Effects of N-chlorobenzyl analogues of amiloride on myocardial contractility, Na-Ca-exchange carrier and other cardiac enzymatic activities.

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)
AuthorsM Floreani, M Tessari, P Debetto, S Luciani, F Carpenedo
JournalNaunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 336 Issue 6 Pg. 661-9 (Dec 1987) ISSN: 0028-1298 [Print] GERMANY, WEST
PMID2832772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Phosphodiesterase Inhibitors
  • Sodium-Calcium Exchanger
  • 2-chlorobenzylamiloride
  • 3',4'-dichlorobenzamil
  • Amiloride
  • Calcium-Transporting ATPases
  • Sodium-Potassium-Exchanging ATPase
  • Amiloride (analogs & derivatives, pharmacology)
  • Animals
  • Calcium-Transporting ATPases (antagonists & inhibitors)
  • Carrier Proteins (antagonists & inhibitors)
  • Electric Stimulation
  • Guinea Pigs
  • In Vitro Techniques
  • Mitochondria, Liver (metabolism)
  • Myocardial Contraction (drug effects)
  • Myocardium (enzymology)
  • Oxidative Phosphorylation (drug effects)
  • Phosphodiesterase Inhibitors
  • Rats
  • Sodium-Calcium Exchanger
  • Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)

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