Mechanisms involved in the vasorelaxant effect of (-)-stepholidine in rat mesenteric small arteries.
The purpose of the present investigation was to clarify whether the hypotensive action of the protoberberine alkaloid, and dopamine receptor antagonist, (-)-stepholidine, can be ascribed to an effect on peripheral small arteries. For this purpose isolated mesenteric small arteries were suspended in microvascular myographs for isometric tension recording. Relaxations mediated by dopamine D1 receptors were antagonized by (-)-stepholidine. (-)-Stepholidine inhibited in a concentration-dependent manner the contractile responses evoked by noradrenaline (10(-6) M), but not the contractile responses evoked by depolarizing solution (KCl, 60 mM) or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F2alpha (U46619, 10(-7) M). Mechanical endothelial cell removal, blockade of K+ channels, muscarinic receptors or adrenoceptors did not influence the inhibitory effect of (-)-stepholidine on the contractile response evoked with noradrenaline in the segments. (-)-Stepholidine caused rightward shifts of the concentration-response curves for noradrenaline and phenylephrine. The pA2 values for (-)-stepholidine were 6.05 and 5.94 against noradrenaline and phenylephrine, respectively. Electrical field stimulation induced prazosin-sensitive frequency-dependent contractions in mesenteric small arteries. These contractions were significantly inhibited by 10(-6) and 10(-5) M (-)-stepholidine. In membranes from the rat cerebral cortex labelled with [3H]prazosin, (-)-stepholidine (10(-7)-10(-4) M) completely inhibited the specific binding of the ligand with a pKi of 5.6. The present investigation suggests the inhibitory effect of (-)-stepholidine on the alpha1-adrenoceptor-mediated contractions induced by exogenously added and nerve-released noradrenaline in peripheral small arteries might contribute to a hypotensive effect of the drug.
Lei
S
S
Department of Pharmacology, University of Aarhus, Denmark.
Orensanz
L M
LM
Mulvany
M J
MJ
Simonsen
U
U
D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D012701:Serotonin / Q000502:physiology