Cardiovascular effects elicited by milonine, a new 8,14-dihydromorphinandienone alkaloid.
The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N(w) -nitro-L-arginine methyl esther (L-NAME; 20 mg/kg, i.v.). In phenylephrine (10 μM), pre-contracted mesenteric artery rings, milonine (10⁻¹⁰ M to 3 × 10⁻⁴ M) caused a concentration-dependent relaxation (EC₅₀ = 1.1 × 10⁻⁶ M, E(max) = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC₅₀ = 1.6 × 10⁻⁵, p < 0.001), or after L-NAME 100 μM (EC₅₀ = 6.2 × 10⁻⁵, p < 0.001), hydroxocobalamin 30 μM (EC₅₀ = 1.1 × 10⁻⁴, p < 0.001) or ODQ 10 μM (EC₅₀ = 1.9 × 10⁻⁴ p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO₃⁻ levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K(+) (EC₅₀ = 1.2 × 10⁻⁵, p < 0.001), or different potassium channel blockers such as glibenclamide (10 μM) (EC₅₀ = 6.3 × 10⁻⁵, p < 0.001), TEA (1 mM) (EC₅₀ = 2.3 × 10⁻⁵ M, n = 6) or Charybdotoxin (0.2 μM) plus apamin (0.2 μM) (EC₅₀ = 3.9 × 10⁻⁴ M, n = 7). In addition, pre-contraction with high extracellular potassium concentration prevented milonine-induced vasorelaxation (EC₅₀ = 1.0 × 10⁻⁴, p < 0.001). Milonine also reduced CaCl₂ -induced contraction in Ca²(+) -free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide-cGMP pathway and opening of K(+) channels.
Cavalcante
Horacinna M M
HM
Federal University of Paraiba, João Pessoa, PB, Brazil.
Ribeiro
Thaís P
TP
Silva
Darízy F
DF
Nunes
Xirley P
XP
Barbosa-Filho
José M
JM
Diniz
Margareth F F M
MF
Correia
Nadja A
NA
Braga
Valdir A
VA
Medeiros
Isac A
IA
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001030:Apamin / Q000494:pharmacology; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005905:Glyburide / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced*; D016014:Linear Models; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects*; D009019:Morphinans / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000378:metabolism; D011189:Potassium Chloride / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013610:Tachycardia / Q000139:chemically induced*; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
D000470:Alkaloids; D009019:Morphinans; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; C557713:milonine; D018999:Charybdotoxin; D001030:Apamin; D009569:Nitric Oxide; D011189:Potassium Chloride; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester