Alleviation of contractile dysfunction in ischemic hearts by slowly inactivating Na+ current blockers.
We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Le Grand
B
B
Division of Cardiovascular Diseases, Centre de Recherche Pierre Fabre, Castres, France.
Vie
B
B
Talmant
J M
JM
Coraboeuf
E
E
John
G W
GW
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D052160:Benzothiazoles; D001696:Biomechanical Phenomena; D004553:Electric Conductivity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D012016:Reference Values; D012964:Sodium / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
D052160:Benzothiazoles; D010880:Piperidines; D013844:Thiazoles; D013779:Tetrodotoxin; C054551:R 56865; D012964:Sodium