The cardiovascular and renal effects of a highly potent mu-opioid receptor agonist, cyclo[N epsilon,N beta-carbonyl-D-Lys2,Dap5]enkephalinamide.

Investigation of the acute cardiovascular and renal effects of cyclo[Nepsilon,Nbeta-carbonyl-D-Lys2,Dap5]enkephalinamide (cUENK6), the most potent mu-opioid receptor agonist, revealed dose-related effects, but most pronounced during the first hour post i.v. injections. During first hour, cUENK6 (3 microg/rat) stimulated (P<0.001) excretion of urine (1.1+/-0.2 vs. 3.3+/-0.3 ml/h), sodium (60+/-10 vs. 124+/-12 microeq/h), potassium and cGMP (1.76+/-0.19 vs. 4.92+/-0.80 nmol/h). These effects were inhibited by naloxone (4 mg/kg i.v.), but not by naloxonazine (35 mg/kg s.c.), or 4 mg/kg i.v. naloxone methiodide. cUENK6 stimulated urinary atrial natriuretic peptide (ANP)-like activity (113+/-12 vs. 167+/-20 pg/h, P<0.02) and the effect was totally abolished by naloxone. cUENK6 also suppressed the transient stress-induced elevation in blood pressures and heart rate that occurred over the first 30-min post-injection, an effect attenuated by naloxone. Plasma ANP increased 2-h post-injection (123+/-11 vs. 192+/-21 pg/ml, P<0.005), and was associated with augmented ANP mRNA levels in right atria and left ventricles. Thus, cUENK6 evokes renal effects by enhancing activity of the renal natriuretic peptide system.