Differential effects of phosphodiesterase-sensitive and -resistant analogs of cAMP on initiation of contraction in cardiac ventricular myocytes

Amplitudes of cardiac contractions initiated by Ca²⁺-induced Ca²⁺ release (CICR) are proportional to the magnitude of Ca²⁺ current (I_Ca-L). However, large contractions accompanied by little inward current have been reported in some but not all studies in which cells were dialyzed with different analogs of cAMP. This study compares the effects of different phosphodiesterase (PDE)-resistant and PDE-sensitive analogs of cAMP on CICR, and investigates whether cAMP sensitizes CICR so that small currents induce large contractions. Experiments were conducted in voltage-clamped guinea pig ventricular myocytes at 37°C, with different analogs of cAMP added to patch pipette solutions. With PDE sensitive Tris-cAMP, contraction-voltage relations were bell-shaped and proportional to I_Ca-L. In contrast, dialysis with PDE-resistant dibutyryl-cAMP resulted in sigmoidal contraction-voltage relations and large responses with little inward current. Similarly, in cells loaded with fura-2, large Ca²⁺ transients were elicited with little inward current in cells dialyzed with PDE-resistant but not PDE-sensitive cAMP. However, large transients were observed with PDE-sensitive cAMP when PDE was inhibited with 3-isobutyl-1-methylxanthine. When the amplitude of I_Ca-L was varied by partial block with Cd²⁺, or by partial inactivation, CICR remained proportional to the amplitude of I_Ca-L. Thus, cAMP altered the relationship between Ca²⁺ transients and membrane potential but did not sensitize conventional CICR coupled to I_Ca-L. Our results show that effects of different analogs of cAMP on contraction depend on the PDE resistance of the analog tested. Furthermore, PDE can play a major role in modulating cardiac contraction by altering the relationship between membrane potential and Ca²⁺ release.