Potent inhibition of thermal edema in rat by des-Tyr-Dynorphin A.
In an earlier study, dynorphin A(1-13) [Dyn A(1-13)] was shown to inhibit heat-induced edema in the anesthetized rat's paw but the potency of this action was low, with effective doses in the range of 3-4 mg/kg i.v. In this study, Dyn A and related fragments were tested. Thermal edema was elicited in anesthetized male albino rats by immersion of the hindpaw in 58 degrees C water for 1 min. The median effective dose (ED50 and 95% confidence limits) in mg/kg i.v. for inhibition of edema were: Dyn A, Dyn A(2-17), and Dyn A(1-13), 1.7 (1.2-2.4), 0.15 (0.09-0.24), and 3.2 (1.9-5.5), respectively. The ED50 values of [D-Ala2]Dyn A, [D-Ala2]Dyn A(2-17), and [D-Ala2]Dyn A(2-17)-amide were found to be 0.92 (0.40-2.10), 1.25 (0.60-2.63), and 0.65 (0.36-1.16) mg/kg i.v., respectively. Dyn A(2-17), 0.5 mg/kg i.v., also inhibited pulmonary edema produced by i.v. injection of epinephrine. The anti-edema action of Dyn A(2-17) was not blocked by naloxone, an opioid receptor antagonist, or dependent on the hypotensive action of this peptide. It is postulated that the antiedema activity of Dyn A resides in the core fragment Dyn A(6-12). Two peptides, N-acetyl-Dyn A(6-12)-amide and N-acetyl-[D-Leu12]Dyn A(6-12)-amide, were synthesized and, when tested, were effective in reducing thermal edema with ED50 values of 1.4 (0.6-3.7) and 2.2 (1.2-4.1) mg/kg i.v., respectively.
Thomas
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School of Public Health, University of California, Berkeley 94720, USA.
Wei
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D000595:Amino Acid Sequence; D000818:Animals; D004399:Dynorphins / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy* / Q000209:etiology; D006614:Hindlimb; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010446:Peptide Fragments; C095267:dynorphin A (6-12); D004399:Dynorphins; C082245:dynorphin (2-17)