[N-methyl-Tyr1,N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8)ethylamide, a stable dynorphin analog, produces diuresis by kappa-opiate receptor activation in the rat.
The i.v. administration of E-2078 ([N-methyl-Tyr1-N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8) ethylamide) to conscious animals in doses of 15, 50 or 200 micrograms/rat caused a dose-related diuretic response associated with a significant in crease in glomerular filtration rate (GFR) and in blood pressure. The overall excretion of Na+ was not modified by the opioid, whereas it reduced K+ output and its fractional excretion. Time course studies demonstrated that the increase in GFR and in blood pressure were transient and did not parallel the changes in urine outflow. Pretreatment of the animal with 1 mg/kg of naltrexone or of naloxone reduced the pressor response but did not reduce the renal action of E-2078. Doses of naltrexone 10 times larger (10 mg/kg) were required to attenuate the diuretic effect and abolish completely the changes in K+ excretion; however, the increase in GFR was not antagonized by 10 mg/kg of naltrexone. Consonant with the studies in conscious rats, perfusion of isolated rat kidneys with 0.2 to 1.8 microM E-2078 increased urine flow in a dose-dependent manner, and this effect was prevented by the simultaneous perfusion of 2 microM naltrexone with the peptide. In pentobarbital-anesthetized animals, E-2078 elicited a diuretic response that was not parallelled by changes in GFR or electrolyte excretion. In addition, E-2078 caused a long lasting decrease in blood pressure which was blocked completely by pretreatment of the animal with 1 mg/kg of naltrexone. The diuretic effect of E-2078 was not modified by pretreatment of the animals with beta-funaltrexamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Salas
S P
SP
Department of Endocrinology, Faculty of Medicine, Catholic University of Chile, Santiago.
Roblero
J S
JS
López
L F
LF
Tachibana
S
S
Huidobro-Toro
J P
JP
D000818:Animals; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000494:pharmacology*; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa
D004232:Diuretics; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C061285:E 2078; D004399:Dynorphins