Effects of [N-(L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (SCH32615), a neutral endopeptidase (enkephalinase) inhibitor, on levels of enkephalin, encrypted enkephalins and substance P in cerebrospinal fluid and plasma of primates.
In halothane-anesthetized and -ventilated cynomologus macaque monkeys, the effects of administering vehicle (n = 3) or the neutral endopeptidase inhibitor N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (16 mg/kg, n = 5; or 100 mg/kg, n = 3, intravenously) was examined. Cisternal CSF aliquots were examined by radioimmunoassay: 1) for Met enkephalin; 2) after trypsin and carboxypeptidase B treatment for encrypted enkephalin (X-ENK); 3) for substance P; and 4) for unmetabolized drug. Similar measures were carried out in femoral artery and femoral venous plasma, except that substance P was not assayed. In CSF, prior to drug, low, but measurable levels of enkephalin (61 pg/ml), X-ENK (285 pg/ml) and substance P (16 pg/ml) were observed. Vehicle-injected animals showed no change from baseline levels over a 4-hr sampling period in either plasma or CSF levels. In contrast, following 16 mg/kg, in CSF, there was a significant 9-fold increase in MET and 11-fold increase in X-ENK at 30 min. CSF-substance P levels rose also by a factor of 2, with the peak effect observed at 60 min. All levels displayed a significant reduction by 4 hr. There was no statistical difference between the maximum effects observed with either the 16- or 100-mg/kg dose. Plasma peptide levels of enkephalin and X-ENK were not altered by drug. CSF displayed significant drug levels by 30 min, which were between 0.1 and 1% of levels observed concurrently in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Yaksh
T L
TL
Department of Anesthesiology, University of California, San Diego, La Jolla 92093.
Sabbe
M B
MB
Lucas
D
D
Mjanger
E
E
Chipkin
R E
RE
D000818:Animals; D004151:Dipeptides / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D004562:Electrocardiography; D004569:Electroencephalography; D004744:Enkephalin, Methionine / Q000097:blood / Q000134:cerebrospinal fluid; D004745:Enkephalins / Q000097:blood / Q000134:cerebrospinal fluid*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011863:Radioimmunoassay; D013373:Substance P / Q000097:blood / Q000134:cerebrospinal fluid*
D004151:Dipeptides; D004745:Enkephalins; D013373:Substance P; D004744:Enkephalin, Methionine; C062344:SCH 32615; D015260:Neprilysin