The authors examined effects of positive (dopamine and digoxin) and negative (nifedipine and lidocaine) inotropic interventions on the instantaneous cyclic relationship between myoplasmic [Ca2+] and simultaneously developed left ventricular pressure (LVP) in intact guinea pig hearts. Novel indices were developed to quantify this relationship based on (1) transient [Ca2+] and LVP signal morphology, ie, maxima and minima, peak derivatives, beat areas, durations, and ratios of indices of LVP to [Ca2+]; (2) temporal delay; and (3) LVP versus [Ca2+] loop morphology, ie, orientation, size, hysteresis, position, shape, and duration. These analyses were used to assess the cost of phasic [Ca2+] for contraction and relaxation over one beat after inotropic intervention. It was found that dopamine and digoxin increased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike dopamine, digoxin did not decrease relaxation response time. Nifedipine and lidocaine decreased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike lidocaine, nifedipine decreased net available Ca2+ and Ca2+ influx. Positive inotropic agents increased [Ca2+]-LVP loop area and hysteresis and resulted in a more vertically oriented loop. Nifedipine and lidocaine decreased these loop indices and lidocaine exhibited greater loop hysteresis than did nifedipine. These novel indices provide a quantitative assessment of myoplasmic [Ca2+] handling for cardiac contractile function.