31P nuclear magnetic resonance study of the effects of the calcium ion channel antagonist fantofarone on the rat heart.
The biochemical and mechanical effects of a new calcium ion channel antagonist, fantofarone ((2-isopropyl-1-((4-(3-(N-methyl-N-(3,4-dimethoxy-beta-phenethyl)-amino) propyloxy)benzenesulfonyl))-indolizine), on isovolumic perfused rat heart have been assessed by using 31P nuclear magnetic resonance (NMR) spectroscopy together with simultaneous monitoring of myocardial mechanical function. Cytosolic pH and phosphocreatine, adenosine triphosphate and inorganic phosphate contents were monitored by using 31P NMR. Heart rate, coronary flow and left ventricular developed pressure were measured routinely to assess mechanical function. Perfusion with 10 nM, 100 nM or 1 microM fantofarone for a period of 48 min did not cause any measurable metabolic changes. However, coronary vasodilatation and a partial positive inotropic effect were noted. A 15-min pretreatment with 100 nM did not protect against the deleterious effects of an 18-min period of normothermic, zero-flow ischemia. In contrast, a 20-min pretreatment period with 1 microM fantofarone significantly improved the recovery of mechanical performance, metabolic activity and pH after the same 18 min of ischemia. While only a slight protection of the ATP pool was noted during the ischemic period, major beneficial effects were observed during the reperfusion period, such that reflow was characterized by high recoveries of left ventricular pressure and rate pressure product (70-80%), low end diastolic pressure (< 10 mm Hg), significant recovery of ATP content (to 55%), a complete repletion of the phosphocreatine pool and a fast return of cytosolic pH to normal value.
Vander Elst
L
L
University of Mons Hainaut, NMR Laboratory, Faculty of Medicine, Mons, Belgium.
Chatelain
P
P
Manning
A S
AS
Laruel
R
R
Van Haverbeke
Y
Y
Muller
R N
RN
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects; D003600:Cytosol; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology* / Q000627:therapeutic use; D007424:Intracellular Fluid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D010725:Phosphocreatine / Q000494:pharmacology; D010758:Phosphorus; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects
D002121:Calcium Channel Blockers; D007212:Indolizines; D010627:Phenethylamines; D010725:Phosphocreatine; D010758:Phosphorus; D000255:Adenosine Triphosphate; C059901:fantofarone