[Ganglion blockers, alarm reaction and experimental shock caused by burns].
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Burns↗
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[Effect of ganglion-blockers on anesthetic effect and toxicity of thiopental].
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Analgesia↗
Management of systemic and pulmonary hypertension.
The major therapeutic approach to systemic and pulmonary hypertension and vasospasm in cardiac surgery patients involves the use of parenteral agents that reverse systemic vasoconstriction and produce vasodilation. Potential pharmacologic approaches include 1) alpha1-adrenergic receptor blockers, ganglionic blockers, and calcium channel blockers; 2) central alpha2-adrenergic receptor agonists, dopamine1-adrenergic receptor agonists, potassium channel modulators, and vascular cyclic nucleotide stimulators; 3) phosphodiesterase enzyme inhibitors, and 4) angiotensin-converting enzyme inhibitors. Of the currently available intravenous vasoactive therapies, the mainstay agents are the nitrovasodilators and the dihydropyridine-type calcium channel blockers. The nitrovasodilators, a diverse group of drugs that achieve vascular relaxation by stimulating cyclic nucleotides and thereby releasing nitric oxide, include nitroglycerin and sodium nitroprusside. Although these drugs are useful, rapid development of tolerance is a drawback to nitroglycerin, while nitroprusside can cause coronary steal and increase intracranial pressure. Intravenous dihydropyridine-type calcium channel blockers inhibit mechanical responses of cardiac muscle and vascular smooth muscle by blocking inward calcium currents. Nicardipine is an arterial specific vasodilator. Treatment for vasospasm is usually empiric; pharmacologic options include nitroglycerin, but dihydropyridine calcium channel blockers and phosphodiesterase inhibitors should also be considered.
Cardiac Surgical Procedures↗
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↗
Evidence that distinct neural pathways mediate parasympathetic contractions and relaxations of guinea-pig trachealis.
1. The guinea-pig trachea was isolated with its extrinsic innervation intact and pinned to the bottom of a water-jacketed dissecting dish filled with warmed, oxygenated Krebs solution. The trachea was not separated from the oesophagus. Isometric tension was measured in a segment of the rostral portion of the trachea. 2. Stimulation of the vagus nerves caudal to the nodose ganglia elicited contractions of the trachealis that were blocked by the muscarinic receptor antagonist atropine. Following addition of atropine and contraction of the trachealis with prostaglandin F2 alpha (PGF2 alpha), vagus nerve stimulation elicited non-adrenergic, non-cholinergic relaxations. Both responses elicited by stimulation of the vagi were abolished by cutting the recurrent laryngeal nerves and were considered parasympathetic in nature as they were sensitive to the autonomic ganglion blockers trimetaphan and hexamethonium. 3. Experiments were designed in which ganglionic blockers were added to the buffer bathing the entire preparation or, alternatively, added only to the buffer perfusing the tracheal lumen. When given equal access to the trachea and oesophagus, hexamethonium was 56-fold more potent an inhibitor of vagally mediated relaxations of the trachealis than vagally mediated contractions. Selective administration of hexamethonium to the buffer perfusing the tracheal lumen did not decrease the potency of the ganglionic blocker versus vagally mediated contractions. By contrast, even at a concentration of 1 mM, intratracheally administered hexamethonium failed to inhibit vagally mediated relaxations by 50%. Comparable results were obtained using trimetaphan. 4. Consistent with previous observations, removing the portion of the oesophagus contiguous with the region of the trachea at which isometric tension was measured abolished parasympathetic relaxations of the trachealis. Oesophagus removal was without effect on parasympathetic nerve-induced contractions. Removing the dorsal half of the oesophagus or the mucosa and submucosa of the oesophagus did not affect the parasympathetic relaxant innervation. 5. The compound action potential of guinea-pig recurrent laryngeal nerves evoked by vagus nerve stimulation consisted of three distinct peaks representing populations of axons with fast, intermediate and slow conduction velocities. The voltage-response characteristics of vagally mediated contractions were identical to those of the compound action potential peak representing fibres with intermediate (10 m/s) conduction velocities. By contrast, the voltage-response characteristics of the vagally mediated relaxations were best correlated with the compound action potential peak representing fibres with slow (0.4-3 m/s) conduction velocities.(ABSTRACT TRUNCATED AT 400 WORDS)
Action Potentials↗
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↗
[Ion channel topography of the neuronal nicotinic acetylcholine receptor : pharmacochemical approaches].
Forty-three bisammonium ganglionic blockers were synthesized to study the structure of the ion channel of nicotinic acetylcholine receptor. The conformational parameters of these blockers were studied, and their effects toward the ganglionic transmission in situ on the sympathetic feline upper cervical ganglions and in vitro on the parasympathetic guinea-pig small intestine ganglions were determined. A model of the binding site for the bisammonium ganglionic blockers in the neuronal ion channel was proposed.
Amino Acid Sequence↗
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↗
Comparison of hypotensive, orthostatic and sympathetic inhibitory actions of antihypertensive drugs in rats.
Hypotensive and orthostatic activities of a variety of orally administered antihypertensive drugs were concurrently evaluated in conscious spontaneously hypertensive rats and attempts were made to relate these responses to effects on peripheral sympathetic function. The alpha-adrenergic blockers phentolamine and prazosin and the adrenergic neuron blocker guanethidine inhibited compensatory responses to upright tilt at antihypertensive doses. The ganglionic blocker mecamylamine produced milder inhibition. The centrally active agents methyldopa and clonidine and the vasodilator minoxidil did not alter tilt responses appreciably. In contrast, the vasodilator hydralazine exerted marked postural effects. Autonomic interactions were evaluated in pithed rats. alpha-Adrenergic receptor, adrenergic neuron and ganglionic blockers inhibited pressor responses to i.v. phenylephrine and/or to sympathetic nerve activation. Vasodilators did not produce specific effects. The tilt and pithed rat models, when used in conjunction, are very useful in predicting orthostatic potential of drugs in humans although absolute correlation cannot be expected.
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↗
Vasodilator effect of insulin on the microcirculation of the rat cremaster muscle.
We recently showed that, in conscious rats, acute infusions of insulin (10-15 fold increase in plasma insulin) produced decreases in hindquarter vascular resistance, but only if, changes in sympathetic outflow were prevented with a ganglionic blocker. The aim of the present investigation was to determine if similar effects of insulin could be observed in a preparation that allowed direct visualization of striated muscle (cremaster) microvessels. Initial studies with topical application of insulin showed that third-order arterioles (A3), but not first- or second-order arterioles vasodilated in response to 800 microU/ml and 8 mU/ml of insulin. Systemic (euglycemic) infusion of insulin (6 mU/ml, but not 2 mU/ml) also increased A3 arteriole diameter in animals treated with a ganglionic blocker, but not in control rats. These data show that insulin can have a direct vasodilator effect on striated muscle microvessels if concomitant increases in sympathetic outflow are absent. However, the response was only present with supraphysiological doses of the hormone.
Administration, Topical↗
Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion.
GLUT2-/- mice reexpressing GLUT1 or GLUT2 in their beta-cells (RIPGLUT1 x GLUT2-/- or RIPGLUT2 x GLUT2-/- mice) have nearly normal glucose-stimulated insulin secretion but show high glucagonemia in the fed state. Because this suggested impaired control of glucagon secretion, we set out to directly evaluate the control of glucagonemia by variations in blood glucose concentrations. Using fasted RIPGLUT1 x GLUT2-/- mice, we showed that glucagonemia was no longer increased by hypoglycemic (2.5 mmol/l glucose) clamps or suppressed by hyperglycemic (10 and 20 mmol/l glucose) clamps. However, an increase in plasma glucagon levels was detected when glycemia was decreased to < or =1 mmol/l, indicating preserved glucagon secretory ability, but of reduced sensitivity to glucopenia. To evaluate whether the high-fed glucagonemia could be due to an abnormally increased tone of the autonomic nervous system, fed mutant mice were injected with the ganglionic blockers hexamethonium and chlorisondamine. Both drugs lead to a rapid return of glucagonemia to the levels found in control fed mice. We conclude that 1) in the absence of GLUT2, there is an impaired control of glucagon secretion by low or high glucose; 2) this impaired glucagon secretory activity cannot be due to absence of GLUT2 from alpha-cells because these cells do not normally express this transporter; 3) this dysregulation may be due to inactivation of GLUT2-dependent glucose sensors located outside the endocrine pancreas and controlling glucagon secretion; and 4) because fed hyperglucagonemia is rapidly reversed by ganglionic blockers, this suggests that in the absence of GLUT2, there is an increased activity of the autonomic nervous system stimulating glucagon secretion during the fed state.
Animals↗