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)
Floreani
M
M
Dipartimento di Farmacologia, Università di Padova, Italy.
Tessari
M
M
Debetto
P
P
Luciani
S
S
Carpenedo
F
F
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008930:Mitochondria, Liver / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors; D051381:Rats; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D002352:Carrier Proteins; D010726:Phosphodiesterase Inhibitors; D019831:Sodium-Calcium Exchanger; C051584:2-chlorobenzylamiloride; C041470:3',4'-dichlorobenzamil; D000584:Amiloride; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase