Cross tolerance between cromakalim and RP49356 in the uterus of the rat in vivo and in vitro.
We investigated tolerance to the potassium (K+) channel openers, cromakalim and RP49356 and cross tolerance between them in the uterus of the rat. Continuous infusion of RP49356 in vivo produced 5.2-fold (200 or 300 micrograms/kg per h) and 7.2-fold (600 micrograms/kg per h) desensitization of the uterus to RP49356. Uterine sensitivity to RP49356 was reduced 7.4-fold in cromakalim-tolerant rats and sensitivity to cromakalim was reduced 7.9-fold in RP49356-tolerant rats. Incubation of isolated uterus with 10 microM cromakalim for 4 h reduced uterine sensitivity to cromakalim by about 45-fold and to RP49356 by 2.1-fold but did not alter sensitivity to salbutamol. Incubation with 10 microM RP49356 for 4 h reduced sensitivity to RP49356 by 2.5-fold and to cromakalim by 3.8-fold. Occurrence of uterine tolerance to K+ channel openers in vitro suggests that tolerance in vivo has a pharmacodynamic basis. Cross tolerance between cromakalim and RP49356 provides evidence that these two K+ channel openers possess common binding sites and/or mechanism(s) of action. However, the greater extent of self-tolerance to cromakalim than to RP49356 suggests a difference in their actions.
Piper
I
I
Department of Physiological Sciences, University of Manchester, UK.
Downing
S J
SJ
Hollingsworth
M
M
D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D019806:Cromakalim; D004361:Drug Tolerance; D005260:Female; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D010847:Picolines / Q000008:administration & dosage / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects*
D001578:Benzopyrans; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D019806:Cromakalim; C061043:aprikalim