Muscarinic receptors: Relationships among phosphoinositide breakdown, adenylate cyclase inhibition, in vitro detrusor muscle contractions and in vivo cystometrogram studies in guinea pig bladder

L. Noronha-Blob, V. Lowe, A. Patton, B. Canning, D. Costello, W. J. Kinnier

Research output: Contribution to journalArticlepeer-review

Abstract

The relationships between activation of muscarinic receptors in guinea pig bladder measured as carbachol-stimulated inositol phosphate (IP) accumulation, oxotremorine-induced adenylate cyclase (AC) inhibition and bladder detrusor smooth muscle contraction determined in vitro as well as in vivo in the slow filling cystometrogram (CMG), were analyzed from the potencies of a number of muscarinic antagonists to block these responses. Significant positive linear correlations were found among the inhibitory potencies of 10 muscarinic antagonists to inhibit phosphoinositide (PI) turnover and both detrusor muscle contraction in vitro, as well as peak intravesical bladder pressure in vivo in the CMG (r = 0.8, P < .01). In contrast, there was no significant correlation between the potency of antagonists to block the AC inhibitory response and either in vitro or in vivo guinea pig bladder contractions (P > .05). Muscarinic agonists inhibited basal AC activity to a maximum of 20% in a GTP-dependent, Na+-sensitive manner and dose dependently stimulated both PI breakdown (3- to 4-fold) and isolated detrusor contractions. Again, a significant correlation (r = 0.9, P < .01) was calculated among the potencies of seven muscarinic agonists to elicit PI turnover and in vitro muscle contraction, whereas no significant correlation was observed between their potencies to inhibit AC activity and contractile responses in vitro. Collectively, the data suggest that IP accumulation and presumably IP-induced Ca++ release may function as the transducing mechanism for cholinergic contraction of the urinary bladder. Also, inasmuch as pirenzepine and AF-DX 116 were among the least potent inhibitors of PI stimulation, AC inhibition and detrusor muscle contraction both in vitro and in vivo in the CMG, it appears that M2 receptors distinct from the cardiac M2 subtype are involved in bladder function.

Original languageEnglish (US)
Pages (from-to)843-851
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume249
Issue number3
StatePublished - Jan 1 1989
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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