Voltage-gated sodium channels (VGSCs) are responsible for the initial inwards current during the depolarisation phase of action potential in excitable cells. Therefore, VGSCs are crucial for cardiac and nerve function, since the action potential of nerves and muscle cannot occur without them. Their importance in generation and transmission of signals has been known for more than 40 years but the more recent introduction of new electrophysiological methods and application of molecular biology techniques has led to an explosion of research on many different ion channels, including VGSCs. Their extraordinary biological importance makes them logical and obvious targets for toxins produced by animals and plants for attack or defence. The action of these and similar substances modulating the function of the VGSCs is interesting with respect to their possible use in medicine or use as tools in the study of these molecules. This review summarises recent progress in this research field and, in particular, considers what is known about the relationship of the structure to function, including a current understanding of the pharmacological modulation of VGSCs.

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The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10(-7) and 3 X 10(-6) mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 mumol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 mumol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecula septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 dit not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

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Intravenous phenylephrine increases, and isoproterenol and fenoterol decrease the frequency and amplitude of ureteral contractions in the pig. The same effects are observed with the topical administration of phenylephrine, which causes a significant local but not systemic side effect. Topical administration of isoproterenol and fenoterol produced local as well as systemic effects, suggesting absorption by the urothelium. However, to our knowledge a drug that relaxes ureteral peristalsis in pigs without causing systemic side effects has not yet been identified.