The influence of intracellular and extracellular angiotensin II (Ang II) on the L-type calcium current of cardiomyocytes isolated from cardiomyopathic hamsters was investigated. The results indicated that Ang II (10⁻⁸ mmol/L), added to the bath, increased the peak inward calcium current (I_Ca) density by 37±3.4% (P<0.05), an effect that depends on the activation of protein kinase C. Intracellular administration of the same dose of Ang II (10⁻⁸ mmol/L) also elicited an increase of peak I_Ca density but enhanced the rate of I_Ca inactivation, an effect not seen with extracellular Ang II. Moreover, in control animals, no change in the rate of I_Ca inactivation was seen with intracellular Ang II. Thapsigargin (1 μmol/L), a potent inhibitor of sarcoplasmic reticulum (SR) ATPase, which depletes the SR, decreased the rate of I_Ca inactivation elicited by intracellular Ang II, although the cytoplasmic calcium concentration was highly buffered with 10 mmol/L EGTA. These findings might indicate that intracellular Ang II releases calcium from the SR and inactivates I_Ca. The effect of intracellular Ang II on peak I_Ca was not altered by extracellular losartan (10⁻⁷ mmol/L), supporting the notion that the peptide acted intracellularly. Other studies showed that intracellular Ang I administration (10⁻⁸ mmol/L) enhanced the peak I_Ca density and the rate of I_Ca inactivation, an effect that was reduced by intracellular enalaprilat (10⁻⁸ mmol/L). Moreover, intracellular enalaprilat by itself reduced the peak I_Ca density. These observations might indicate that endogenous Ang II is contributing to I_Ca modulation in the failing heart.