1. In electrically driven guinea pig left atria, micromolar concentrations (2 mumol/l to 80 mumol/l) of N-chlorobenzyl derivatives of
amiloride (o-chlorobenzamil and 3',4'-dichlorobenzamil) produced quantitatively similar positive inotropic effects.
Contracture developed with
3',4'-dichlorobenzamil. Endogenously released
catecholamines contributed 30% to the positive inotropic effect of
o-chlorobenzamil but did not contribute at all to the effect of
3',4'-dichlorobenzamil. When tested in the presence of the inhibitor of
phosphodiesterase isobutylmethylxanthine,
o-chlorobenzamil antagonized its positive inotropic effect, whereas
3',4'-dichlorobenzamil potentiated it.
o-Chlorobenzamil also antagonized the positive inotropic effect of
ouabain in that it shifted its concentration-effect curve to the right. Moreover,
o-chlorobenzamil prevented the appearance of
ouabain toxicity in terms of a rise in the resting force. 2. Also, in electrically driven guinea pig papillary muscle, micromolar concentrations (5 mumol/l to 30 mumol/l) of both N-chlorobenzyl derivatives of
amiloride produced a positive inotropic effect. This effect was more marked with
3',4'-dichlorobenzamil than with
o-chlorobenzamil and was associated for both compounds with lengthening of relaxation time. 3.
o-Chlorobenzamil and
3',4'-dichlorobenzamil influenced, though not to the same extent, several systems involved in the onset and in the control of cardiac contractility.
3',4'-Dichlorobenzamil inhibited with the same potency Na-K-
ATPase, sarcotubular Ca-
ATPase, Na-Ca-exchange carrier, cAMP-dependent
phosphodiesterase isolated from bovine heart and oxidative phosphorylation of mitochondria isolated from rat liver. Low micromolar concentrations of
o-chlorobenzamil mainly inhibited Na-Ca-exchange carrier and cAMP-dependent
phosphodiesterase.(ABSTRACT TRUNCATED AT 250 WORDS)