Characterization of muscarinic receptors mediating the contraction of the urinary detrusor muscle in cynomolgus monkeys and guinea pigs.
We have characterized in vitro the muscarinic receptors mediating the contraction of the detrusor muscle in Cynomolgus monkeys and guinea pigs using carbachol as the agonist and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M3-selective), methoctramine (M2-selective) and pirenzepine (M1-selective) as the antagonists. Carbachol induced a concentration-dependent contraction of the detrusor muscle of monkey and guinea pig yielding similar pD2 values of 6.67+/-0.03 (n=50) and 6.77+/-0.06 (n=36), respectively. In the detrusor muscle of Cynomolgus monkey, all antagonists produced a concentration-dependent inhibition of carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded slopes not different from unity for all antagonists. The order of antagonist potency was: 4-DAMP (pA2=8.96)>pirenzepine (pA2=6.66)>methoctramine (pA2=6.03), suggesting that M3 receptors have a dominant role in mediating detrusor contraction. In the detrusor muscle of the guinea pig, 4-DAMP and pirenzepine, but not methoctramine, produced a concentration-dependent inhibition of the carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded a slope not different from unity for 4-DAMP and pirenzepine. 4-DAMP (pA2=9.07) had a higher potency than pirenzepine (pA2=6.66), a finding consistent with previously published data. The present study shows that in Cynomolgus monkey stimulation of the M3 subtype is dominant in mediating detrusor contraction upon carbachol stimulation.
Lai
F M
FM
Cardiovascular/Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.
Cobuzzi
A
A
Spinelli
W
W
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D008252:Macaca fascicularis; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*
D003959:Diamines; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; C054938:methoctramine