Muscarinic Receptor Stimulation of Phosphoinositide Hydrolysis in the Human Isolated Urinary Bladder

Abstract

The stimulatory action of carbachol and acetylcholine (ACh) on phosphoinositide turnover, as well as their contractile effects, were investigated in human isolated detrusor muscle. Carbachol, and ACh in combination with 10(-7) M physostigmine, induced increases in phosphoinositide turnover. However, at all the concentrations tested, carbachol was more effective than ACh (plus physostigmine), and at the highest concentration used (10(-4) M), the difference was significant (p less than 0.05). Also in a Ca(2+)-free medium containing the chelator EGTA (10(-4) M), both agonists (10(-4) M) induced small but distinct increases in phosphoinositide breakdown. Carbachol and ACh contracted the detrusor preparations concentration-dependently, and the responses were almost identical when ACh was combined with 10(-7) M physostigmine. In Ca(2+)-free medium the agonists elicited a moderate but concentration-dependent contractile response at high concentrations. The results show that muscarinic receptor agonists stimulate phosphoinositide turnover in the human bladder. Possibly, this effect is coupled to multiple muscarinic receptor subtypes. More studies are required to elucidate to what extent phosphoinositide breakdown participates in the contractile activation of this tissue.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…4) and to cause contraction through phosphoinositide hydrolysis (Andersson et al, 1991b;Harriss et al, 1995). In cat detrusor muscle, contraction induced by acetylcholine was found to be mediated via M 3 receptor-dependent activation of G q/11 and phospholipase C-␤ 1 and inositol tris phosphate (IP 3 )-dependent Ca 2ϩ release .…”

Rho-kinase and effects of Rho-kinase inhibition on the lower urinary tract

“…41 Stimulation of M 3 receptors has previously been considered to cause contraction through phosphoinositide hydrolysis. 42,43 However, Jezior et al 44 suggested that muscarinic receptor activation of detrusor muscle includes both non-selective cation channels and activation of Rho-kinase. Supporting a role of Rho-kinase in the regulation of rat detrusor contraction and tone, Wibberley et al 45 found that in the rat, Rho-kinase inhibitors (Y27632, HA-1077) inhibited contractions evoked by carbachol without affecting the contraction response to KCl.…”

Smooth Muscle Physiology

“…These results show that levcromakalim relaxes detrusor smooth muscle, possibly by hyperpolarizing the cell membrane by opening K+ (Iacovou et al 1990;Andersson et al 1991). A second intracellular system of Ca2+ mobilization involving Ca2+_ induced Ca2+ release (CICR) occurs in many smooth muscle cells.…”

“…Cultured bladder smooth muscle cells have been used to demonstrate agonist-induced Ca2+ mobilization directly (Chambers & Gillespie, 1994) and the ability of agonists to stimulate phosphoinositide turnover in human bladder has been reported (Andersson et al 1991 Strips of guinea-pig aorta were suspended in an organ bath and perfused (IP3 ml min') at 37°C with a physiological salt solution (PSS) containing (mM): 112 NaCl, 5 KCl, 1 MgCl2, 18 CaCl2, 5 Hepes, 0 5 KH2PO4, 0 5 NaH2PO4, 15 NaHCO3, 10 glucose and 0-02 Phenol Red, (pH 7 4, 95% 02 and 5% C02). Tension was measured isometrically, and muscle strips precontracted either with phenylephrine (PE; 3-6 /uM) or by raising extracellular K+ concentration by an equimolar replacement of NaCl for KCI.…”