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EFFECTS OF RMI 12330A, A NEW INHIBITOR OF ADENYLATE CYCLASE ON MYOCARDIAL FUNCTION AND SUBCELLULAR ACTIVITY
Author(s) -
GRUPP G.,
GRUPP I.L.,
JOHNSON C.L.,
MATLIB M.A.,
ROUSLIN W.,
SCHWARTZ A.,
WALLICK E.T.,
WANG T.,
WISLER P.
Publication year - 1980
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1980.tb08721.x
Subject(s) - adenylate kinase , cyclase , ouabain , isoprenaline , histamine , chemistry , medicine , endocrinology , inotrope , enzyme , biochemistry , biology , sodium , stimulation , organic chemistry
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 (IC 50 of 1.5 × 10 −5 m ). 2 In the isolated work‐performing heart of the guinea‐pig, RMI 12330A (IC 50 of 1.1 × 10 −6 m ) depressed all cardiac functions: pressures developed, d P /d t , contractile force, d F /d t , 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 m m to 4.5 and 6.5 m m 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 (IC 50 of 1.7 × 10 −4 m ) and inhibited ouabain binding to the same enzymes (IC 50 of 1.5 × 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.