Pumiliotoxin Alkaloids: Relationship of Cardiotonic Activity to Sodium Channel Activity and Phosphatidylinositol Turnover

The cardiotonic activity of pumiliotoxin B (PTX-B, 6-(6',7'-dihydroxy-2',5'-dimethyl-(E)-4'-octenylidene)-8-hydroxy-8 -methyl-1- azabicyclo[4.3.0]nonane) as assessed in guinea pig atrial preparations is markedly dependent on the nature of the 6-alkylidene side chain. Pumiliotoxin A (PTX-A), which differs from PTX-B only in lacking the 7'-hydroxy moiety, is much less active than PTX-B. Alteration in the configuration of the 6'- and/or 7'-hydroxy side chain moieties in synthetic isomers of PTX-B reduces activity, while the lack of such moieties or replacement with methoxy or ketone moieties in PTX-B or PTX-A analogues yields cardiodepressant compounds. PTX-B markedly stimulates phosphoinositide turnover in atrial and brain preparations and sodium influx in brain preparations, while analogues that are cardiac depressant or have low cardiotonic activity have no or minimal effects on such parameters. It is suggested that activation of sodium channels and resultant stimulation of phosphoinositide breakdown play a role in the cardiotonic activity of pumiliotoxin alkaloids.