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L Noronha-Blob, V Lowe, A Patton, B Canning, D Costello and WJ Kinnier
Nova Pharmaceutical Corporation, Baltimore, Maryland.
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 less than .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 greater than .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 less than .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.(ABSTRACT TRUNCATED AT 250 WORDS)
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