Inhibition Of Twitch Response Research Articles

The effect of guanethidine and local anesthetics on the electrically stimulated mouse vas deferens.

Complex regional pain syndrome is often treated with the sympatholytic guanethidine and a local anesthetic in a Bier's block. The efficacy of this treatment has been questioned. Because local anesthetics inhibit the norepinephrine uptake transporter, we hypothesized that this variable efficacy results from the local inhibiting the uptake of guanethidine. In this study, we tested this hypothesis by using a sympathetically innervated mouse vas deferens preparation. Organ bath-mounted mouse vasa deferentia were electrically stimulated in the absence and presence of guanethidine, prilocaine, procaine, and cocaine in various combinations. Prilocaine (1 mM) induced an immediate inhibition of twitch response (maximum 100% after 2 min) that fully reversed after washing. Guanethidine (3 microM) also inhibited twitching by 95% +/- 3% in 15 min, but this effect was only partially reversed after 1 h of washing (33% +/- 12% of control). When prilocaine and guanethidine were added in combination, a reversal of 80% +/- 13% (at 1 h) was observed. Procaine (300 micro M) produced a transient increase (152% +/- 14%) in response. When co-incubated with guanethidine (3 microM), the twitch was reduced to 24% +/- 4% of control and was reversed to 77% +/- 7% after 1 h. Cocaine (30 microM) inhibited the twitch response to 53% +/- 8%, which was fully reversed by 1 h of washing. When co-incubated with guanethidine, the response was reduced to 39% +/- 6% of control and was reversed to 86% +/- 10% after 1 h. In all cases, the reversal produced by the combination was significantly more intense (P < 0.05) than that produced by guanethidine alone. Local anesthetics reduce the sympatholytic actions of guanethidine, and this may explain the variable efficacy of guanethidine in the treatment of complex regional pain syndrome. In this study, with a sympathetically innervated vas deferens preparation, local anesthetics reduced the efficacy of the sympatholytic guanethidine, questioning its co-administration in the pain clinic.

The effects of dopaminergic and adrenergic drugs on twitch response of guinea-pig common bile duct

1. 1. Effects of various doses of bromocriptine and apomorphine, dopamine receptor agonists, on electrically evoked contractile responses of guinea pig common bile duct (CBD) were investigated in this study. 2. 2. Bromocriptine and apomorphine produced a concentration-dependent reduction of the twitch heights. IC 50 values for bromocriptine and apomorphine were 2.75±0.715 × 10 −6M, and 1.69±0.11 × 10 −5M, respectively. 3. 3. Pretreatment with sulpiride, 0.1 and 1.0 μM, prevented bromocriptine- and apomorphine-induced inhibition. pA 2 values of sulpiride against bromocriptine and apomorphine were 8.26 and 6.29, respectively. 4. 4. Clonidine, 0.1–100 μM, produced 49.3±2.5% inhibition of twitch responses. Its effect was partially antagonized by 1 μM of yohimbine. 5. 5. It would appear that both dopamine D 2- and α 2-adrenergic presynaptic receptors are present on the guinea-pig CBD cholinergic nerve.

Effect of green tea ( Camellia sinensis) extract on the rat diaphragm

The effect of hot water extract of green tea on skeletal muscle and its neurotransmission was studied employing innervated and denervated rat diaphragm. Green tea extract (GTE) has a facilitatory effect at lower concentrations and a paralytic effect at higher concentrations on skeletomotor function. GTE did not have any effect on direct twitch responses or on acetylcholine (ACh) and KCl induced contractures of denervated rat diaphragm and it antagonised the submaximal paralytic effect of d-tubocurarine and decamethonium. GTE-induced facilitation and inhibition were nullified in the presence of magnesium chloride. Nifedipine, reduced GTE-induced facilitation as well as inhibition of twitch responses as a function of its concentration. It was suggested that GTE might act on Ca 2+ channels at the skeletomotor junction. The effect of crude polyphenol on neuromuscular junctions was found to be similar to that of GTE. Therefore, it is suggested that the crude polyphenol content of GTE was the active constituent responsible for its effect on neuromuscular junction.

Activation and desensitization of presynaptic alpha 2-adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens.

The isolated field-stimulated vas deferens of the rat (0.1 Hz, 3 ms, 30-40 V) was used to study the relationship between the in vivo inhibition of neuronal uptake of noradrenaline (NA) by cyclic antidepressant drugs and the subsequent activation/desensitization of presynaptic alpha 2-adrenoceptors. Receptor activation was indirectly measured by quantifying the ability of each drug to inhibit basal twitch responses after their acute administration. Receptor desensitization was also indirectly measured by quantifying the ability of the drugs to reduce the inhibitory effects of selective alpha 2-adrenoceptor agonists on the electrically-induced twitch responses after their long-term administration. The acute in vivo administration of desipramine and other antidepressants (0.5-10 mg kg-1; i.p.; 2 h) resulted in dose-dependent inhibitions of the basal twitch responses which were rapidly reversed to control values by idazoxan (10-5 M). In vitro, desipramine and other antidepressants also inhibited in a concentration-dependent manner (10(-9)-10(-5) M) the twitch responses. In rats pretreated 12 h earlier with reserpine (1 mg kg-1; i.p.) or oxypertine (4 mg kg-1; i.p.), desipramine (10 mg kg-1; 2 h) did not induce inhibition of the basal twitch responses or it induced a smaller effect, respectively. For the various antidepressants the degree of inhibition of the basal twitch responses (desipramine greater than protriptyline greater than nortriptyline greater than maprotiline = imipramine greater than amitriptyline greater than viloxazine greater than iprindole much greater than zimelidine) was highly correlated (r = 0.914) with the potency for blockade of [3H]-NA uptake into rat brain synaptosomes. Clonidine and xylazine inhibited in a concentration-dependent manner (10(-9)-10(-6) M) the twitch responses. The long-term (7-14 days) administration of antidepressants or cocaine (10 mg kg-1, i.p.) resulted in significant decreases in sensitivity to clonidine or xylazine. Short-term (3 days) treatment with desipramine did not reduce the sensitivity to clonidine. The results indicate that the acute in vivo inhibition of NA neuronal uptake by antidepressants leads to the activation (through endogenous NA) of presynaptic inhibitory alpha 2-adrenoceptors which results in inhibition of the twitch responses. In contrast, prolonged in vivo inhibition of NA reuptake is followed by a slow desensitization process of the same receptors which results in a reduction of sensitivity to clonidine.

GABA-related activities of amino phosphonic acids on guinea-pig ileum longitudinal muscle.

The effects of phosphonic analogues of GABA, beta-alanine and glycine on guinea-pig ileum longitudinal muscle were measured. Aminomethylphosphonic acid (AMPh) and 2-aminoethylphosphonic acid (2-AEPh) were devoid of any effect both in non-stimulated preparations and in electrically-stimulated preparations. The phosphonic analogue of GABA, 3-aminopropylphosphonic acid (3-APPh) possessed a GABAB agonistic effect (relaxation and inhibition of twitch response) at doses of 10(-3)M. No agonistic effect on GABAA receptors was observed. 3-APPh at doses tested (2 X 10(-4)M and 10(-3)M) also displayed antagonistic action on the effects of GABAB agonists producing a parallel shift of the log dose-effect curves of GABA- and (-)-baclofen-inhibition of twitch responses. In contrast 3-APPh did not antagonize the inhibitory effect of morphine and noradrenaline. The contractile effect of GABA, mediated via GABAA receptors, was unaffected by 3-APPh(10(-3)M). It is concluded that 3-APPh is a partial agonist at the GABAB site in guinea-pig ileum.

Pressor responses to central injection of H2 antagonists not caused by GABA blockade

In awake rats, ranitidine was more effective than cimetidine in elevating blood pressure following intracerebroventricular (i.c.v.) injection, yet neither drug affected the hypotensive response to subsequent injections of muscimol (8.8 nmol i.c.v.). Bicuculline (0.01 nmol) microinjected into the inferior colliculus of rats caused clonic seizures whereas cimetidine (100 nmol) had no effect. The antihistamines did not prevent GABAB receptor-mediated inhibition of twitch responses in transmurally stimulated guinea-pig ileum. Ranitidine potentiated rather than inhibited GABAA receptor-mediated contractions of ileum longitudinal muscle. Cimetidine had no effect on these responses except at high concentrations (3 X 10(-4) M) which caused a slight dextral shift in the contractile response curve for GABA that may be attributed to antimuscarinic actions of cimetidine. Taken together, these data do not support the concept that the centrally mediated pressor effects of H2 antagonists are caused by GABA receptor blockade.

PURINE METABOLISM BY GUINEA-PIG ILEUM: 226

In guinea-pig ileum adenosine and adenosine analogs act presynaptically to inhibit cholinergic transmitter release and this has been shown to be due to actions at A1 (Ri) receptors. The I.C.50 of adenosine on the twitch response of this tissue is about 2μM. The purine content of the medium and tissues was measured throughout the pharmacological studies. The tissue released purines into the medium at 7.8±1.0 SEM pmol/mg/min and this was mostly uric acid. NAD (2μM) was rapidly hydrolysed to 5'-AMP (2.8±0.3pmol/mg /min). Both 5'- and 2'-AMP formed adenosine (2.8±0.6 and 3.2±0.6 pmol/mg/min). Adenosine was deaminated (3.2±0.2 pmol/mg/min) then oxidised to uric acid. Deoxycoformycin (dCF, 2μM) increased adenosine to 1-2μM in the medium from all substrates but the effect of adenosine on the twitch was not simply related to the increased adenosine concentration except when adenosine itself was the substrate, when a linear correlation was found between the inhibition of twitch response and the concentration of adenosine in the medium.