Role of protein kinase C in central muscarinic inhibitory mechanisms regulating voiding in rats.
To evaluate the role of protein kinase C in central muscarinic mechanisms regulating voiding, cystometry was performed in conscious rats. Oxotremorine methiodide, a muscarinic agonist was injected i.c.v. in a dose (0.1 microg/rat) shown previously to alter voiding function. Oxotremorine methiodide was also tested after i.c.v. injection of chelerythrine chloride (a protein kinase C inhibitor, 2 microg/rat) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, a protein kinase inhibitor, 5 nmol/rat). In untreated rats, oxotremorine methiodide elicited a bimodal response consisting of an initial increase in bladder capacity, maximal voiding pressure, pressure threshold and post voiding intravesical pressure, but reduced voiding efficiency and bladder compliance. The second response consisted of a decrease in bladder capacity and bladder compliance, increases in maximal voiding pressure and post voiding intravesical pressure, but no change in pressure threshold or voiding efficiency. However, approximately 20 min after pre-treatment with chelerythrine chloride or H-7 in doses that did not alter voiding function, oxotremorine methiodide decreased bladder capacity, increased maximal voiding pressure, but did not change pressure threshold or voiding efficiency. These results indicate that inhibitory and facilitatory muscarinic mechanisms in the brain that control voiding function involve different second messenger systems. Inhibitory mechanisms which are blocked by chelerythrine chloride or H-7 must involve protein kinase C and normally be inactive because the protein kinase inhibitors alone did not alter voiding. On the other hand, facilitatory muscarinic mechanisms which previous studies showed were tonically active are not mediated by chelerythrine chloride or H-7 sensitive signaling pathways.
Nakamura
Y
Y
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. uroyasuo@yu.incl.ne.jp
Ishiura
Y
Y
Yokoyama
O
O
Namiki
M
M
De Groat
W C
WC
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007276:Injections, Intraventricular; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010095:Oxotremorine / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014554:Urination / Q000187:drug effects / Q000502:physiology*
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D010617:Phenanthridines; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C016299:chelerythrine; D011493:Protein Kinase C