Phosphorylation of Na channels has been suggested to increase their Ca permeability. Termed “slip-mode conductance” (SMC), this hypothesis predicts that Ca influx via protein kinase A (PKA)-modified Na channels can induce sarcoplasmic reticulum (SR) Ca release. We tested this hypothesis by determining if SR Ca release is graded withINain the presence of activated PKA (with Isoproterenol, ISO). Vm,Im, and [Ca]iwere measured in feline (n=26) and failing human (n=19) ventricular myocytes. Voltage steps from −70 through −40 mV were used to gradeINa. Na channel antagonists (tetrodotoxin), L-type Ca channel (ICa,L) antagonists (nifedipine, cadmium, verapamil), and agonists (Bay K 8644, FPL 64176) were used to separate SMC fromICa,L. In the absence of ISO,INawas associated with SR Ca release in human but not feline myocytes. After ISO, gradedINawas associated with small amounts of SR Ca release in feline myocytes and the magnitude of release increased in human myocytes.INa-related SR Ca release was insensitive to tetrodotoxin (n=10) but was blocked by nifedipine (n=10) and cadmium (n=3). SR Ca release was induced over the same voltage range in the absence of ISO with Bay K 8644 and FPL 64176 (n=9). Positive voltage steps (to 0 mV) to fully activate Na channels (SMC) in the presence of ISO and Verapamil only caused SR Ca release when block ofICa,Lwas incomplete. We conclude that PKA-mediated increases inICa,Land SR Ca loading can reproduce many of the experimental features of SMC.