atrial or Purkinje fibers which showed partial depolarization. They attributed this effect to activation of electrogenic cation transport on the basis of experiments with 2,4-dinitrophenol, sodium cyanide, and iodoacetic acid.

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