1
RMI 12330A, a
lactam-
imine, at concentrations of 10(-4) M and higher, inhibited basal as well as
isoprenaline and NaF-stimulated
adenylate cyclase activity of guinea-pig heart homogenates. However,
RMI 12330A was a more potent inhibitor of
histamine-stimulated
adenylate cyclase (IC50 of 1.5 X 10(-5) M). 2 In the isolated work-performing heart of the guinea-pig,
RMI 12330A (IC50 of 1.1 X 10(-6) M) depressed all cardiac functions: pressures developed, dP/dt, contractile force, dF/dt, work performance and
stroke work. Left atrial pressure rose and the positive inotropic response to increasing heart rate (staircase) became negative.
Histamine,
isoprenaline and
ouabain no longer caused positive inotropic effects. 3 Increasing the perfusate
calcium concentration from 2.5 mM to 4.5 and 6.5 mM completely restored cardiac function after its depression by
RMI 12330A. 4
RMI 12330A uncoupled mitochondrial oxidative phosphorylation; the classical uncoupler, dinitrophenol, had the same effects on cardiac dynamics as
RMI 12330A. 5 RMI in high doses inhibited hydrolytic activity of Na+, K+-
ATPase of crude and purified heart preparations (IC50 of 1.7 X 10(-4) M) and inhibited
ouabain binding to the same
enzymes (IC50 of 1.5 X 10(-4) M). 6 A
lactam-
imine analogue of
RMI 12330A that had no effect on
adenylate cyclase, was also without effect on any of the systems examined.