title: Differential effects of pinacidil and levcromakalim on the contractions elicited electrically or by noradrenaline in the portal vein of the rabbit.
abstract: The present study was undertaken to examine the antivasoconstrictor effects of pinacidil and levcromakalim, two potassium channel openers (PCOs), on the isolated rabbit portal vein and to define the role for different subtypes of pre- and/or post-synaptic K+ channels in the antivasoconstrictor action of the PCOs. The vein strips were contracted by electrical field stimulation (EFS) or by exogenous noradrenaline (NA). The results of this study showed that pinacidil produced a more potent inhibition of the neurogenic contractions (pD2 = 6.04 +/- 0.05) than of contractions induced by exogenous NA (pD2 = 4.90 +/- 0.10). Glibenclamide (1 microM), a selective blocker of adenosine triphosphate (ATP)-sensitive K+ channels (K(ATP)), did not affect the pinacidil-induced inhibition of contractions evoked by exogenous NA. In contrast, glibenclamide (0.1-10 microM) significantly antagonized the effect of pinacidil on EFS evoked contractions in a noncompetitive manner. There was no difference between the inhibitory effects of levcromakalim on neurogenic contractions (pD2 = 7.58 +/- 0.05) and contractions evoked by exogenous NA (pD2 = 7.64 +/- 0.08). Glibenclamide (1 microM) antagonized in the same manner the levcromakalim-induced inhibition of neurogenic contractions and contractions evoked by exogenous NA. Moreover, glibenclamide competitively antagonized the effect of levcromakalim on EFS induced contractions of the rabbit portal vein (pA2 = 6.40 +/- 0.10). Charybdotoxin (0.4 microM) and apamin (0.1 microM) did not influence the inhibitory effects of pinacidil and levcromakalim, both on contractions evoked by EFS and contractions evoked by exogenous NA. These results suggest that the antivasoconstrictor effect of levcromakalim might be postsynaptic and associated with opening of the smooth muscle K(ATP) channels. In contrast, it is hypothesized that the effect of pinacidil on neurogenic contractions is due to an interference with K(ATP) channels in the neuromuscular synapse. It seems that the action of pinacidil on the NA contractions is mediated by another still undefined mechanisms of pinacidil.
authors.affiliation: Department of Clinical Pharmacology, Pharmacology and Toxicology, Medical Faculty, Belgrade, Yugoslavia.
authors.forename: L
authors.initials: L
authors.lastname: Gojković-Bukarica
authors.forename: T
authors.initials: T
authors.lastname: Kazić
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D020110:Pinacidil / Q000494:pharmacology*; D011169:Portal Vein / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects; D011817:Rabbits; D013779:Tetrodotoxin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019806:Cromakalim; D018999:Charybdotoxin; D001030:Apamin; D013779:Tetrodotoxin; D020110:Pinacidil; D005905:Glyburide; D009638:Norepinephrine