1. The nitric oxide (NO) synthesis inhibitors NG-monomethyl L-arginine (L-NMMA) and L-nitroarginine methyl ester (L-NAME) reduced relaxations of guinea-pig tracheal smooth muscle elicited by stimulation of intramural non-adrenergic, non-cholinergic (NANC) nerves, but D-NMMA had no effect. L-NAME was 10-30 times more potent than L-NMMA. Relaxations produced by sodium nitroprusside and vasoactive intestinal polypeptide (VIP) were not affected by L-NMMA or L-NAME. 2. The inhibitory effect of L-NMMA on NANC-mediated relaxations was partially reversed by L-arginine but was not affected by D-arginine. 3. VIP antibody and alpha-chymotrypsin abolished or greatly reduced the relaxant action of VIP and reduced relaxations elicited by stimulation of NANC nerves; the residual NANC relaxation was further reduced by L-NAME. 4. The results suggest that NO and VIP are mediators of NANC-induced relaxations of guinea-pig tracheal smooth muscle. We propose the term 'nitrergic' to describe transmission processes which are mediated by NO.

Evidence that part of the NANC relaxant response of guinea-pig trachea to electrical field stimulation is mediated by nitric oxide.

1. The actions of two calcium channel antagonists, the N-channel blocker omega-conotoxin GVIA (omega-CgTx) and the L-channel antagonist nisoldipine, on synaptic transmission were investigated in the hippocampus and nucleus accumbens of the rat in vitro. 2. omega-CgTx (100 nM for 10 min) produced a marked and irreversible reduction of focally evoked population spikes and intracellularly recorded excitatory postsynaptic potentials (e.p.s.ps) in the nucleus accumbens, which could not be overcome by increasing the stimulus strength. 3. Nisoldipine (10 microM for 10 min) had no effect on population spikes in the nucleus accumbens or the CA1 of the hippocampus. 4. In the hippocampus, population spikes were not irreversibly reduced by omega-CgTx (100 nM for 10 min) but rather, multiple population spikes were produced along with spontaneous synchronous discharges. This indicated that inhibitory synaptic transmission was being preferentially reduced. 5. Intracellular recordings demonstrated that omega-CgTx powerfully reduced inhibitory synaptic transmission in an irreversible manner and that excitatory transmission was also reduced but to a lesser extent. Unlike excitatory transmission in the nucleus accumbens and inhibitory transmission in the hippocampus, increasing the stimulus strength overcame the reduction of hippocampal excitatory transmission. 6. It is concluded that omega-CgTx-sensitive calcium channels are involved in the calcium entry that precedes the synaptic transmission in all these synapses. The apparent lower sensitivity of the hippocampal excitatory fibres to omega-CgTx may indicate that calcium entry that promotes transmitter release at central synapses may be mediated by pharmacologically distinct calcium channels.

The effect of ω‐conotoxin GVIA on synaptic transmission within the nucleus accumbens and hippocampus of the rat in vitro

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 ( 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.

/pdf/effects-of-n-p-and-q-type-neuronal-calcium-channel-3q6bz0dxz7.pdf

Effects of N‐, P‐ and Q‐type neuronal calcium channel antagonists on mammalian peripheral neurotransmission

Nitric oxide (NO) is a neurotransmitter and neuromodulator in the central nervous system, but this small labile substance also seems to serve as a peripheral neurotransmitter. Abundant evidence is now available that NO, synthesized from L-arginine by NO synthase (NOS), is a nonadrenergic noncholinergic relaxant transmitter of gastrointestinal smooth muscle. Electrically induced nonadrenergic noncholinergic relaxations are antagonized by NOS inhibitors in vitro and in vivo. In a bioassay superfusion system, the release of a substance with the pharmacological characteristics of NO from a gastrointestinal smooth muscle preparation was detected; also, indirect measurements (e.g. of the NO metabolite nitrite or of the co-product of its synthesis L-citrulline) suggest NO release. Immunohistochemistry with antibodies raised against the neuronal NOS showed immunoreactivity in cell bodies of neurones in the myenteric plexus and in nerve fibres in the muscular layer. These data suggest that nerve endings, innervati...

Nitric oxide in the peripheral nervous system.

Toxins affecting calcium channels in neurons

1. The effects of omega-conotoxin GVIA (conotoxin), a potent inhibitor of neuronal N-type Ca2+ channels, have been examined on responses to stimulation of noradrenergic, cholinergic and non-adrenergic, non-cholinergic (NANC) nerves in a range of isolated tissues to investigate the role of conotoxin-sensitive Ca2+ channels in neurotransmission. 2. Contractions elicited by field stimulation of noradrenergic nerves in rat and mouse anococcygeus muscles, rabbit ear artery and rat vas deferens (epididymal portion) were inhibited by conotoxin. Responses to noradrenaline, and to adenosine triphosphate in the vas deferens, were not affected. 3. Positive chronotropic responses to field stimulation of noradrenergic nerves were inhibited by conotoxin in rat and mouse atria, but responses to noradrenaline and tyramine were not affected. 4. The stimulation-induced release of noradrenaline was inhibited by conotoxin in the rabbit ear artery and in rat and mouse atria. 5. Relaxations in response to stimulation of the noradrenergic perivascular mesenteric nerves were reduced or abolished by conotoxin in rat and rabbit jejunum. The response to noradrenaline in rat jejunum was not affected. 6. Contractions elicited by stimulation of cholinergic nerves were inhibited by conotoxin in rat jejunum and mouse ileum (perivascular mesenteric nerves), and in guinea-pig taenia caeci (field stimulation). Responses to acetylcholine in rat jejunum and mouse ileum were not affected. 7. Contractions elicited by stimulation of the cholinergic plus NANC pelvic nerves were inhibited by conotoxin in rabbit colon, and to a lesser extent in guinea-pig colon. The stimulation-induced contraction of the guinea-pig colon was inhibited by conotoxin by a greater proportion in the presence than in the absence of atropine. Responses to acetylcholine were not affected in the rabbit colon but were slightly reduced in the guinea-pig colon. 8. Relaxations in response to field stimulation of NANC nerves were inhibited by conotoxin in guinea-pig taenia caeci and rat gastric fundus strips, and in rat anococcygeus muscle when the tone was raised by guanethidine but not when it was raised by carbachol. The relaxations produced by sodium nitroprusside in the rat gastric fundus and anococcygeus were not affected. 9. Contractions of the rat bladder elicited by stimulation of the peri-urethral nerves, which are NANC- and cholinergically mediated, were relatively insensitive to inhibition by conotoxin. The response were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. The responses were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. 11. The inhibitory effect of conotoxin was inversely proportional to the frequency of stimulation (in several preparations) and to the Ca2+ concentration in the bathing solution (in rat vas deferens). These observations suggest that the inhibition by conotoxin of the Ca2+ influx required for excitation-secretion coupling in autonomic nerve terminals is not absolute, and can be overcome by repeated stimulation or by raising the Ca2 + concentration.

/pdf/effects-of-o-conotoxin-gvia-on-autonomic-neuroeffector-209h7zfw1n.pdf

Effects of ω-conotoxin GVIA on autonomic neuroeffector transmission in various tissues

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Effects of ω-conotoxin GVIA on autonomic neuroeffector transmission in various tissues