The effect and pharmacokinetics of nafamostat mesilate adjunct to cold nondepolarizing cardioplegia in a canine model of cardiac preservation.
We examined the effects of nafamostat mesilate (NM) on myocardial, biochemical, and functional changes in canine hearts. An isolated heart was preserved for 6 h at 5 degrees C and then reperfused for 2 h at 37 degrees C. NM wa added to the cardioplegic solution. At concentrations of both 10(-7) M (n = 8) and 10(-6) M (n = 6), NM was able to maintain myocardial cyclic adenosine monophosphate (cAMP) at a normal level and to reduce guanosine monophosphate (cGMP) concentrations at the end of both preservation and reperfusion. The serum N-acetyl-b-D-glucosaminidase (NAG) concentration during reperfusion was lower in hearts treated with NM 10(-6) or 10(-7) M than in those without NM (P < 0.05). Although NM failed to preserve myocardial concentrations of adenine nucleotide compounds, NM 10(-7) M maintained the +/- dp/dt of the left ventricle after reperfusion at the same level as in the nonischemic control group and better than NM 10(-6) M or no NM (P < 0.05). Myocardial uptake of NM 10(-5) M (higher concentration) was 55% +/- 8% (6-h preservation) and 29% +/- 15% (2-h reperfusion). We conclude that NM 10(-7) M adjunct to non-depolarizing solution does not preserve myocardial adenine nucleotide concentrations but does facilitate the recovery of left ventricular function. NM 10(-5) M (higher concentration) seems to have a high affinity for the myocardium and may depress the recovery of left ventricular function.
Sunamori
M
M
Department of Thoracic-Cardiovascular Surgery, Tokyo Medical and Dental University, School of Medicine, Japan.
Yoshida
T
T
Miyamoto
H
H
Wang
Y
Y
Suzuki
A
A
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001550:Benzamidines; D002314:Cardioplegic Solutions / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004734:Energy Metabolism; D006146:Guanidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation; D007036:Hypothermia, Induced; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism; D009926:Organ Preservation / Q000379:methods*; D010725:Phosphocreatine / Q000378:metabolism; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
D000227:Adenine Nucleotides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D002314:Cardioplegic Solutions; D006146:Guanidines; D011480:Protease Inhibitors; D010725:Phosphocreatine; D000242:Cyclic AMP; D006152:Cyclic GMP; C032855:nafamostat