M1 muscarinic receptor‐induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C.

Abstract

NA release. 5. The PKC inhibitor H-7 (50-100 /M) inhibited the CS-or eserine-facilitated release of both ACh and NA, but did not affect the non-facilitated release evoked by IS. H-7 also inhibited 05 AuM PDB-induced facilitation of ACh release but not NA release. 6. Down-regulating PKC by pretreatment for 30 min with 5/tM PDB decreased the facilitated release of ACh and the eserine-induced facilitation of NA release. 7. Electrically evoked contractions of the bladder strips exhibited a biphasic response to PDB (2-5 /M), which consisted of an initial enhancement of the peak amplitude and area followed after 20 min by an inhibition of contractions. H-7 inhibited the electrically evoked contractions in a dose-dependent fashion. 8. It is concluded that a phospholipase C-PKC signal transduction pathway is essential for muscarinic receptor-induced facilitation of ACh and NA release but is not involved in the non-facilitated release of transmitters in the rat urinary bladder.

Neural Control of the Lower Urinary Tract

“…Activation of PKC by phorbol dibutyrate elicits a concentration dependent increase in ACh release, and the PKC blocker, H-7, suppresses the facilitation of ACh release induced by continuous stimulation. H-7 does not block non-facilitated release of ACh during intermittent stimulation indicating that the PKC system only participates in transmitter release under facilitatory conditions (582). Nifedipine significantly reduces facilitated release but not non-facilitated release indicating a role for L type Ca 2+ channels in muscarinic receptor mediated facilitation.…”

“…High frequency (10 Hz) continuous stimulation enhances norepinephrine release from noradrenergic terminals (582). This effect is blocked by an M1 muscarinic receptor antagonist (pirenzepine) indicating that heterosynaptic cholinergic facilitation can modulate adrenergic transmission.…”

“…Various evidence indicates that the phosphatidylinositolprotein kinase C (PKC) cascade which is known to be a signal transduction pathway linked to M1 muscarinic receptors (627) is involved in the prejunctional facilitation in the rat bladder (582). Activation of PKC by phorbol dibutyrate elicits a concentration dependent increase in ACh release, and the PKC blocker, H-7, suppresses the facilitation of ACh release induced by continuous stimulation.…”

“…ACh release in rat urinary bladder strips is influenced by various stimulation parameters including frequency, pattern, and number of stimuli (108,232,580,582,641,642). During intermittent field stimulation (IS), consisting of short trains (10 shocks) separated by 5 s quiescent periods, the duration of stimulation (5-360 shocks) had little effect on the total ACh output (nonfacilitatory stimulation).…”

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

“…Acetylcholine also stimulates prejunctional M 1 muscarinic receptors on post-ganglionic parasympathetic nerve terminals to facilitate its own release, and thereby amplify excitatory input to the detrusor. 64 In overactive bladders, there is increased coupling of the smooth muscle bundles of the detrusor, which leads to greater nerve excitability in response to low-grade efferent stimuli. 65 Bladder strips from animals with spinal cord injuries show an upregulation of presynaptic muscarinic facilitatory mechanisms in cholinergic nerve terminals.…”