cyclic-gmp and nafamostat

The negative charges of dextran sulfate (DS) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by the production of bradykinin. This study was undertaken to see whether cyclic nucleotide plasma levels are affected by DS LDL apheresis. Previously, we showed the rise in plasma levels of prostaglandins and nitric oxide derivatives accompanied by the rise in bradykinin levels. The physiologic effects of prostaglandins and nitric oxide become manifest through the intracellular signal of cyclic nucleotides. The plasma levels of the cyclic nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. The plasma levels of cAMP during LDL apheresis using heparin were 9.2 +/- 0.3 (mean +/- SE) 12.4 +/- 0.6, 12.0 +/- 0.5, and 12.1 +/- 0.3 pmol/ml, respectively, at the 0, 1,000, 2,000, and 3,000 ml stages. The rise in cAMP levels was suppressed during apheresis using NM. There were no significant increases in cGMP during apheresis with heparin or with NM. There were significant negative correlations between changes in cAMP and those in the blood pressure. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects via activation of the adenylate cyclase dependent pathway.

Topics: Adrenomedullin; Anticoagulants; Benzamidines; Blood Component Removal; Bradykinin; Cyclic AMP; Cyclic GMP; Dextran Sulfate; Guanidines; Heparin; Humans; Hypercholesterolemia; Lipoproteins, LDL; Male; Middle Aged; Nitric Oxide; Nucleotides, Cyclic; Peptides; Prostaglandins

The negative charges of dextran-sulfate (DS) used for low-density-lipoprotein (LDL) apheresis initiate the intrinsic coagulation pathway in which plasma kallikrein acts on the high-molecular-weight kininogen to produce large amounts of bradykinin. This study was undertaken to assess whether bradykinin generated during DS LDL apheresis has any physiologic effects in vivo. The plasma levels of bradykinin, prostaglandins and cyclic guanosine monophosphate (cGMP) were compared. when either of two anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the plasma levels of prostaglandin E2 (PGE2) increased significantly (5.6 +/- 1.2 (mean +/- SE, n = 4) pg/ml before apheresis and 33.4 +/- 13.2 after apheresis, p < 0.05) in association with an increase in bradykinin levels (17.9 +/- 2.6 pg/ml before apheresis and 470 +/- 135 after apheresis, p < 0.01). Interestingly, these changes were suppressed during apheresis using NM. There were no appreciable changes in cGMP during DS LDL apheresis with either of the anticoagulants. This finding suggests that bradykinin generated during apheresis has some pathophysiological effects via activation of the prostaglandin system. Our results support the view that in patients taking angiotensin-converting-enzyme inhibitors, the anaphylactoid reaction occurring during apheresis may be caused by an excessive rise in the bradykinin levels.

Topics: 6-Ketoprostaglandin F1 alpha; Anticoagulants; Benzamidines; Blood Component Removal; Bradykinin; Cyclic GMP; Dextran Sulfate; Dinoprostone; Factor XII; Guanidines; Heparin; Humans; Hyperlipoproteinemia Type II; Kallikreins; Kininogens; Lipoproteins, LDL; Male; Middle Aged; Prekallikrein

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.

Topics: Adenine Nucleotides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamidines; Cardioplegic Solutions; Cyclic AMP; Cyclic GMP; Dogs; Energy Metabolism; Guanidines; Heart; Heart Transplantation; Hypothermia, Induced; Lysosomes; Myocardium; Organ Preservation; Phosphocreatine; Protease Inhibitors; Ventricular Function, Left