A comparison between the effects of BMS-180448, a novel K+ channel opener, and cromakalim in rat and dog.
BMS-180448 [(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(6-cyano-3, 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) guanidine] is a structural analog of cromakalim, which was found to similarly decrease ischemic injury, but was 18- to 100-fold less potent as a vasodilator. In the present study, the vascular and cardiac effects of cromakalim and BMS-180448 were evaluated in both in vitro and in vivo preparations. Cromakalim evoked a concentration-dependent relaxation to a K(+)-induced contracture in rat aorta. BMS-180448 behaved in a similar fashion but was 18-fold less potent than cromakalim. Measurements of ischemic damage made in isolated perfused rat hearts demonstrated that cromakalim and BMS-180448 were equipotent as cardioprotective agents; time to contracture was increased with an EC25 value of 4.8 and 4.7 microM, respectively, and lactate dehydrogenase levels were significantly reduced compared to those in the presence of vehicle. In vivo electrophysiologic studies in anesthetized dogs were conducted at basic cycle lengths of 400, 333, and 286 ms, and showed that BMS-180448 caused no significant effect on electrophysiologic parameters with the exception of decreasing atrial effective refractory periods by 12 +/- 3% and 17 +/- 4% at 3 and 10 mg/kg, respectively. There was also a significant drop in mean blood pressure of 18 +/- 5% and 33 +/- 4% at these doses. In contrast, cromakalim was shown to produce shortening of atrial to His conduction time (20 +/- 7%; basic cycle length = 286 ms), atrial effective refractory period (34 +/- 3%; basic cycle length = 400 ms), ventricular effective refractory period (14 +/- 2%; basic cycle length = 400 ms), wavelength (13 +/- 3%; basic cycle length = 400 ms), PR-interval (14 +/- 3%; basic cycle length = 333 ms) and mean blood pressure (65 +/- 3%; basic cycle length = 400 ms) at a dose of 0.3 mg/kg. No supraventricular or ventricular arrhythmias were observed for either compound tested. Based on the reduced cardiac electrophysiologic and vascular effects of BMS-180448, we suggest that BMS-180448 should provide cardioprotective efficacy similar to cromakalim with reduced risk of hypotension or arrhythmias.
D'Alonzo
A J
AJ
Department of Cardiovascular Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Darbenzio
R B
RB
Sewter
J C
JC
Hess
T A
TA
Grover
G J
GJ
Sleph
P G
PG
Normandin
D E
DE
Lodge
N J
NJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019806:Cromakalim; D004285:Dogs; D004594:Electrophysiology; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013045:Species Specificity
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D002316:Cardiotonic Agents; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C084684:BMS 180448