Cardiovascular responses evoked by carbachol microinjection into the posterior hypothalamus involves ganglionic nicotinic and muscarinic mechanisms

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The action of methylated derivatives of 5-hydroxytryptamine at ganglionic receptors

Changes in resting membrane potential induced by 5-HT, methylated derivatives of 5-HT and DMPP were recorded from the rabbit isolated superior cervical ganglion by the sucrose-gap method. Responses were evoked by injections into the superfusion stream to the ganglion of 0.01–0.2 μmol. Whereas 5-HT and DMPP evoked a relatively brief depolarization followed by an after-hyperpolarization, N,N-dimethyl 5-HT (DM5-HT) and N,N,N-trimethyl 5-HT (TM5-HT) evoked depolarizations of long duration. 5-Hydroxytryptamine and DMPP were approximately equipotent; DM5-HT was 8 times and TM5-HT 70 times more active than 5-HT.Quipazine was a selective antagonist of responses to 5-HT and hexamethonium a selective antagonist of responses to DMPP. Quipazine (1 μM) reduced in amplitude responses to 5-HT by 94%, those to DM5-HT by 37%, and those to TM5-HT by 10%; responses to DMPP increased in amplitude by 42%. When superfused over the ganglion 5-HT (10 μM) reduced responses to 5-HT by 56%, those to DM5-HT by 27%, those to TM5-HT by 25%, and those to DMPP by 9%. Hexamethonium (100 μM) reduced responses to DMPP by 84%, those to DM5-HT by 64% and those to TM5-HT by 86%; there was no reduction of responses to 5-HT which were potentiated in 7 of 13 experiments. Thus, during nicotinic receptor blockade responses to 5-HT were often enhanced, while in the presence of quipazine responses to DMPP were often enhanced.A dual action of DM5-HT and TM5-HT at ganglionic nicotinic and 5-HT receptors is likely. Potentiation of responses mediated via one species of receptor during blockade of the other suggests that 5-HT and nicotinic receptors may be in close association in the membrane.     

Cardiovascular responses to cholinergic agonists in sinoaortic denervated rats

1. The cardiovascular effect of systemic nicotinic and muscarinic cholinergic stimulation were studied in conscious sham operated and sinoaortic denervated (SAD) rats, 7 days after the corresponding operation.2. The administration of the nicotinic ganglionic agent 1,1-dimethyl-4-phenylpiperazinium (DMPP, 50–100 μg·kg⁻¹, i.v.) induced a fall of heart rate that was significantly higher in SAD rats than in sham rats. DMPP induced in sham rats an increase of arterial pressure but in SAD animals a biphasic response: an initial hypotension followed by an increase of arterial pressure.3. Under muscarinic blockade, DMPP only showed a pressor and tachycardic action in both groups of rats without differences between them.4. The muscarinic agonist, carbachol (0.1–10 μg·kg⁻¹, i.v.) showed the same hypotensive and bradycardic action in both groups of rats.5. Our results suggest that after 7 days of SAD, differences in the response to DMPP between sham and denervated animals could be due to the loss of baroreflex mechanisms. The increased bradycardic effect of DMPP in SAD rats could be mediated by a supersensitivity of parasympathetic ganglionic nicotinic receptors, whilst the sympathetic ganglionic nicotinic receptors remained unaltered.On the other side, the cardiovascular muscarinic responses to carbachol remain unaffected in SAD rats.     

NEUROLEPTICS INDUCE PENILE ERECTION IN THE RABBIT

1. Intramuscular (i.m.) administration of the neuroleptics chlorpromazine, haloperidol and spiperone at doses ranging from 0.1 to 0.4 mg/kg in male rabbits induced a dose-dependent penile erection. 2. The i.m. administration of the α₁-adrenoceptor antagonists prazosin and bunazosin (0.1–0.4 mg/kg), induced a dose-dependent penile erection. However, that of the peripheral dopamine receptor antagonist domperidone (0.4–4.0 mg/kg) and the dopamine receptor agonist apomorphine (0.1–1.0 mg/kg) did not. Penile erection was not induced by i.m. injection of chlorpromazine in combination with intrapenile administration of the α₁-adrenoceptor agonist methoxamine. 3. Penile erection was induced by the administration of chlorpromazine (0.25–1.00 mg/body) into the lateral cerebral ventricle. At a low dose, however, the administration of chlorpromazine into the lateral ventricle induced a less notable penile erection than that induced intramuscularly. 4. Penile erection was induced by i.m. injection of the ganglionic blocker hexamethonium (5–20 mg/ kg). When chlorpromazine was given after pretreatment with hexamethonium, penile erection was more notable than that induced by either drug given alone. 5. These results suggest that neuroleptics could act locally in the penile structure to cause penile erection by α₁-adrenoceptor-blocking actions.     

The effects of 1,1-dimethyl-4-phenyl-piperazinium (DMPP) in the cat superior cervical ganglion in situ

Summary The response of the cat superior cervical ganglion (SCG) in situ to injections of DMPP into its arterial blood supply was investigated by recording continuously both the ganglionic surface (demarcation) potential and the activity in a postganglionic nerve.Almost all ganglionic effects of DMPP can be explained by two basic mechanisms, namely a) the shunt of the ganglion cell membrane resistance caused by the interaction of DMPP with the nicotinic receptors on the ganglion cell membrane, and b) the activity of an electrogenic Na⁺-pump triggered by the disturbance of the ionic distribution resulting from the primary action.When medium doses of DMPP are injected by bolus-injections, the ganglionic response can easily be separated into two phases representing in almost pure form the consequences of the two mechanisms. An early phase of depolarization with ganglionic excitation, facilitation and depression of synaptic transmission is due directly to nicotinic receptor stimulation. A longer lasting late phase of hyperpolarization with non-specific depression of ganglionic excitability is caused by an electrogenic Na⁺-pumping which lasts until the pre-injection resting conditions of ionic gradients are restored.An additional presynaptic site of action of DMPP is postulated to explain the transient recovery of ganglionic transmission separating the initial depolarization block from the late phase of inhibition.Certain circulatory conditions and high doses of DMPP render the responses more complex, but the interaction of the two basic processes are revealed by appropriate pharmacological procedures.     

Effect of Ganglionic Blocking Compounds on In-vivo Fluid Secretion in the Rat Small Intestine

It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced fluid secretion in the rat small intestine. This notion is, in part, derived from experiments on anaesthetized animals in which the response to cholera toxin was antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In the current study, such anti-secretory action of ganglionic blocking compounds was analysed in an experiment designed to minimize any possible negative effect of general anaesthesia on intestinal secretion. Rats were anaesthetized with ether for 5–10 min, during which time a jejunal loop (10–12 cm) was constructed. The loop was challenged with one of the secretagogues, cholera toxin, prostaglandin E₁ (PGE₁) or okadaic acid. Saline (control) or either of the ganglionic blockers, hexamethonium and chlorisondamine, was administered intravenously. The rats were killed 5 h (cholera toxin) or 1–5 h (PGE₁ and okadaic acid) after challenge, and the amount of fluid accumulated in the loops was determined. Cholera toxin-induced secretion was unchanged by hexamethonium but reduced by approximately 80% by chlorisondamine. The difference in effect between the two blockers might relate to the duration of ganglionic blockade. Chlorisondamine blocked secretion induced by either PGE₁ or okadaic acid by approximately 60%. It is suggested that the anti-secretory effect of ganglionic blocking compounds might be a result of blockade of secreto-motor nerves but other mechanisms, for example interference with haemodynamic factors, cannot be ruled out.     

Effects of alpha 1- and alpha 2-adrenoceptor antagonists on venous tone in conscious rats

The dose-response effects of hexamethonium, prazosin and rauwolscine - a ganglionic blocker, alpha 1- and alpha 2-adrenoceptor antagonists, respectively - on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were examined in conscious and unrestrained rats. Prazosin and rauwolscine were also administered to rats after venous tone was elevated by drug-induced hypotension via the infusion of the vasodilator drug hydralazine. The effects of these drugs were compared with those of the vehicle, acidified glucose solution, administered to control rats. In intact rats, i.v. infusions of prazosin and rauwolscine dose dependently decreased MAP; the highest dose of rauwolscine, but not prazosin slightly reduced MCFP. The i.v. infusion of hexamethonium reduced MAP and caused a marked dose-dependent decrease in MCFP. After venous tone was raised by hydralazine, both prazosin and rauwolscine dose dependently decreased MCFP. The decrease in MCFP caused by rauwolscine was significantly greater than that caused by prazosin. Our results show that in the basal condition, the capacitance vessels are somewhat resistant to the effects of alpha-adrenoceptor antagonists in contrast to the effects of ganglionic blockers. After venous tone was raised by reflex mechanisms, both alpha-adrenoceptor antagonists were effective in lowering venous tone, however, the effect of alpha 2-adrenoceptor antagonist is significantly greater than that of alpha 1-adrenoceptor antagonist.     

六甲溴铵阻断交感神经元烟碱受体的机理

使用膜片钳全细胞记录技术，观察了六甲溴铵(C₆)对培养新生大鼠颈上交感节(SCG)神经元烟碱受体的阻断作用，并对其作用机理进行了研究. 本实验发现C₆对神经元烟碱受体的抑制作用具有明显的浓度依赖性和电压依赖性，可明显加速烟碱受体的失敏，提示C₆主要以阻断受体开放离子通道的方式拮抗烟碱受体.     

Peptide YY administration into the posterior hypothalamic nucleus of the rat evokes cardiovascular changes by non-adrenergic, non-cholinergic mechanisms

1 Microinjection of peptide YY (PYY) (0.23-2.3 nmol) into the posterior hypothalamic nucleus (PHN) of conscious rats evokes a dose-dependent pressor response and a bradycardia. 2 The increase in mean arterial pressure evoked by 2.3 nmol of PYY was not blocked by intravenous pretreatment with: (i) the nicotinic ganglionic receptor antagonist pentolinium (PENT, 10 mg kg(-1)) alone, or in combination with the muscarinic receptor antagonist methylatropine (MeATR, 1 mg kg(-1)); (ii) the alpha(1)-adrenoceptor antagonist prazosin (PRAZ, 0.2 mg kg(-1)); (iii) the V(1)-vasopressin receptor antagonist [d(CH(2))(5)Tyr(Me)]AVP (AVPX, 20 microg kg(-1)); (iv) the combination of AVPX, PENT and MeATR; (v) the combination of PRAZ, AVPX, PENT, MeATR, and the alpha(2)-adrenoceptor antagonist yohimbine (0.3 mg kg(-1)); or (vi) the angiotensin II type 1 receptor antagonist ZD 7155 (1 mg kg(-1)). 3 Adrenal demedullation inhibited the PYY-evoked responses of drug-naive rats, and rats pretreated with the combination of PENT, MeATR and AVPX. 4 Transection of the splanchnic nerve innervating the adrenal medullae attenuated the bradycardia, as did ZD 7155, but not the PYY-evoked pressor response. 5 Systemic pretreatment of rats with the neuropeptide Y(1) receptor antagonist BIBP 3226 (1 mg kg(-1)) blocked the PYY-evoked cardiovascular changes, but not those evoked by microinjection of carbachol (5.5 nmol) into the PHN. 6 These results suggest that the cardiovascular changes evoked from the PHN by PYY requires the presence of the adrenal medullae, which are stimulated by: (i) a hormone to release an NPY-like substance that evokes the pressor response, and (ii) the splanchnic nerve to evoke the release of a substance that results in the bradycardia.     

Cutaneous arterial and venous alpha receptor blocking activity following intraduodenal indoramin to dogs

Indoramin is a selective α₁ receptor antagonist, with pharmacologic activity similar to prazosin. However, indoramin differs from prazosin in that indoramin has membrane stabilizing activity; does not cause reflex tachycardia, first dose syncope, or orthostatic hypotension; and requires several days for onset of its antihypertensive action. Thus, indoramin may lower blood pressure independent of arterial or venous α₁ adrenoceptor blockade. This study compares the relative arterial and venous α₁ adrenoceptor blocking activity of indoramin and prazosin, following intraduodenal (id) administration, in the canine hindpaw preparation perfused at constant flow, to their blood pressure lowering activity. Indoramin (5 and 20 mg/kg, id) inhibited the arterial and venous pressor responses to sympathetic nerve stimulation (SNS) and norepinephrine (NE). No significant differences in the magnitude of arterial and venous blockade existed. Blockade of α₁ adrenoceptors was maximal at 5 mg/kg of indormin. In contrast, 20 mg/kg of indoramin lowered mean arterial blood pressure (MAP) but did not affect paw perfusion pressure (PP). Prazosin (0.25 and 1.0 mg/kg, id) produced both dose-related α₁ adrenoceptor blockade and reduction of MAP. Prazosin was more effective as an inhibitor of venous vs. arterial responses to SNS, and produced a different profile of inhibition of SNS than indoramin. Thus, indoramin differs from prazosin as an inhibitor of α₁ adrenoceptors of the canine paw. Since indoramin does not lower MAP in doses which block α₁ adrenoceptors of the paw and does not lower PP in the decentralized paw in doses which lower MAP, we conclude that indoramin acutely lowers MAP in the dog by a mechanism unrelated to postsynaptic α₁ receptor blockade, and may inhibit a subtype of α₁ adrenoceptor different from that inhibited by prazosin.     

Acute effects of a sarin-like organophosphorus agent,bis(isopropyl methyl)phosphonate,on cardiovascular parameters in anaesthetized,artificially ventilated rats

The organophosphorus compound sarin irreversibly inhibits acetylcholinesterase. We examined the acute cardiovascular effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate (BIMP), in anaesthetized, artificially ventilated rats. Intravenous administration of BIMP (0.8 mg/kg; the LD50 value) induced a long-lasting increase in blood pressure and tended to increase heart rate. In rats pretreated with the non-selective muscarinic-receptor antagonist atropine, BIMP significantly increased both heart rate and blood pressure. In atropine-treated rats, hexamethonium (antagonist of ganglionic nicotinic receptors) greatly attenuated the BIMP-induced increase in blood pressure without changing the BIMP-induced increase in heart rate. In rats treated with atropine plus hexamethonium, intravenous phentolamine (non-selective α-adrenergic receptor antagonist) plus propranolol (non-selective β-adrenergic receptor antagonist) completely blocked the BIMP-induced increases in blood pressure and heart rate. In atropine-treated rats, the reversible acetylcholinesterase inhibitor neostigmine (1 mg/kg) induced a transient increase in blood pressure, but had no effect on heart rate. These results suggest that in anaesthetized rats, BIMP induces powerful stimulation of sympathetic as well as parasympathetic nerves and thereby modulates heart rate and blood pressure. They may also indicate that an action independent of acetylcholinesterase inhibition contributes to the acute cardiovascular responses induced by BIMP.     

Inhibition of serotonin-induced increase in canine external carotid blood flow by drugs that decrease the sympathetic outflow

1 The present study was designed to analyse the effect of the centrally-acting sympatho-inhibitory drugs, prazosin and ketanserin, on the increase in external carotid blood flow (external CBF) produced by 5-hydroxytryptamine (5-HT) in pentobarbital-anaesthetized dogs. 2 Intracarotid (i.c.) infusions of 5-HT (10 μ g min^?1 during 1 min) produced an increase in external CBF without changes in mean arterial blood pressure or heart rate. This response to 5-HT was dose-dependently blocked by intravenous (i.v.) administration of prazosin (1, 3, 10, 30 and 100 μg kg^?1) or ketanserin (10, 30, 100 and 300 μg kg^?1). 3 Furthermore, 5-HT-induced increase in external CBF was inhibited by either the ganglionic blocking agent, mecamylamine (0.03, 0.1, 0.3, 1, 3 and 10 mg kg^?1), the mixed 5-HT₁-like and 5-HT₂ receptor antagonist, methiothepin (3, 10 and 30 μ g kg^?1) or the 5-HT_1A ligand, spiroxatrine (10, 30, 100 and 300 μg kg^?1). In contrast, the selective 5-HT₂ and 5-HT_1C receptor antagonist, ritanserin (30 and 100 μg kg^?1, i.v.), was unable to block the above response to 5-HT. 4 It is concluded that the inhibition of 5-HT-induced increase in external CBF by prazosin, ketanserin, mecamylamine and spiroxatrine is due to a reduction in the sympathetic tone and not to a blockade of 5-HT receptors.     

The effects of various “nicotine-like” agents in the cat superior cervical ganglion in situ

Summary The effects of nicotine, lobeline, anabasine, cytisine, coniine, sparteine, piperidine, acetylcholine, tetramethylammonium (TMA) and dexamphet-amine, given as i.a. bolus injections, were studied in the cat superior cervical ganglion (SCG) in situ and compared with those of (DMPP) 1,1-dimethyl-4-phenylpiperazinium described in a preceding paper.Two main events are thought to determine the ganglionic response to these agents. A non-selective conductance increase of the ganglion cells by stimulation of nicotinic receptors is responsible for depolarization, firing, facilitation of ganglionic transmission and depolarization block. The accumulation of Na⁺ resulting from the altered conductance activates an electrogenic Na ⁺-pump which tends to increase the membrane potential and causes a delayed unspecific depression of ganglionic excitability. After agents with a brief agonistic action (acetylcholine, DMPP, TMA), the two mechanisms lead to a distinct biphasic effect on ganglionic polarity (initial depolarization, later hyperpolarization) and transmission (early and later block); with the nicotinic agonists of long duration of action the effect of the electrogenic Na⁺-pump was obscured by the long-lasting activation of nicotinic receptors and was usually revealed only by special pharmacological procedures. An additional preganglionic depression of transmitter release is very likely. A desensitization of nicotinic receptors occurred after high single or repeated doses of nicotine, resulting in a selective unsurmountable block. A competitive block of nicotinic receptors occurred after coniine. Local anaesthetic properties of lobeline and dexamphetamine interfered with the two main events when high doses were given. The only effect of sparteine was to produce a short-lasting hexamethonium-like block of transmission.     

Characterization of the muscarinic receptor mediating contraction of the dog prostate

1 We have studied the effects of muscarinic cholinoceptor agonists and subtype-preferring antagonists on the isometric contraction of smooth muscle strips from dog prostate. 2 Acetylcholine and carbachol induced contraction of prostate strips from the peripheral zone, (‘the capsule’). Bethanechol contracted the tissue but not at lower doses. McN-A-343 and oxotremorine-M showed the same effects. 3 Blocking α- and β-adrenoceptors with phentolamine and propranolol, respectively, did not modify carbachol-induced contractions. 4 The nicotinic receptor blocker, hexamethonium (10^??6–10^??4 m ) did not affect the contractile response evoked by a single dose of carbachol (10^??5 m ), whilst the muscarinic receptor antagonist, atropine (10^??11–10^??9 m ), inhibited it in a competitive manner. 5 The muscarinic M₁ (pirenzepine), M₂[AF-DX 116, himbacine (M₂/M₄) and methoctramine], M₃ (HHSID and f-F-HHSID), and putative M₄ (tropicamide) antagonists reduced significantly the carbachol-induced contractions. The pIC₅₀ values were: atropine (10.01) > himbacine (8.3) > methoctramine (7.85) > AF-DX 116 (7.60) > HHSID (7.21) > p-F-HHSID (7.10) > pirenzepine (7.30) > tropicamide (7.00). 6 The antagonist profile indicates that an predominant M₂ receptor subtype could mediate the muscarinic contraction in the canine prostate.     

Effect of picrotoxin on adrenal catecholamine secretion

The effect of picrotoxin (PT) on catecholamine (CA) secretion was investigated in perfused bovine adrenal glands. A low dose of PT (3 microM) enhanced the CA secretion evoked by a 15-min exposure to 1,1-dimethyl-4-phenylpiperazinium (DMPP, a nicotinic agonist; 0.1 mM), but a higher dose (0.3 mM) of PT inhibited the DMPP-evoked CA secretion. The rate of decline of secretory response to the prolonged DMPP stimulation was also accelerated by a higher dose (0.1 mM) of PT. In the dose-response curves for DMPP-evoked CA secretion, the inhibitory action of PT (0.3-1 mM) was more prominent at high doses than at low doses of DMPP. The inhibition pattern was similar to the pattern of a barbiturates blockade. In separate experiments, PT (0.1 mM) augmented calcium (10 mM)- and high potassium (56 mM)-evoked secretory responses. Spontaneous CA secretion was unaffected by PT at the concentrations indicated above. These results indicate that a low dose of PT potentiates, but higher doses inhibit, the adrenal CA secretion by a nicotinic agonist and that the inhibitory effect of PT resembles that of barbiturates.     

Prejunctional α2-adrenoreceptors modulate the stimulated release of noradrenaline in isolated follicle strips from bovine ovaries

1 Strips from the follicle wall of bovine ovaries were incubated in Krebs-Ringer solution containing ³H-noradrenaline for measurement of transmitter liberation during electrical field stimulation (5 Hz frequency, 1 ms pulse duration, 10 V between the electrodes). The effects of noradrenaline as well as selective α-adrenoreceptor agonists and antagonists were studied on the electrically induced efflux of radioactivity. 2 Noradrenaline (1 μM) inhibited the stimulated release of radioactivity. The α₂-adrenoreceptor agonist, oxymetazoline, significantly reduced the release of radioactivity in concentrations as low as 0.01 μM. The α1-adrenoreceptor agonist, phenylephrine (0.01–1 μm), was without significant effect. 3 Phentolamine (0.01–1 μm) and the selective α₂-adrenoreceptor antagonist, idazoxan (0.01–1 μm) significantly enhanced the electrically evoked release. The α₁-adrenoreceptor antagonist, prazosin (0.01–1 μm), was without effect. Idazoxan (0.1 μm) reversed the inhibitory effect of oxymetazoline (0.1 μm). 4 It is concluded that administration of noradrenaline or the α₂-adrenoreceptor agonists reduces the release of labelled noradrenaline by acting on prejunctional α₂-adrenoreceptors in the noradrenergic nerves distributed in the wall of the bovine ovarian follicle. This is one of several prejunctional receptor mechanisms that modulate the activity of the sympathetic nerves innervating the smooth musculature of the follicle wall.     

Phenoxybenzamine blocks dopamine autoreceptors irreversibly: Implications for multiple dopamine receptor hypotheses

Phenoxybenzamine in μM concentrations increased the electrically evoked overflow of recently taken up [³H]dopamine from superfused slices of cat caudate nucleus, an effect which is also observed for dopamine receptor antagonists. The magnitude of the increase in electrically evoked [³H]dopamine release caused by 1 μM phenoxybenzamine was equal to that elicited by maximally effective concentrations of the specific dopamine receptor antagonist, S-sulpiride. Phenoxybenzamine (1 μM) completely antagonized the inhibition of [³H]dopamine release caused by the dopamine receptor agonist pergolide (10 nM). The α-adrenoceptor antagonist phentolamine (1 μM) had no effect on the electrically evoked overflow of [³H]dopamine, ruling out the possibility that the effect of phenoxybenzamine could be attributed to α-adrenoceptor blockade. A 20 min exposure to 1 μM phenoxybenzamine increased the electrically evoked [³H]dopamine overflow even after the tissue had been washed for two and a half hours. When the caudate slices were exposed for 30 min to the reversible dopamine receptor antagonist S-sulpiride (1 μM) and washed for two and a half hours, no similar increase in stimulation-evoked [³H]dopamine overflow was observed. When sulpiride (1 μM) was present during the exposure to phenoxybenzamine (1 μM), no increase in electrically evoked [³H]dopamine overflow was observed after the washout period. Thus phenoxybenzamine at 1 μM appears to block irreversibly the dopamine autoreceptor in the caudate nucleus. Phenoxybenzamine has been previously reported to block irreversibly dopamine-stimulated adenylate cyclase (D₁) and neuroleptic receptor binding (D₂). The present demonstration that phenoxybenzamine also blocks the dopamine autoreceptor irreversibly thus supports the view that all currently well-established dopamine receptors are sensitive to phenoxybenzamine.     

Activation of nicotinic ACh receptors with alpha4 subunits induces adenosine release at the rat carotid body

The effect of ACh on the release of adenosine was studied in rat whole carotid bodies, and the nicotinic ACh receptors involved in the stimulation of this release were characterized. ACh and nicotinic ACh receptor agonists, cytisine, DMPP and nicotine, caused a concentration-dependent increase in adenosine production during normoxia, with nicotine being more potent and efficient in stimulating adenosine release from rat CB than cytisine and DMPP. D-Tubocurarine, mecamylamine, DHbetaE and alpha-bungarotoxin, nicotinic ACh receptor antagonists, caused a concentration-dependent reduction in the release of adenosine evoked by hypoxia. The rank order of potency for nicotinic ACh receptor antagonists that inhibit adenosine release was DHbetaE>mecamylamine>D-tubocurarine>alpha-bungarotoxin. The effect of the endogenous agonist, ACh, which was mimicked by nicotine, was antagonized by DHbetaE, a selective nicotinic receptor antagonist. The ecto-5'-nucleotidase inhibitor AOPCP produces a 72% inhibition in the release of adenosine from CB evoked by nicotine. Taken together, these data indicate that ACh induced the production of adenosine, mainly from extracellular ATP catabolism at the CB through a mechanism that involves the activation of nicotinic receptors with alpha4 and beta2 receptor subunits.     

Effect of General Anaesthetics and Organic Solvents on α1–Adrenoceptors in the Myometrium

Abstract: The α₁ selective radioligand ³H–prazosin was used to assay α₁ receptors in membranes prepared from the rabbit myometrium. ³H–Prazosin was found to bind to a single high affinity site in these membranes which was the presumed α₁ receptor. A series of general anaesthetics and organic solvents were tested for their ability to inhibit ³H–prazosin binding. The order of potency of the tested agents to inhibit the binding was: chloroform = halothane = trichloroethylene > carbon tetrachloride > dichloromethane. The depression of ³H–prazosin binding seemed to be induced on the α₁ receptor since non–specific radioligand binding was not affected as revealed by a saturation experiment with ³H–prazosin where halothane was used as inhibiting agent. Computer analysis of the latter experiment also showed that halothane depressed mainly the affinity of ³H–prazosin for the α₁ receptor. The ability of the general anaesthetics and organic solvents to inhibit contractions elicited by α₁ stimulation with phenylephrine in the rabbit uterus was also investigated. In these tests the order of potency for the inhibition of the contractile response was: carbon tetrachloride ≥ halothane = chloroform > trichloroethylene > dichloromethane. The mechanism of action for α₁ receptor and myometrial depression is discussed     

Dimethylphenylpiperazinium (DMPP)-induced relaxation and elevation of cyclic GMP content in canine lower esophageal sphincter (LES)

Cyclic GMP has been proposed as an intracellular mediator of neuronally-induced relaxation in lower esophageal sphincter (LES) smooth muscle. If cyclic GMP is indeed an intracellular messenger, then agents that activate enteric neurons of the sphincter [e.g. the ganglionic nicotinic receptor agonist dimethylphenylpiperazinium (DMPP)] also should cause a relaxation that is associated with an increase in cyclic GMP content. In isolated smooth muscle strips of canine LES, DMPP produced a rapid relaxation that was accompanied by a significant (P less than 0.05) increase in cyclic GMP content with no change in cyclic AMP content. Pretreatment of tissues with either tetrodotoxin or hexamethonium antagonized both the DMPP-induced relaxation and the associated increase in cyclic GMP. The combination of phentolamine and meclofenamic acid also antagonized both the relaxation and the elevation of cyclic GMP produced by DMPP. Electrical field stimulation (EFS)-induced relaxation and elevation in cyclic GMP was unaltered by meclofenamic acid and phentolamine. In conclusion, DMPP (like neuronal electrical activation) relaxed isolated canine LES through an enteric neuronal inhibitory pathway. The presence of phentolamine and meclofenamic acid did not affect EFS-induced effects, but blocked both the relaxation and the increase in cyclic GMP produced by DMPP, suggesting a more complicated pathway for DMPP in the release of inhibitory transmitter.