Effects of N-, P- and Q-type neuronal calcium channel antagonists on mammalian peripheral neurotransmission.
1. The effects of N-, P- and Q-type neuronal voltage-operated calcium (Ca2+) channel antagonists on neurotransmission were determined in a range of cardiovascular and urogenital tissues, as well as the diaphragm, isolated from rat or mouse. 2. The pharmacological tools chosen were omega-conotoxin GVIA (CTX GVIA), a selective N-type Ca2+ channel antagonist, the P-type channel blocker (< or = 100 nM) omega-agatoxin IVA (AGA IVA) and omega-conotoxin MVIIC (CTX MVIIC), a non-selective antagonist of N-, P- and Q-type channels. The effects of these antagonists on nerve-mediated responses were assessed in right atria, vasa deferentia, phrenic nerve-hemidiaphragms and small mesenteric arteries. 3. Rat mesenteric artery contractile responses to perivascular nerve stimulation were concentration-dependently inhibited by CTX GVIA (1-10 nM); inhibition was 92% with 10 nM. CTX MVIIC was > 100 fold less potent and only caused an inhibition of 46% at the highest concentration (1000 nM). AGA IVA (100 nM) had no effect. 4. In rat vas deferens stimulated at 0.05 Hz, CTX GVIA (10 nM) completely inhibited the twitch response and CTX MVIIC, about 100 fold less potent, caused total inhibition at 1000 nM. AGA IVA did not affect the twitch. In rat preparations stimulated at 20 Hz, a CTX GVIA-resistant (< or = 1000 nM) twitch response of 25% was apparent which could be blocked by 1000 nM AGA IVA or CTX MVIIC. In mouse vas deferens (20 Hz stimulation), CTX GVIA 10 nM caused an 87% inhibition of the twitch, the remainder being resistant to CTX GVIA, 100 nM. CTX MVIIC was only 10 fold less potent than CTX GVIA and completely inhibited the response at 1000 nM. AGA IVA (100 nM) inhibited the twitch by 55%. 5. The twitch response of the mouse phrenic nerve-hemidiaphragm was concentration-dependently inhibited by AGA IVA (1-100 nM); inhibition was 92% at 100 nM. CTX MVIIC was about 10 fold less potent than AGA IVA with an inhibition of 80% at 1000 nM. CTX GVIA was without effect. In the rat diaphragm preparation, AGA IVA (< or = 100 nM) and CTX GVIA (< or = 1000 nM) had little effect on the twitch response. CTX MVIIC (1000 nM) inhibited the twitch by 57%. 6. In rat and mouse right atria, sympathetic responses were concentration-dependently inhibited by CTX GVIA with almost complete block at 10-100 nM. CTX MVIIC was 100 fold less potent and caused complete inhibition at 1000 nM in the mouse preparation. AGA IVA did not affect atrial sympathetic responses. 7. These data suggest that N-type Ca2+ channels predominate in the control of sympathetic transmission in the mesenteric artery, vas deferens and right atrium. In the mouse vas deferens (and rat tissue at high stimulus frequency), P- and Q-type channels also mediate Ca2+ influx. P- and Q-type Ca2+ channels control neurosecretion at the motor endplate, with no role for N type channels.
Wright
C E
CE
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Angus
J A
JA
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism* / Q000502:physiology; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008978:Mollusk Venoms / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D020867:omega-Agatoxin IVA; D020866:omega-Conotoxin GVIA; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008978:Mollusk Venoms; D018377:Neurotransmitter Agents; D010455:Peptides; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D020866:omega-Conotoxin GVIA