The effects of hypothyroidism and 3,5,3'-triiodothyronine (T3) treatment on passive Na+-K+ fluxes and Na+-K+ pump concentration were investigated in isolated rat muscle. Within 12 h after a single dose of T3 (20 micrograms/100 g body wt), K+ efflux had increased by 21% in soleus and by 20% in extensor digitorum longus muscle. In the presence of ouabain, even larger effects were observed. These changes were associated with a 12% rise in amiloride-suppressible Na+ influx but no significant increase in [3H]ouabain binding site concentration. After 3 days of T3 treatment, the stimulating effect on K+ efflux and Na+ influx in soleus reached a plateau approximately 80 and 40% above control levels, respectively, whereas the maximum increase in [3H]ouabain binding site concentration (103%) was only fully developed after 8 days. Hypothyroidism decreased 86Rb efflux by 30%. The efflux of K+ and the influx of Na+ per contraction (both approximately 7 nmol/g wet wt) as well as the net loss of K+ induced by electrical stimulation were unaffected by T3 treatment. The rise in resting K+ efflux after 12-24 h of T3 treatment could be partly blocked by dantrolene or trifluoroperazine, indicating that an increase in the cytoplasmic Ca2+ concentration may contribute to the early rise in K+ efflux. It is concluded that the early rise in the resting passive leaks of Na+ and K+ induced by T3 is a major driving force for Na+-K+ pump synthesis.