Inhibitory effects of dynorphin-A on norepinephrine uptake by cardiac synaptosomal-mitochondrial fractions.
The effect of dynorphin A-(1-13) (Dyn A-(1-13)) on [3H]norepinephrine ([3H]NE) uptake was examined in cardiac synaptosomal-mitochondrial fractions of control rats (Wistar, WR; Wistar-Kyoto, WKY) and spontaneously hypertensive rats (SHR). In adult WR, Dyn A-(1-13) caused naloxone-insensitive dose-dependent inhibition of [3H]NE uptake with an IC50 of 4.0 microM. The nonopioid Dyn A fragments Dyn A-(2-13) and Dyn A-(6-10) displayed 89 and 11% of the potency of Dyn A-(1-13), respectively, whereas Dyn A-(1-8), Leu-enkephalin, and the selective opioid agonists [D-Ala2, N-MePhe4, Glyol5]enkephalin (DAGO, mu), [D-Ser2, Thr6]Leu-enkephalin (DSLET, delta), and U-50488H (kappa) were inactive. The relative potency of various analogues and fragments of Dyn A in inhibiting [3H]NE uptake correlated well (r = 0.96) with their potency in inhibiting binding of [3H]Dyn A-(1-13) to nonopioid sites on cardiac membrane preparations. Dyn A-(1-13) showed the same potency in inhibiting [3H]NE uptake in prehypertensive (4-week-old) SHR as in age-matched WR and WKY. However, at ages 8 and 16 weeks Dyn A-(1-13) was twice as potent in SHR as in WR and WKY. The increased inhibitory potency of Dyn A-(1-13) in 8-week-old SHR was accompanied by a 1.3-fold increase in number of cardiac nonopioid [3H]Dyn A-(1-13) binding sites. Dyn A and related peptides inhibit [3H]NE uptake by cardiac synaptosomes by a nonopioid mechanism. The possible involvement of such a mechanism in development of hypertension in SHR is discussed.
Dumont
M
M
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Lemaire
S
S
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D018847:Opioid Peptides / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D018847:Opioid Peptides; D009270:Naloxone; D004399:Dynorphins; D009638:Norepinephrine