[The effects of some ganglion stimulants and ganglion blockers upon the electrical activity of rabbit retinas in vitro].
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Acetylcholine↗
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The effect of adrenergic and ganglionic blockers upon the L-dopa-stimulated release of glucagon in the rat.
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Animals↗
Catecholamines in turkeys with high or low blood pressure: effects of tyrosine hydroxylase inhibitor and ganglionic blocker.
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Adrenal Glands↗
Beta-adrenergic receptors in ischemic and nonischemic canine myocardium: relation to ventricular fibrillation and effects of pretreatment with propranolol and hexamethonium.
To explore possible roles of the sympathetic nervous system (especially the beta-adrenergic receptor and cAMP system) in the pathogenesis of ventricular fibrillation (VF), the authors examined changes in the number of myocardial beta-adrenergic receptors and the cAMP level in animals showing VF after experimental induction of myocardial ischemia. In animals that developed VF approximately 15 min after coronary ligation, the ischemic myocardium had a significantly larger number of beta-adrenergic receptors (90 +/- 8 fmol/mg protein) and a significantly higher level of cAMP (1.4 +/- 0.17 nmol/g weight) compared with the nonischemic area where the number of beta-receptors was 68 +/- 7 fmol/mg protein and the cAMP level was 0.80 +/- 0.20 nmol/g weight. In animals in which VF was electrically induced 20 min after coronary ligation, no elevation was recorded in the ischemic area in terms of the number of beta-adrenergic receptors (49 +/- 6 fmol/mg protein) and the level of cAMP (0.79 +/- 0.06 nmol/g weight). When animals were pretreated with a beta-blocker or a ganglion blocker, coronary ligation did not result in VF. In the ischemic area of these animals, no significant change was noted in the number of beta-adrenergic receptors (54 +/- 7 fmol/mg protein for animals pretreated with a beta-blocker, 56 +/- 3 fmol/mg protein for animals pretreated with a ganglion blocker). These results suggest that there is a strong correlation between the pathogenesis of VF (observed about 15 min after coronary ligation) and the increase of the number of beta-adrenergic receptors and cAMP levels.
Animals↗
Cardiovascular effects of cocaine in conscious rats: relative significance of central sympathetic stimulation and peripheral neuronal monoamine uptake and release mechanisms.
Cocaine (0.03-3 mg/kg, i.v.) produced a dose-dependent increase in mean arterial blood pressure and heart rate in conscious Sprague-Dawley rats. Pretreatment with the competitive ganglionic blockers pentolinium or hexamethonium attenuated cocaine's pressor effect, whereas noncompetitive (chlorisondamine) or mixed (mecamylamine) type blockers not only abolished, but also reversed it to a depressor effect. Cocaine's tachycardiac effect was attenuated by all four ganglionic blockers. The relative effectiveness of the four ganglionic blockers in antagonizing cocaine-induced cardiovascular effects was similar to that of antagonism of phenylephrine-induced, centrally mediated reflex bradycardia. All four ganglionic blockers at all the doses tested produced similar reductions in base-line BP, thereby suggesting that these agents produced similar degrees of maximal reduction of basal sympathetic tone. The pressor responses to norepinephrine (0.2 micrograms/kg) were potentiated, whereas those to tyramine (0.3 mg/kg) were inhibited by cocaine (0.3-3 mg/kg); the former effect was not dose dependent (bell-shaped dose-response curve), whereas the latter effect was dose-dependent. The amine uptake inhibitory potency (ED50, 0.85 mg/kg) of cocaine is about 10 times less than its potency to produce pressor (ED50, 0.075 mg/kg) and tachycardiac (ED50, 0.083 mg/kg) effects. Chlorisondamine did not antagonize the pressor effects of the indirect sympathomimetic agent, tyramine. These results suggest that the blockade of cocaine's pressor and tachycardiac effects by ganglionic blockers is not related to their ability to eliminate basal sympathetic tone and, thereby, indirectly blunt cocaine's inhibitory effect on sympathetic neuronal uptake of norepinephrine. Rather, the results indicate that these effects are mainly due to their antagonistic actions on cocaine-induced central stimulation of sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Molecular mechanisms of open-channel blockade in nicotinic acetylcholine receptors of autonomic ganglia neurons.
The results of recent attempts to estimate the dimensions of ionic channels in nicotinic acetylcholine receptors of sympathetic and enteric ganglia neurons are reviewed. The channel dimensions, obtained from comparison of the sizes of the open-channel blocking molecules with their blocking activities, are 6.1 x 8.3 A (1 A = 0.1 nm) in both sympathetic and enteric ganglia. None of the competitive ganglionic blockers fit within this channel size. In addition, a chemical structure that binds the open-channel blockers in ganglionic nicotinic acetylcholine receptors is suggested to be formed by serine and threonine residues, as found by comparing the differences between the structures of the neuronal and muscle nicotinic acetylcholine receptors with the differences in their pharmacology.
Amino Acid Sequence↗
An electrophysiological study of ganglion blockade by paraquat and diquat.
1. The bipyridilium herbicides, particularly paraquat, have chemical and toxicological features in common with the bi-quaternary ammonium ganglion blockers. 2. Paraquat and diquat were tested for ganglion blocking activity. Rabbit cervical ganglia were superfused with both agents and subsequently with hexamethonium to confirm susceptibility to ganglion blockade. 3. No evidence for ganglion blockade was found at either supra maximal or sub maximal stimulation, and none following repetitive stimulation. 4. The similarities and differences between the bipyridyl herbicides and bi-quaternary ganglion blockers can be explained on the basis of their structures. 5. It is concluded that neither paraquat nor diquat have significant ganglion blocking activity.
Animals↗
Circulating catecholamines modulate ischemic brain damage.
In search of factors influencing the outcome of an ischemic insult, we induced 10 min of forebrain ischemia in rats and assessed neuronal necrosis by quantitative histopathology after 1 week of recovery. Procedures for inducing ischemia included bilateral carotid artery clamping and reduction of blood pressure to 40-50 mm Hg by bleeding. To facilitate rapid lowering of blood pressure, a ganglionic blocker, trimethaphan (TMP), was administered at the onset of ischemia. Omission of the ganglionic blocker proved to markedly ameliorate neuronal damage. Similarly favorable effects were obtained when a mixture of adrenaline and noradrenaline (1 microgram kg-1 min-1 each) was infused during the early recirculation period in animals previously given TMP. Infusion of noradrenaline alone also ameliorated the damage, though the efficacy was somewhat less. The results suggest that catecholamines, released as a response to stress, ameliorate ischemic brain damage.
Animals↗
Intragastric nicotine protection against 40% ethanol injury in rat stomach. Role of ganglionic stimulation or blockade.
Intragastric nicotine (4 mg/kg) protects against 40% ethanol-induced gastric mucosal injury and raises mean blood pressure. We postulated that this protective effect was mediated by the ganglionic stimulatory property of nicotine and therefore could be abolished by ganglionic blockers. Rats were pretreated with intraperitoneal hexamethonium (10 mg/kg) or mecamylamine (2 mg/kg) to block peripheral or central autonomic ganglia, respectively. Intragastric vehicle or nicotine (4 mg/kg) was then administered. The total lengths of the linear gastric corpus mucosal lesions induced by intragastric 40% ethanol were measured by an unbiased observer using a caliper. The results showed that both intraperitoneal hexamethonium and mecamylamine pretreatments protected against 40% ethanol-induced gastric mucosal injury. Neither modified the protective effect of intragastric nicotine. The protective effect of hexamethonium and mecamylamine was associated with a significant increase in the volume of gastric mucus and gastric juice. The increase in the volume of gastric content (mucus and juice) was partially responsible for the protective effect of these ganglionic blockers. In a separate experiment, intraperitoneal nicotine (4 mg/kg) also protected against 40% ethanol-induced gastric mucosal injury and raised mean blood pressure. These data indicate that the protection against 40% ethanol-induced gastric mucosal injury is not unique to intragastric nicotine. Such protection can be induced by ganglionic blocking doses of hexamethonium and mecamylamine, or a ganglionic stimulatory dose of intraperitoneally administered nicotine. Whether ganglionic stimulation or blockade plays a role in the mechanism of intragastric nicotine protection, however, remains to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Mechanisms involved in the respiratory depressant actions of nicotine in anesthetized rats.
In the urethane-pentobarbital anesthetized rat, the respiratory depressant and lethal effects of intravenously infused (-)-nicotine (120 micrograms/kg/min) or (+)-nicotine (600 micrograms/kg/min) were effectively prevented by pretreatment with the opioid antagonist, naltrexone, whereas the lethal effect of (-)-nicotine (120 micrograms/kg/min) was not altered by bilateral adrenalectomy. Further, pretreatment with either the nicotinic ganglion-blocker, mecamylamine, a secondary amine, or the quarternary nicotinic ganglion-blocker, hexamethonium, completely prevented the lethal effects of (-)-nicotine (120 micrograms/kg/min). These data suggest that central opioidergic and nicotinic processes are involved in nicotine's respiratory depressant and lethal effects.
Anesthesia↗
Characterization of the effect of nicotine on vasopressin and atrial natriuretic factor in the rabbit.
The effects of nicotine on the secretion of arginine vasopressin (AVP) and of the atrial natriuretic factor (ANF) were examined in conscious rabbits. Nicotine was shown to produce significant increases in plasma AVP from 1.7 +/- 0.4 to 75.3 +/- 35.1 pg/ml (P less than .05) and in plasma ANF levels from 39 +/- 11 to 121 +/- 52 pg/ml (P less than .05) within 5 min of an i.v. dose of 0.5 mg/kg. These nicotine-induced stimulations could not be inhibited by muscarinic (atropine), dopaminergic [(+/-)-sulpiride], alpha (phenoxy-benzamine) or beta adrenergic (propranolol) blockers or by a rapid infusion of fluids. Trimetaphan was ineffective in blocking the stimulation of AVP secretion but completely abolished the nicotine-induced secretion of ANF. The more lipophilic ganglionic blocker, mecamylamine, blocked the stimulation of the secretion of both peptides. The effect of nicotine on AVP production was confirmed in vitro using the rat hypothalamo-neurohypophysial system preparation where nicotine increased AVP secretion in a dose-dependent manner. This in vitro stimulation was blocked by the ganglionic blocker hexamethonium. The increase in ANF plasma concentrations was probably due to a primary response to nicotine, for although exogenous AVP (1 microgram i.v.) increased ANF levels by a factor of 3 (P less than .05), the AVP antagonist [-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-2- (O-methyl)tyrosine]arginine vasopressin did not prevent the nicotine-induced increase in ANF. Thus, nicotine or its effects appear to stimulate the secretion of ANF and not AVP. It was concluded that nicotine stimulates the secretion of AVP by activating central nicotinic projections to the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reflex pressor response to gastric mechanical stimulation in rats.
Neural and humoral mechanisms involved in the reflex pressor response during mechanical stimulation of the stomach of rats were investigated. The arterial blood pressure response was prevented by inhibition of alpha-adrenergic vasoconstriction using either an alpha-adrenergic blocker or a ganglionic blocker. In addition, there was a small decrease in the response after nephrectomy. However, there were no alterations in the response after beta-adrenergic blockade, bilateral adrenalectomy, inhibition of converting enzyme activity with enalapril or bilateral cervical vagus nerve transection. The heart rate was not modified after either intervention. After vagotomy the time of recovery of the basal blood pressure was significantly prolonged. It can be concluded that the blood pressure response to mechanical stimulation of the stomach wall is of neural rather than of humoral origin and mainly involves activation of alpha-adrenergic receptors. Vagal efferent pathways could be also involved.
Adrenalectomy↗
Differential autonomic control of SAN and AVN regions of the canine heart: structure and function.
Both anatomical and physiologic evidence for relatively rich autonomic innervation of sinoatrial (SAN) and atrioventricular (AVN) regions of the canine heart exist, with indication that SAN is especially responsive to parasympathetic, while AVN is preferentially sensitive to sympathetic regulation. The distribution of autonomic pathways are sufficiently separate and discrete that careful surgical intervention can selectively delete either parasympathetic or sympathetic nerve supplies to either (or both) SAN and AVN regions. Selective blockade by restricted injections of lidocaine (general neuronal blocker) or hexamethonium (ganglionic blocker) indicate that the vast majority (perhaps all) of vagal ganglia supplying SAN reside in the pulmonary vein fat pad and associated adipose tissues. In contrast, the vagal ganglia supplying AVN are found within a smaller fat pad overlying epicardium at the junction of inferior vena cava-inferior left atrium. These vagal pathways to either automatic cells of SAN or conductile tissues of AVN can be selectively interrupted without interfering with vagal regulation of the remaining intact system. Electroneurograms from large neurons situated within PVFP of the anesthetized, open-chest animal, reveal vigorous, phasic electrical activity associated with the cardiac and respiratory cycles, as well as with sensory stimulation of the heart, great vessels, and lungs. Spontaneous electrical activity of presently unknown origin is also observed. Direct neuronal stimulation, plus retrograde transport of fluorescent markers suggest that highly selective postganglionic intracardiac pathways may regulate discharge patterns of the sinus automatic cells.
Animals↗
Dopamine, noradrenaline and isoprenaline: secretory and electrophysiological effects in vitro on mouse pancreas.
The amylase release from mouse pancreatic fragments was studied after dopamine (DA), and alpha- or beta-sympathomimetic agonist application. The electrical parameters of the acinar cell membrane were also monitored. Both DA (from 5 X 10(-6) to 10(-4) M) and beta-stimulants (isoprenaline from 5 X 10(-6) to 5 X 10(-5) M; noradrenaline from 3 X 10(-4) to 10(-3) M) evoked an increase in amylase release, while noradrenaline in alpha-receptor stimulating doses failed to have any effect. The stimulatory effect of DA was blocked by ganglion blockers (Arfonad 10(-5) M; pentamethonium 3 X 10(-5) M) in a competitive manner and a dual antagonism was observed with atropine (10(-7) M, 10(-9) M). An alpha-receptor antagonist (phentolamine 10(-5) M) and a beta-receptor antagonist (propranolol 10(-5) M) had no influence on the dopamine response. Moreover, the DA-induced stimulation was dependent on the presence of extracellular calcium. Perfusion with 10(-4) and 10(-3) M-DA or local application (from 77 micrograms to 4.3 mg), resulted in marked membrane depolarization with diminution of the input resistance. This effect was blocked by atropine (10(-5) M) and pentamethonium (10(-4) M), but not by propranolol (10(-5) M) or phentolamine (10(-5) M). The isoprenaline- (IP) and noradrenaline- (NA) induced increase in amylase release was competitively blocked by propranolol (10(-5) M) but not by phentolamine (10(-5) M). Atropine caused a dose-dependent (10(-7) M, 10(-6) M) decrease in the maximal response (non-competitive antagonism), while the ganglion blocker pentamethonium (10(-4) M) was without effect. NA caused membrane depolarization accompanied by a decrease in the input resistance after local application (from 77 micrograms to 1.6 mg). This effect persisted in the presence of 10(-5) M-phentolamine but was abolished by 10(-5) M-propranolol. IP perfusion (10(-4) and 10(-3) M) or local application (0.3 M; from 32 to 130 micrograms) caused the same electrical changes as those induced by NA and DA. The effect of IP persisted in the presence of 10(-5) M-phentolamine, 10(-4) M-pentamethonium and 10(-4) M-domperidone, but was abolished by propranolol (10(-5) M) and tetrodotoxin (5 X 10(-6) M) and markedly diminished by atropine (10(-5) M).(ABSTRACT TRUNCATED AT 400 WORDS)
Action Potentials↗
Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization.
The effect of intravenous (i.v.) serotonin (5-HT) on nociception and blood pressure was examined in male Sprague-Dawley rats. Intravenous 5-HT produced a dose-dependent (6-192 micrograms/kg, i.v.) inhibition of the nociceptive tail-flick (TF) reflex in lightly pentobarbital-anesthetized (ED50 = 40 micrograms/kg) and conscious rats (ED50 = 44 micrograms/kg). In the lightly pentobarbital-anesthetized rat, the blood pressure response to i.v. 5-HT was typically a triphasic response with a marked Bezold-Jarisch reflex-induced decrease in pressure (associated with a brief period of apnea) followed by a pressor phase and a subsequent delayed hypotension. In the conscious rat, the response was typically biphasic with the late hypotensive phase absent. A variety of anatomical and pharmacological manipulations were performed to characterize the 5-HT-induced inhibition of the TF reflex and associated changes in blood pressure. Prevention of 5-HT-induced reflex apnea by artificial ventilation did not affect inhibition of the TF reflex produced by 5-HT. Pharmacological manipulations were performed to mimic, as closely as possible, the acute increases and decreases in blood pressure associated with i.v. 5-HT. Nitroprusside (8 micrograms/kg, i.v.) produced a decrease in blood pressure of similar magnitude and rate as that associated with the Bezold-Jarisch reflex-induced decrease in pressure produced by 72 micrograms/kg 5-HT, but did not change TF latency from baseline. Similarly, acute increases in pressure produced by phenylephrine (8 micrograms/kg, i.v.), intended to mimic the secondary pressor effect of 5-HT, did not change TF latency. The short-acting ganglion blocker trimethaphan (5 mg/kg, i.v.) closely mimicked the late hypotensive phase produced by 5-HT, but again resulted in no change in TF latency. Pretreatment with the ganglion blocker chlorisondamine (2.5 mg/kg) abolished all depressor responses to 72 micrograms/kg 5-HT, but did not significantly affect the TF reflex. These results indicate that acute changes in blood pressure and respiration associated with i.v. 5-HT do not contribute to inhibition of the TF reflex. This conclusion was confirmed in experiments in which bilateral vagotomy abolished approximately 70% of the 5-HT-induced inhibition of the TF reflex (and all depressor responses), and resulted in a significantly greater pressor response. Finally, low thoracic spinal cord transection (T9-10) abolished the inhibition of the TF reflex produced by i.v. 5-HT. Therefore, 5-HT stimulates vagal afferents and inhibits the TF reflex by activating descending inhibitory systems from the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)
Afferent Pathways↗
Capsaicin-sensitive primary afferents are involved in the hypotensive effect of neurotensin in ganglion-blocked guinea pigs.
The mechanism of the blood pressure (BP)-lowering effect of neurotensin (NT) in the anesthetized, ganglion-blocked guinea pigs was further examined using animals in which the basal BP was artificially raised by an IV infusion of noradrenaline (NA) to overcome the BP-lowering effect of the anesthesia as well as of the ganglion blocker. The animals were also vagotomized and given atropine at the beginning of the experiments to prevent potential baroreceptor-mediated vagal reflexes and/or activation of muscarinic receptors by endogenous acetylcholine. Under these experimental conditions, the IV bolus injections of NT as well as of capsaicin (a reference drug) produced dose-dependent hypotensive effects and variable levels of tachycardia. Omitting the ganglion blocker from the animal drug regimen attenuated but did not abolish the BP-lowering effect of NT and of capsaicin. Neither the hypotensive nor the tachycardic effects of NT and of capsaicin in ganglion-blocked guinea pigs were affected by prior animal treatment with propranolol (a beta adrenoceptor blocker), antihistaminics (mepyramine, cimetidine) or indomethacin (a cyclooxygenase inhibitor). Morphine was found to slightly reduced the hypotensive effect of NT without altering its slight tachycardic effect. Both the hypotensive and tachycardic effects of NT and of capsaicin, in contrast to those elicited by substance P (SP) and calcitonin gene-related peptide (CGRP), were inhibited in ganglion-blocked guinea pigs pretreated four days previously with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)
Afferent Pathways↗
Pharmacological distinctions between functional nicotinic acetylcholine receptors on the PC12 rat pheochromocytoma and the TE671 human medulloblastoma.
Some properties of functional nicotinic acetylcholine receptors (nAcChoR) expressed by the PC12 rat pheochromocytoma or the TE671 human medulloblastoma were studied by the use of an isotopic rubidium ion efflux assay. The assay involves active uptake of 86Rb+ via a ouabain-sensitive mechanism to load cells with isotopic tracer and the subsequent release of ion from cells through agonist-activated opening of nAcChoR-coupled ion channels. For either cell line the rate of receptor-mediated ion efflux is time-dependent and falls as duration of exposure to agonist increases. However, dose-response curves for agonist activation of receptor function (or for antagonist blockade of agonist activation) are temporally invariant. Dose-response curves have characteristic shapes for a given agonist, and the relative and absolute potencies of agonists differ between TE671 and PC12 cells. Most notably, nicotine and cytisine are more potent activators of receptor function on the PC12 cell line whereas TE671 cell nAcChoR are more sensitive to activation by isoarecolone and suberyldicholine. PC12 cell nAcChoR are more sensitive to blockade by the classic "ganglionic" blockers, mecamylamine and hexamethonium, and by the molluscan substance, neosurugatoxin, than are nAcChoR on TE671 cells. The results, illustrating differences in the pharmacological profiles of drugs acting as functional nAcChoR on TE671 and PC12 cells, suggest that structural differences exist in nAcChoR active site(s) and are consistent with the notion that functional nAcChoR are a heterogeneous family of macromolecules.
Animals↗
Adrenal proenkephalin-derived peptides during postnatal development in spontaneously hypertensive rats.
Adrenal enkephalin and enkephalin-containing peptides were studied during postnatal development in normotensive (WKY) and spontaneously hypertensive rats (SHR). The effect of chronic treatment with the ganglionic blocker chlorisondamine (5 mg/kg) was also assessed. Free enkephalin immunoreactivity and total enkephalin immunoreactivity, as determined by enzymatic digestion of large enkephalin containing fragments, were quantitated in the adrenal glands at 11 days and 7, 16, and 24 weeks of age. Both total and free metenkephalin were significantly diminished in the adrenal of SHR when compared to WKY at all ages tested. The analysis of the chromatographic profile showed that SHR displayed reduced levels of high and low molecular weight materials at 11 days and 16 weeks of age; however intermediate compounds were high in the glands of these animals. Similar increased values for free met-enkephalin were found in adrenals of WKY and SHR after ganglionic blocker treatment, which means that the relative increase was larger in SHR than WKY; while for total enkephalin the relative increase and the concentration reached in SHR was about half of those presented in WKY. These and other results presented suggest that the basic alteration of the adrenal proenkephalin system of SHR may be due to a genetic reduction of proenkephalin levels. Otherwise, the free enkephalin decrease could be related to changes in nervous input to the adrenal gland.
Adrenal Glands↗