Effects of omega-conotoxin on adrenergic, cholinergic and NANC neurotransmission in the rabbit urethra and detrusor.
1. The effects of omega-conotoxin GVIA (an inhibitor of N-type voltage-operated calcium channels; VOCCs) were compared on adrenergic, cholinergic and non-adrenergic, non-cholinergic (NANC) responses induced by electrical field stimulation (EFS) in the rabbit urethra and detrusor. 2. EFS induced a relaxation in urethral smooth muscle and lamina propria precontracted by arginine vasopressin (AVP). The relaxation was abolished by tetrodotoxin (TTX) or the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine. omega-Conotoxin inhibited the relaxation induced by EFS, but not that elicited by the NO donor 3-morpholino-sydnonimin. The inhibition, however, decreased with increasing frequencies of stimulation. Nimodipine, tetramethrin and nickel did not affect the omega-contoxin-resistant relaxation in lamina propria, suggesting that neuronal L or T VOCCs were not involved in the response. 3. EFS contracted urethral smooth muscle at resting tension. The contractions were virtually abolished by TTX or prazosin. omega-Conotoxin effectively inhibited the contractile responses to EFS, but not those to exogenous noradrenaline. An omega-conotoxin-resistant contraction was, however, observed at high frequencies of stimulation. 4. The detrusor responded with frequency-dependent contractions upon EFS. A TTX-resistant contraction less than 10% of controls remained at 30 Hz stimulation. At a stimulation frequency of 10 Hz, scopolamine reduced the EFS-induced contraction by 71%. omega-Conotoxin inhibited the responses in both the absence and presence of scopolamine. The inhibition decreased with increasing frequencies of stimulation (examined in the absence of scopolamine). omega-Conotoxin did not affect the contractile responses to carbachol or adenosine 5'-triphosphate. 5. The adrenergic contraction (25 Hz) and NANC relaxation (10 Hz) in the urethra, and cholinergic and NANC contractions (10 Hz) in the detrusor were inhibited concentration-dependently by omega-conotoxin.The adrenergic contraction in the urethra was 10 times and the cholinergic contraction in the detrusor was three times more sensitive to omega-conotoxin than the NANC responses.6. These results suggest that NANC neurotransmission is less inhibited by omega-conotoxin than transmission mediated by adrenergic and cholinergic nerves in the rabbit lower urinary tract. In the urethra a marked omega-conotoxin-resistant component of the NANC relaxation was observed which increased with increasing stimulation frequencies and was unaffected by inhibitors of L and T type VOCCs. This raises the question whether VOCCs of a type other than L, T, and N is involved in the mediation of this response.
Zygmunt
P M
PM
Department of Clinical Pharmacology, University of Lund, Sweden.
Zygmunt
P K
PK
Högestätt
E D
ED
Andersson
K E
KE
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects*; D011817:Rabbits; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D020866:omega-Conotoxin GVIA
D002121:Calcium Channel Blockers; D010455:Peptides; D013779:Tetrodotoxin; D020866:omega-Conotoxin GVIA; D000109:Acetylcholine; D009638:Norepinephrine