The cardioprotective, vasorelaxant and electrophysiological profile of the large conductance calcium-activated potassium channel opener NS-004.
A series of compounds have been reported which open the large conductance calcium activated potassium channel (maxi-K). By utilizing the most potent compound, NS-004 [1-(5-chloro-2-hydroxyphenyl)-5-trifluromethyl-1,3-dihydro-2-be nzimidazol-2- one], we studied the role of maxi-K channels in ischemic myocardium. Isolated rat hearts were pretreated with vehicle or NS-004 (6-36 microM). NS-004 caused a concentration-dependent reduction in left ventricular developed pressure and an increase in coronary flow. In global ischemia (25 min), a concentration-dependent increase in time to contracture was found in NS-004 (6-20 microM)-treated hearts (EC25 = 8.6 microM). Neither iberiotoxin (50 nM), a maxi-K blocker, nor glyburide (1 microM), an adenosine triphosphate-sensitive potassium channel blocker, reversed the preischemic or ischemic effects of 20 microM NS-004. NS-004 relaxed phenylephrine- and KCl- contracted rat aortic smooth muscle (IC50 = 9.2 microM). This relaxation was unaffected by 50 and 200 nM iberiotoxin. Whole cell potassium currents in ventricular myocytes demonstrated no significant increases in outward potassium current after treatment with NS-004 (1-20 microM). A small, but significant, increase in outward potassium current was observed with 50 microM NS-004. When peak inward L-type calcium currents were measured in ventricular myocytes, a concentration-dependent inhibition was observed in the presence of NS-004 (1-50 microM). Iberiotoxin (50 nM) did not alter the inhibition of inward calcium current observed in the presence of NS-004.(ABSTRACT TRUNCATED AT 250 WORDS)
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Cardiovascular Pharmacology, Princeton, New Jersey.
C A
CA
Sargent
G J
GJ
Grover
M J
MJ
Antonaccio
J R
JR
McCullough
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000502:physiology*; D002733:Chlorophenols / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D001562:Benzimidazoles; D002733:Chlorophenols; D015221:Potassium Channels; C083230:NS 004; D002118:Calcium