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Simultaneous 31 P nuclear magnetic resonance spectroscopy and mechanical function in working heart models affected by drugs
Author(s) -
Cohen Sheila M.,
Werrmann Jeffrey G.,
King Brian W.
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430180406
Subject(s) - phosphocreatine , ischemia , enalapril , inotrope , medicine , chemistry , high energy phosphate , endocrinology , intracellular ph , intracellular , energy metabolism , angiotensin converting enzyme , biochemistry , blood pressure
A working heart model was designed which enabled simultaneous measurement of the physiological function of the heart and the levels of high‐energy phosphates and inorganic phosphate, as well as intracellular pH, by high‐resolution 31 P NMR spectroscopy. Careful control of conditions, such as temperature and metallic ions, produced rabbit heart preparations that had stable work output, heart rate, and ATP levels for more than 7 hr. Rat hearts were stable for at least 3 hr. As an example of the utility of the model, the effect of ischemia and two drugs were studied. Global ischemia of a rabbit heart at 36.2°C resulted in almost complete loss of phosphocreatine (PCr) wth 7 min and slower loss of ATP, which reached a plateau at 40% of its initial concentration with 12 min. ntracellular pH fell form 7.01 to 6.03 during 21 min of ischemia. Post‐ischemia, the heart's power output and ATP concentration both returned to about 70% of pre‐ischemia levels, whereas PCr overshot its initial value by 33%. BRL 34915, a K + channel activator, produced an age‐ and species‐dependent negative inotropic effect in non‐ischemic hearts, with only minor changes in ATP, PCr or pH. In hearts obtained from rats pretreated for 2 days with enalapril, an inhibitor of the angiotensin‐converting enzyme, post‐ischemia power output returned to 74 ± 7% of preischemia levels, compared with 33 ± 11% in hearts from sham‐treated rats (N = 6). Enalapril also lessened the decline of ATP during 20 min of global ischemia and enhanced the recovery of ATP in post‐ischemic hearts (both about 30% greater than control). 31 P NMR of working heart preparations enable the effect of drugs and/or ischemia on intracellular energy levels to be determined concurrently with function of the heart. A reproducible method in inducing global ischemia in working hearts facilitates the study of drug effects on functional and metabolic recovery.