Project Abstract |
The following is an abstract detailing only the 1st phase of the project:
We investigated whether activation of the M2 muscarinic receptor inhibits the relaxant effect of isoproterenol on contraction elicited by other receptors. The muscarinic agonist oxotremorine-M caused a weak contraction in urinary bladder from M3 knockout (KO) mice. When measured in the same tissue in the presence of isoproterenol and α,β-methylene-ATP, oxotremorine-M elicited a robust contractile response, but not in bladder from M2/M3 double KO mice. Similar results were observed when PGF2α was used as the non-muscarinic contractile agent, but not α-methyl-serotonin. The combination of isoproterenol and contractile agent (i.e. α,β-methylene-ATP, PGF2α or α-methyl-serotonin) had little effect because of their opposing actions on contraction. To address whether neuronally released acetylcholine acts on the M2 receptor to inhibit relaxation by isoproterenol, we investigated electrical field stimulation of mouse urinary bladder (0.2 Hz, 2 msec duration, 100 V) in the presence of physostigmine (70 nM). Isoproterenol was approximately 12-fold more potent at inhibiting field-stimulated contractions of urinary bladder from M2 KO mice compared to wild type. Our results show that neuronally released or exogenously applied muscarinic agonist can act on the M2 muscarinic receptor to oppose ß-adrenoceptor-mediated relaxation of the detrusor. Supported by the MSTP grant and NIH grant HL079166. |
