Influence of lidocaine on ouabain-induced inotropic response in rat atria.
In this paper we demonstrated that lidocaine broadens the therapeutic range of ouabain action having a protective effect on ouabain-induced toxicity on rat atria. The lidocaine effect on therapeutic ouabain action was associated with the increase in the sensitivity of Na(+)-K(+)-ATPase related to a decreased in the equilibrium dissociation constant (K(d)) of high affinity binding sites. Lidocaine suppressed the ouabain-induced tonotropic effect and arrhythmias, decreasing the number of low affinity binding sites (B(max)) without changes in K(d). Blockade of Na(+)-Ca(2+) exchange with KB-R7943 or dual Na(+)-Ca(2+) channel with flunarizine, mimicked lidocaine effect increasing ouabain therapeutic action, extending its concentration range tolerated, delaying the onset of contracture. Lidocaine itself triggered negative inotropic response at high concentration. This effect was increased in the presence of flunarizine and verapamil but not by the inhibition of calcium/calmodulin with W-7. The mechanism underlying the lidocaine-induced negative inotropic response, appears to be different that underlying the positive inotropic effect on ouabain action. This study provides evidence that lidocaine can interact with the same or similar binding sites for ouabain in rat atrial tissue, providing a protective effect on ouabain-induced changes in contractility. The contribution of Na(+)-Ca(2+) exchange and/or Ca(2+) overload on lidocaine effect is discussed.
Sterin-Borda
Leonor
L
Pharmacology Unit, School of Dentistry, Argentina National Research Council, University of Buenos Aires, 1122AAH Buenos Aires, Argentina. leo@farmaco.odon.uba.ar
Orman
Betina
B
Reina
Silvia
S
Borda
Enri
E
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004347:Drug Interactions; D005444:Flunarizine / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D013449:Sulfonamides; D010042:Ouabain; C017967:W 7; D008012:Lidocaine; D013890:Thiourea; D005444:Flunarizine