Ion channel agonists: expectations for therapy.

Abstract

Some animal or plant toxins and man-made drugs exert agonist activity on Na+, Ca2+ and K+ channels. The increase in current through these channels is essentially due to an increase of 'open probability' and not of single channel conductance. The enhanced open probability is caused by a prolongation of the open time. In the case of voltage-operated channels this change in open time can be accompanied by increased reopenings and thus slowing of inactivation, or a shift in the activation process to more negative potentials. In the case of the ligand-operated K+ channel, a decrease in the affinity for the normal physiological ligand, ATP, is the mechanism underlying the enhancement of open probability. Agonists show potential clinical applications for Na+ and Ca2+ channels more specifically as positive inotropic agents in cardiac tissue. For K+ channels, the potential therapeutic field is even broader and spans from relaxation of smooth muscle (hypertension, asthma, bladder, uterus), reduction in excitability (arrhythmias, certain skeletal muscle myopathies) to inhibition of neurotransmitter release (depression, epilepsy).