Effects of the spin trap alpha-phenyl N-tert-butyl nitrone on myocardial function and flow: a dose-response study in the open-chest dog and in the isolated rat heart.
Alpha-phenyl N-tert-butyl nitrone (PBN) is widely used in spin-trapping experiments, but its possible toxicity has not been systematically evaluated. The purpose of this study was to investigate the effects of different doses of PBN on cardiac function in vivo (open-chest dogs) and in vitro (isolated rat hearts). In open-chest dogs, PBN was infused intracoronarily to achieve coronary arterial concentrations ranging from 1.6 mM to 10.0 mM. At coronary arterial concentrations of 1.6 mM and 2.5 mM, PBN had no appreciable effect on regional myocardial function (assessed as systolic wall thickening). However, coronary arterial concentrations of PBN of 5.0 mM and 10.0 mM produced a marked reduction and, eventually, a complete loss of systolic wall thickening (53% of baseline values after 30 min at 5.0 mM and 14% after 30 min at 10.0 mM). Furthermore, PBN increased coronary blood flow by approximately 25% at 2.5 mM and by > 100% at 10.0 mM. In isolated rat hearts, perfusion with 2.5 and 5.0 mM PBN for 60 min did not significantly affect global myocardial function, assessed as developed pressure, rate-pressure product, and positive and negative dP/dt. At the 10.0 mM concentration, however, these variables were significantly decreased after 30 min (developed pressure: -77% vs. controls; rate-pressure product: -84%; +dP/dt: -60%; -dP/dt: -70%); two out of five hearts stopped beating within 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Li
X Y
XY
Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
Sun
J Z
JZ
Bradamante
S
S
Piccinini
F
F
Bolli
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003497:Cyclic N-Oxides; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000633:toxicity*; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D013113:Spin Labels; D010725:Phosphocreatine; C029217:phenyl-N-tert-butylnitrone; D000255:Adenosine Triphosphate