Pharmacological characterization of muscarinic receptors in the uterus of oestrogen-primed and pregnant rats.
1. Radioligand binding and contractility studies were undertaken to determine the subtype/s of muscarinic receptors present in uteri of oestrogen-treated and late pregnant rats. 2. Competition binding studies with uterine membrane preparations and [3H]-QNB (quinuclidinyl benzilate) provided negative log dissociation constants (pKi) for each antagonist as follows; oestrogen-treated - atropine (7.98) > or = himbacine (7.83) > methoctramine (7.52) > or = hexahydrosiladiphenidol (HHSiD; 7.32) > or = 5,11-dihydro- 11-[[[2-[2 - [(dipropylamino)methyl] - 1 piperidinyl]ethyl]amino] - carbonyl] - 6H-pyrido-[2,3-b][1,4]- benzodiazepin-6-one (AF-DX 384; 7.10)> 11 -[[2- [(diethylamino)methyl]-1-piperidinyl]-acetyl]5,11-dihydro-6H-pyridol+ ++]2,3,-b][1,4]benzodiazepin-6-one (AF-DX 116, 6.77)>pirenzepine (6.17); late pregnant atropine (8.05)> or =methoctramine (7.95)> or =himbacine (7.71)> or =HHSiD (7.52)> or =AF-DX 384 (7.34)>AF-DX 116 (6.72)>pirenzepine (6.18). 3. The potency of carbachol in causing uterine contraction was similar in preparations from pregnant and non-pregnant animals (pD2=5.57 and 5.46, respectively). Each muscarinic antagonist caused parallel, rightward shifts of carbachol concentration-response curves. The pA2 estimates were: oestrogen-treated - atropine (9.42)> himbacine (8.73) HHSiD (8.68) methoctramine (8.49)> or =AF-DX 384 (7.91)> or =AF-DX 116 (7.36)> or =pirenzepine (7.26); late pregnant atropine (9.48)>himbacine (8.37)> or = HHSiD (8.22) > or =methoctramine (8.01) > or =AF-DX 116 (7.73)> or = AF-DX 384 (7.44)> or = pirenzepine (6.92). 4. The relative pKi estimates for antagonists obtained in membrane preparations from oestrogen-treated rats suggest the presence of muscarinic M2 subtypes. In functional studies pA2 values indicated the additional presence of muscarinic M3 receptor or, possibly an atypical receptor subtype. The similarity between pKi and pA2 estimates obtained in uteri from oestrogen-treated and pregnant animals, respectively, indicates that pregnancy does not affect myometrial muscarinic receptors in the rat.
Munns
M
M
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Pennefather
J N
JN
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011813:Quinuclidinyl Benzilate; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects*
D004967:Estrogens; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate