Influence of ovarian steroids on myometrial sensitivity and tolerance to relaxin in the rat in vivo: lack of cross-tolerance between relaxin, salbutamol and cromakalim.
The influence of oestradiol benzoate and progesterone on uterine sensitivity and development of tolerance to relaxin was investigated in bilaterally ovariectomized non-pregnant rats in vivo. Bolus doses of relaxin (2-20 micrograms/kg i.v.) produced rapid and reversible inhibition of uterine contractions in a dose-dependent manner. Treatment with oestradiol benzoate or oestradiol benzoate plus progesterone significantly increased uterine sensitivity to relaxin over 48 h by 2.4- to 8.5-fold. Tolerance to relaxin developed during continuous infusion of the hormone at 20 micrograms/kg per h for 40 h. A 7.8- to 17.4-fold reduction in sensitivity to relaxin was observed in relaxin-infused rats, whereas no change in sensitivity was observed in saline-infused rats. Infusion of relaxin at 50 micrograms/kg per h for 40 h produced a 131.8-fold reduction in uterine sensitivity to relaxin. The uterus remained tolerant to relaxin for up to 24 h after cessation of infusion. Treatment with oestradiol benzoate and/or progesterone did not influence the extent of tolerance development, but a more rapid recovery of uterine sensitivity to relaxin was observed in rats treated with oestradiol benzoate plus progesterone. Cross-tolerance with other uterine relaxant drugs was measured to investigate possible common mechanisms of action and sites of tolerance between relaxin and a beta-adrenoceptor agonist (salbutamol) and potassium channel openers (cromakalim and minoxidil sulphate). No cross-tolerance was observed between relaxin and salbutamol, or relaxin and cromakalim or minoxidil sulphate. Cross-tolerance between cromakalim and minoxidil sulphate was seen.
Downing
S J
SJ
Department of Physiological Sciences, University of Manchester, U.K.
Hollingsworth
M
M
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004361:Drug Tolerance; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D009215:Myometrium / Q000187:drug effects*; D010052:Ovariectomy; D010276:Parasympatholytics / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D012065:Relaxin / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*
D001578:Benzopyrans; D012739:Gonadal Steroid Hormones; D010276:Parasympatholytics; D011758:Pyrroles; D019806:Cromakalim; D011374:Progesterone; D004958:Estradiol; D012065:Relaxin; D000420:Albuterol