Inhibition of ganglionic long-term potentiation decreases blood pressure in spontaneously hypertensive rats.

Long-term potentiation of sympathetic ganglia (gLTP), a unique form of synaptic plasticity, is serotonin dependent and can be blocked with 5-HT3 receptor antagonists. Long-lasting enhancement of the basal tone of ganglionic transmission (as with gLTP) is expected to result in sustained increase in peripheral resistance that would lead to elevated blood pressure. We examined the possibility that in sympathetic ganglia, gLTP may be involved in the expression of stress-induced (neurogenic) form of hypertension. High blood pressure in spontaneously hypertensive rat (SHR), known to show exaggerated cardiovascular defense reactions to environmental stimuli, is partly due to a neurogenic factor. Chronic treatment of SHR and their normotensive counterpart, the Wistar Kyoto (WKY) rats with the 5-HT3 receptor antagonist tropisetron (ICS; 5 mg/kg/day), caused a marked decrease in the blood pressure of the SHR but not of WKY rats. Increasing the daily dose of ICS cumulatively (7 and 10 mg/kg) did not result in significant additional decrease in blood pressure of SHR, indicating that the drug blocks only the neurogenic component of hypertension in the SHR. electrophysiological procedures for indirectly testing for the presence of gLTP in ganglia excised from SHR suggest that gLTP has been previously expressed in these ganglia in vivo. This contrasts with the absence of gLTP in ganglia from normotensive rats. The results support contribution of gLTP to the expression of neurogenic hypertension.

Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion.

Carbon monoxide (CO), produced in the body by the enzyme heme oxygenase (HO), has been suggested as a retrograde synaptic messenger with a prominent role in the long-term potentiation (LTP) of certain areas of the brain. LTP of sympathetic ganglia is 5-HT(3) receptor-dependent and has been shown to require nitric oxide for the maintenance, but not for the induction, phase. We investigated the possibility of CO being required for the induction of ganglionic LTP. Pretreatment of rat isolated superior cervical ganglia with oxyhemoglobin (25-100 microm) completely blocked LTP. In the same ganglia, prolonged washout of oxyhemoglobin did not uncover any potentiation of the compound action potential. Oxyhemoglobin had no significant effect on the maintenance phase in ganglia with established LTP. Pretreatment of ganglia with the HO inhibitor zinc protoporphyrin-IX (ZnPP) (10 microm) completely and irreversibly prevented the expression of tetanus-evoked LTP. However, in the same ganglia, after superfusion of CO in the presence of ZnPP, tetanic stimulation readily evoked LTP. No effect was seen on the maintenance phase when ZnPP was superfused on ganglia with established LTP. Pretreatment of ganglia with the 5-HT(3) receptor antagonist ondansetron (0.4 microm) alone completely and irreversibly blocked LTP. However, in the presence of CO, ondansetron did not block LTP. These results suggest that activation of 5-HT(3) receptors may be involved in the production of CO. The results also suggest that CO, probably originating outside the presynaptic nerve terminal, is involved in the induction of LTP.

Adenosine A1 receptor activation inhibits LTP in sympathetic ganglia.

The effects of adenosine on long-term potentiation of sympathetic ganglia was studied in the isolated superior cervical ganglion of the rat, using extracellularly recorded compound action potential as an index of synaptic transmission. Adenosine in a small concentration (2 microM) blocked the post-tetanic potentiation without affecting long-term potentiation. Higher concentrations blocked both responses with no significant effect on basal transmission. The inhibitory effect appears to be due to activation of adenosine A1 receptors. This was indicated by results from experiments with the A1 agonist N6-cyclopentyladenosine (1 microM) which caused inhibition of the basal transmission as well as long-term potentiation and post-tetanic potentiation. This inhibition was readily antagonized by 8-phenyltheophylline (1 microM), an A1 receptor antagonist. A small enhancement of basal transmission was seen on treatment with 8-phenyltheophylline. The inhibitory effect of N6-cyclopentyladenosine on long-term potentiation was totally prevented when the Ca2+ concentration in the superfusate was doubled (from 2.2 to 4.4 mM). The adenosine A2 receptor agonist 5'-(N-cyclopropyl)-carboxamidoadenosine (1 microM), although caused a slight potentiation of basal transmission, had no significant effect on the post-tetanic potentiation or long-term potentiation. The adenosine transport inhibitors, dipyridamole (2 microM) and S-(4-nitorobenzyl)-6-thioinosine (2 microM) caused significant inhibition of the basal ganglionic transmission without affecting post-tetanic potentiation or long-term potentiation. The effect of dipyradimole on basal transmission was not antagonized in the presence of 8-phenyltheophylline suggesting a non-specific action. The results suggest that exogenous adenosine can inhibit both post-tetanic potentiation and long-term potentiation in sympathetic ganglia, probably by activation of presynaptic A1 receptors. The results also suggest that endogenous adenosine, which is probably released in minute amounts, may only modulate basal transmission without influencing induction or maintenance of long-term potentiation in the superior cervical ganglion.

Cyclic AMP antagonizes adenosine-induced inhibition of ganglionic transmission.

The mechanism of adenosine-induced inhibition of ganglionic transmission was investigated in the isolated superior cervical ganglion (SCG) of the rat. The inhibitory effect of adenosine on the postganglionic compound action potential (CAP) was antagonized by pretreatment of ganglia with forskolin, isoproterenol (IPNE), arginine vasopressin (AVP), or papaverine, all of which are known to increase tissue cAMP level by different mechanisms. Furthermore, pretreatment of ganglia with the adenylate cyclase inhibitor SQ 22, 536, or the phosphodiesterase activator imidazole reversed the effects of IPNE and forskolin. Pretreatment with 8-bromo-cAMP, resulted in a marked antagonism of the adenosine-induced inhibition. By themselves, none of these drugs had any significant effect on the CAP. Adenosine slightly but significantly decreased the basal level of cAMP in untreated ganglia. Formation of cAMP induced by IPNE was markedly reduced by adenosine. This was largely reversed in the presence of the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) but not the A2 receptor antagonist 3, 7-dimethyl-1-propargylxanthine (DPMX). We conclude that the inhibition of ganglionic transmission by adenosine involves reduction of cAMP formation through activation of A1 receptors.

Induction and maintenance of ganglionic long-term potentiation require activation of 5-hydroxytryptamine (5-HT3) receptors.

1. An extracellular recording technique was used to study the effects of 5-hydroxytryptamine (5-HT, serotonin) on the tetanus-induced long-term potentiation (LTP) of the nicotinic pathway of transmission in the superior cervical ganglion (SCG) of the rat. The postganglionic compound action potential (CAP), made submaximal by treatment with hexamethonium (O.4 mM), was used as an index of transmission in the ganglion. 2. Serotonin (10 microM) markedly enhanced the magnitude of LTP without affecting the post-tetanic potentiation (PTP). The serotonin (2-30 microM) concentration-response curve for LTP was bell shaped as no enhancement was seen with 30 microM serotonin. This may largely be due to activation of a 5-HT1 receptor subtype and not to desensitization. 3. When superfused before tetanus, the 5-HT1A receptor agonist 8-hydroxydipropylamino-tetralin (8-OH-DPAT, 5 microM) prevented the expression of LTP without affecting PTP. 4. Pretreatment of ganglia with the 5-HT2 receptor agonist R-(+)-dimethoxy-4-iodoamphetamine (R-(+)-DOI, 1 microM) enhanced the tetanus-induced LTP. Similar treatment with the 5-HT2 receptor antagonist ketanserin (3 microM) had no significant effect on LTP. 5. Pretreatment of ganglia with the 5-HT3 receptor agonist 1-m-(chlorophenyl) biguanide (m-CPGB, 1 microM), markedly increased (300%) the tetanus-induced LTP. Similar pretreatment with the 5-HT3 receptor antagonist 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, 0.5 microM) completely prevented the expression of LTP. Fully expressed LTP was reversibly blocked by MDL 72222 when applied during the maintenance phase of LTP. 6. Tetanic stimulation of monoamine-depleted ganglia (from reserpine-pretreated rats, 3 mg kg-1 for 24 h) failed to induced LTP. 7. In monoamine-depleted ganglia, tetanus preceded by superfusion with m-CPBG readily induced LTP. MDL 72222 completely blocked this LTP. However in these ganglia tetanus failed to induced LTP when m-CPBG was given 2 min (during PTP) or 1 h after tetanus. 8. Tetanic stimulation of monoamine-depleted ganglia in the presence of R-(+)-DOI failed to induced LTP. 9. We conclude that tetanus-induced LTP of the SCG of the rat requires activation of 5-HT3 receptors both for induction and maintenance.

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP) on ganglionic transmission.

1. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP) caused blockade of ganglionic transmission as evidenced by a marked decrease of the amplitude of evoked post-ganglionic compound action potential of the isolated superior cervical ganglion of rat. 2. This effect was not related to its dopaminergic neurotoxicity since pretreatment with pargyline did not prevent the ganglion-blocking action of MPTP. The effects of MPTP on ganglionic transmission were qualitatively similar to those of its narcotic analgesic analogue meperidine. The effects of both drugs were antagonized by the narcotic antagonist naloxone, indicating that the ganglion-blocking effect of MPTP also involved opiate receptors. 3. Like meperidine and morphine, the ganglion-blocking action of MPTP was reduced when the concentration of Ca2+ in the Locke solution was elevated. The blocking effect of methadone on transmission was not reduced by naloxone or elevated Ca2+. 4. The effect of MPTP on nerve action potential was minimal, indicating that the drug blocked synaptic transmission in the ganglion. 5. These results suggest that MPTP inhibits synaptic transmission in the isolated superior cervical ganglion of the rat, probably by interfering with Ca2+ function.

A comparative study of the actions of histamine H2 receptor antagonists on transmission in the isolated superior cervical ganglion of the rat.

Ganglionic effects of the histamine H2 receptor antagonists cimetidine, ranitidine and 1-nitro-2-(2-propynylamino)-2-(2-[dimethylaminomethyl-2-furanyl) methylthiol]-ethylamino)ethylene (ORF 17578) were compared in the isolated superior cervical ganglion of the rat. Extracellular recording of compound action potentials showed that the drugs caused concentration-dependent inhibition of ganglionic transmission, as indicated by depression of the postganglionic compound action potential. Cimetidine-induced inhibition of ganglionic transmission was stimulus frequency-dependent. Increasing the Ca2+ from 2.2 to 4.4 mM in the bathing solution did not significantly affect the inhibitory actions of these agents. In the series with ranitidine, pretreatment with DFP to inhibit acetylcholinesterase similarly had no significant effect on the depression of the compound action potential by ranitidine. All three agents had little or no effect on nerve conduction in isolated vagi of the rat. The results indicate that all three histamine H2 receptor blockers inhibited ganglionic transmission, but only in large concentrations. The results also suggest that the blocking effect of these drugs was unrelated to their reported anticholinesterase action or to blockade of histamine H2 receptors, which are believed to exist on the presynaptic membrane. It is suggested that the ganglion effect may be due to the action of these agents on the acetylcholine receptor-ion channel complex in the postsynaptic membrane.

Effect of calcium on synaptic facilitation by potassium channel blockers in superior cervical ganglion of rat.

The effects of potassium channel blockers on synaptic transmission were studied in the isolated superior cervical ganglia of the rat by means of extracellular recordings. The ganglia were exposed to gradual increase in the concentration of calcium in the presence and absence of potassium channel blockers. At all levels of calcium (0.1-2 mM), 4-aminopyridine (4-AP) produced marked potentiation of both amplitude and duration of the compound action potential. At 0.1 mM, 4-AP completely reversed the failure of transmission regularly seen in low calcium (0.1 mM). The increase in duration, measured as time to peak, was more pronounced in low calcium and became less marked as the concentration of calcium was raised. In media containing low concentrations of calcium (0.8 mM), 4-AP induced a massive spontaneous discharge, often with rhythmic bursts. Cesium (6 mM) abolished the action potential in low calcium media, however, increasing levels of calcium in the presence of cesium resulted in recovery and later marked potentiation of both the amplitude and duration of the action potential in a calcium concentration-dependent manner. Guanidine potentiated the amplitude of the compound action potential but had no measurable effect on its duration and was unable to reverse transmission failure in low calcium. No potentiation of the amplitude or duration of the action potential was seen with tetraethylammonium. Neither guanidine nor tetraethylammonium induced a spontaneous discharge. The results suggest that some actions of 4-AP are unrelated to blockade of potassium channels.

Effects of felodipine and verapamil on transmission in the isolated superior cervical ganglion of the rat.

The effects of Ca2+ channel blockers verapamil and felodipine on transmission in the isolated superior cervical ganglion and conduction in the cervical sympathetic nerve trunk of the rat were examined by recording compound postganglionic action potentials as indexes of ganglionic transmission. Both verapamil and felodipine blocked ganglionic transmission but only at high concentrations, verapamil being more effective in this regard than felodipine. Increasing (from 2.2 to 4.4 mM) or decreasing (from 2.2 to 0.4 mM) Ca2+ concentration did not significantly affect the inhibitory action of these agents. Neither agent had any significant effect on conduction of compound action potential along the preganglionic cervical sympathetic nerve trunk. The results suggest that the observed ganglionic blocking effects of these drugs are apparently unrelated to Ca2+ channel blockade.