Phenamil, an
amiloride derivative, is a potent inhibitor of epithelial type
sodium channels and a relaxant of smooth muscle. In canine cardiac ventricular trabeculae, which do not express epithelial type
sodium channels,
phenamil produces positive inotropy and prolongs twitch duration. Sarcoplasmic reticulum does not appear to be essential for
phenamil-induced inotropy, because
cyclopiazonic acid and
ryanodine do not abolish this effect. Furthermore, in tissues made to contract biphasically with 90 to 98% substitution of
calcium with
strontium,
phenamil enhanced the second phase of the contraction which is transsarcolemmal-
calcium dependent.
Phenamil did not alkalinize or acidify the cytosol (measured with 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, BCECF) during the induction of positive inotropy, therefore the
sodium-
hydrogen exchange is not affected.
Sodium-
calcium exchange, as assessed by twin rapid cooling
contractures, was not inhibited by
phenamil. Direct inhibition of this exchanger is therefore not necessary for the inotropic action of
phenamil.
Phenamil did not inhibit the
sodium pump in smooth muscle. Unlike
ouabagenin, it significantly prolonged the action potential duration at 90% repolarization. We have demonstrated recently that prolongation of cardiac action potential duration with
phenamil is due to inhibition of the inwardly rectifying
potassium current without any direct effect on cardiac
calcium channels. The resulting delay in repolarization of the terminal part of the action potential reduces the driving force for the forward mode of
sodium-
calcium exchange. This indirectly reduces the activity of the
sodium-calcium exchanger and slows the extrusion of
calcium from the cell at the end of the action potential leading to a gradual development of positive inotropy.