Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger.
1. The NHE1 isoform of the Na(+)/H(+) exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na(+)/H(+) antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. 2. Recovery of pH(i) following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na(+)/H(+) exchanger. pH(i) recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC(50) 3.3+/-1.3 nM) versus NHE2-expressing cells (2.3+/-1.0 microM). The respective IC(50) values for cariporide were 103+/-28 nM (NHE1) and 73+/-46 microM (NHE2). 3. In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10 - 100 microg kg(-1) min(-1) i.v.) inhibited ischaemia-mediated ventricular tachycardia (71 - 100%) and reperfusion-induced ventricular fibrillation (75 - 87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg(-1)) produced anti-arrhythmic effects when administered either before or during ischaemia. 4. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2+/-3.4% (control group) versus 15.3+/-3.9% (SL 59.1227 0.6 mg kg(-1) i.v.). 5. SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na(+)/H(+) exchanger inhibitor. It possesses marked cardioprotective properties.
Lorrain
J
J
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France. Janine.lorrain@sanofi-synthelabo.com
Briand
V
V
Favennec
E
E
Duval
N
N
Grosset
A
A
Janiak
P
P
Hoornaert
C
C
Cremer
G
G
Latham
C
C
O'Connor
S E
SE
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D006146:Guanidines; D007093:Imidazoles; D010880:Piperidines; C418784:SL 59.1227; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide