Effects of Ro 5-4864 and PK 11195 in rat duodenum and vas deferens.
Ro 5-4864 and PK 11195 inhibit in a concentration-dependent manner carbachol-induced contractions in rat duodenum (IC50: 1.56 +/- 0.07 x 10(-5) M and 1.18 +/- 0.07 x 10(-5) M respectively). The antagonism is non-competitive and is not mediated by peripheral-type benzodiazepine receptors. The Ro 5-4864 effect is modulated by the calcium concentration of the Tyrode-Ringer solution. In the presence of 1 mM NaF/10 microM AlCl3, Ro 5-4864 and PK 11195 do not inhibit carbachol-induced contractions. Moreover, Ro 5-4864 and PK 11195 significantly relax AlF(4-)-induced contractions, with IC50 values of 2.01 +/- 0.12 x 10(-5) M and 1.28 +/- 0.11 x 10(-5) M respectively. This effect is also modulated by the calcium concentration of the medium. Pertussis toxin potentiates the antagonist effects of Ro 5-4864 and PK 11195 on carbachol-induced contractions, but cholera toxin does not affect them. Ro 5-4864 and PK 11195 inhibit 45Ca2+ uptake induced by KCl (120 mM) in rat vas deferens, but do not affect either basal 45Ca efflux or noradrenaline-induced 45Ca2+ efflux. Only high doses of PK 11195 (above 5 x 10(-5) M) are able to produce a slight reduction of the accumulation of inositol phosphates induced by methoxamine in rat vas deferens, while Ro 5-4864 has no significant effect. Finally, Ro 5-4864 and PK 11195 reduce calcium influx, but do not seem to be the only mechanism of the antagonistic effect on carbachol-induced contractions. An alteration of other second messengers, probably cyclic monophosphate nucleotides, may be involved.
Escubedo
E
E
Laboratory of Pharmacology and Pharmacognosy, Faculty of Pharmacy, University of Barcelona, Spain.
Pallas
M
M
Nuñez
C
C
Camarasa
J
J
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012969:Sodium Fluoride / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001570:Benzodiazepinones; D007546:Isoquinolines; D010716:Phosphatidylinositols; D010566:Virulence Factors, Bordetella; C028513:4'-chlorodiazepam; D002217:Carbachol; D012969:Sodium Fluoride; D002772:Cholera Toxin; D037342:Pertussis Toxin; D002118:Calcium; C037850:PK 11195