Abstract
Fluoride, a known activator of the adenylate cyclase in broken-cell preparations of heart and other tissue [21, 22] was tested for its ability to act as a positive inotropic agent in cardiac muscle and for its ability to concomitantly induce Ca2+ channels. The induction of slow Ca2+ channels was tested in myocardial cells in which the fast Na+ channels were blocked by tetrodotoxin (TTX) or inactivated by partial depolarization in 25 mm K+. In the isolated perfused embryonic chick heart and in reaggregates of cultured cells derived from the embryonic chick ventricle, addition of NaF (0.5–5.0 mm), to myocardial cells whose excitability was abolished, rapidly (1–6 min) induced slowly-rising overshooting electrical responses accompanied by contractions. These slow responses were blocked by Mn2+ (1 mm) or D-600 (10?6 g/ml), known inhibitors of transmembrane Ca2+ current. Consistent with this induction of slow Ca2+ channels, fluoride (2–3 mm) showed a positive inotropic action in intact hearts perfused with normal Ringer solution. Because many positive inotropic agents, in common, elevate cyclic AMP, it is possible that the action of fluoride in inducing slow Ca2+ channels was mediated by changes in cyclic AMP levels leading to possible changes in phosphorylation of a protein constituent of the slow channels. However, the cyclic AMP content of the fluoride-treated hearts did not increase as compared to control hearts. But since fluoride also inhibits phosphatases [8, 11], the action on the membrane slow channels could be mediated by inhibition of dephosphorylation of the slow channel.