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British Journal of Clinical Pharmacology Jan 1982
Topics: Animals; Blood Pressure; Cats; Hexamethonium Compounds; Humans; Hypertension; Structure-Activity Relationship
PubMed: 7066156
DOI: 10.1111/j.1365-2125.1982.tb01331.x -
British Journal of Pharmacology and... Dec 1958The influence of hexamethonium and pentolinium on the responses of certain peripheral effector cells to adrenaline, noradrenaline or postganglionic stimulation was...
The influence of hexamethonium and pentolinium on the responses of certain peripheral effector cells to adrenaline, noradrenaline or postganglionic stimulation was studied in the cat. The actions of adrenaline and noradrenaline on the blood vessels of a limb and of adrenaline and postganglionic stimulation on the nictitating membrane were increased after the administration of hexamethonium and pentolinium. This effect was considered to be due to sensitization of the peripheral effector cells. The possible significance of these findings is discussed.
Topics: Animals; Cardiovascular Agents; Cats; Epinephrine; Hexamethonium; Hexamethonium Compounds; Muscle Relaxants, Central; Nictitating Membrane; Norepinephrine; Pentolinium Tartrate; Peripheral Nerves; Pharmaceutical Preparations
PubMed: 13618555
DOI: 10.1111/j.1476-5381.1958.tb00242.x -
Anesthesiology Jan 1991Previous studies have demonstrated that bupivacaine administered directly into the central nervous system (CNS) is capable of producing signs of bupivacaine...
Previous studies have demonstrated that bupivacaine administered directly into the central nervous system (CNS) is capable of producing signs of bupivacaine cardiovascular toxicity. To investigate the mechanisms by which bupivacaine may act within the CNS to produce cardiovascular toxicity, we studied four groups of halothane-anesthetized rabbits in which infusion of intracerebroventricular (icv) bupivacaine or intravenous (iv) phenylephrine resulted in dysrhythmias and hypertension. In group 1 (n = 5), icv bupivacaine (500 +/- 79 micrograms [mean +/- SEM]) produced dysrhythmias lasting 73 +/- 13 min, whereas icv saline caused no dysrhythmias or hypertension. In group 2 (n = 9), icv bupivacaine-induced hypertension and dysrhythmias were abolished by icv midazolam in 4.4 +/- 0.6 min, and when dysrhythmias and hypertension recurred (22 +/- 0.9 min), hexamethonium (10 mg/kg iv) promptly terminated dysrhythmias and hypertension (14 +/- 1 s). In group 3 (n = 10), icv bupivacaine-induced dysrhythmias and hypertension were not affected by increasing the inspired halothane concentration from 0.8 to 1.6%. In group 4 (n = 6), iv phenylephrine-induced dysrhythmias and hypertension were not affected by icv midazolam. These results suggest that icv bupivacaine produces dysrhythmias and hypertension by increasing autonomic nervous system (ANS) outflow from the brain stem. The finding that peripheral autonomic blockade by hexamethonium rapidly terminated dysrhythmias and hypertension supports this mechanism. We speculate that icv bupivacaine produces an increase in autonomic outflow by blockade of the inhibitory gamma-aminobutyric acid (GABA) neurons that are known to be the principal tonic inhibitors of the ANS.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Brain; Bupivacaine; Halothane; Hexamethonium; Hexamethonium Compounds; Hypertension; Injections, Intraventricular; Midazolam; Phenylephrine; Rabbits; Receptors, GABA-A
PubMed: 1670915
DOI: 10.1097/00000542-199101000-00015 -
British Journal of Pharmacology Oct 19681. The present investigation was made on the left kidney of the dog. The animals were anaesthetized intravenously with pentobarbitone (30 mg/kg) and the kidneys were...
1. The present investigation was made on the left kidney of the dog. The animals were anaesthetized intravenously with pentobarbitone (30 mg/kg) and the kidneys were perfused with saline at room temperature (20 degrees -22 degrees C). The renal innervation was untouched.2. Stimulation of the left splanchnic major nerve at T10-T12, and of the renal nerves, consistently caused renal vasoconstriction.3. Repeated stimulation of both supradiaphragmatic vagi failed to induce any vasomotion in the kidney.4. The vasoconstrictor effect was not blocked by either nicotine or hexamethonium even in enormous doses (30,000 mug). This may indicate that renal ganglia do not exist, for these ganglion blockers would prevent transmission across the ganglia.5. Kidney perfusate, re-injected into the kidney after vasoconstriction induced by stimulation of the renal nerves, brought about a notable reduction in outflow. This effect was not observed when perfusate from a non-stimulated kidney was used. This points to the release of a vasoconstrictor substance after nervous stimulation.6. Acetylcholine (ACh) in concentrations ranging from 0.001 mug/ml. caused a reduction in renal outflow. Thresholds were extremely variable. Higher concentrations of ACh (100-1,000 mug/ml.) often induced vasodilatation. The vasoconstrictor effect of ACh was not blocked by atropine.7. Nicotine and hexamethonium (10,000-30,000 mug) induced blockade which elevated the threshold for ACh to values of 1,000 mug/ml.8. Noradrenaline (0.0001 mug/ml.) induced a strong renal vasoconstriction.9. Hydergine (5-10 ml. solutions in concentrations ranging from 15 to 30 mug/ml.) blocked the renal response to nerve stimulation. This suggests that the nature of the renal innervation is adrenergic.10. In diseased kidneys which show reduction of the lumen of the arterioles, the thresholds for ACh, nicotine and noradrenaline are greatly increased, which might explain why we failed to show any effect of these drugs on renal vasomotion in several kidneys, many of which were not examined histologically.11. The collision technique was applied in an attempt to discover the nature of the fibres activated by ACh. It was found that ACh greatly reduced the size of the action potentials generated by splanchnic stimulation. This would seem to indicate that these impulses are conducted antidromically by sympathetic postganglionic fibres.12. These findings are discussed in relation to the hypothesis that the renal innervation is chiefly adrenergic and that ACh acts as a sympathetic transmitter, liberating noradrenaline, and that this effect is blocked at postganglionic endings, or at some structure intervening between adrenergic nerve endings and the effector cells, or at sensory nerve endings.
Topics: Acetylcholine; Animals; Dogs; Electric Stimulation; Ergoloid Mesylates; Hexamethonium Compounds; Kidney; Nicotine; Norepinephrine; Splanchnic Nerves; Vagus Nerve; Vasoconstrictor Agents; Vasomotor System
PubMed: 4972068
DOI: 10.1111/j.1476-5381.1968.tb07051.x -
British Journal of Pharmacology and... Dec 1960Histamine stimulated the isolated auricles and heart of the guinea-pig. The effect was best seen in auricles which had been previously depressed by treatment with...
Histamine stimulated the isolated auricles and heart of the guinea-pig. The effect was best seen in auricles which had been previously depressed by treatment with reserpine. Ganglionic blocking drugs (hexamethonium and pempidine), applied to auricles which had been previously treated with reserpine, abolished the diphasic effect of nicotine, but did not alter the response to histamine. Dichloroisoproterenol did not modify the stimulant action of histamine in isolated auricles, either before or after treatment with reserpine; nor did it alter the response of the isolated heart. Diphenhydramine reduced or blocked the stimulant action of histamine in auricles which had been previously treated with reserpine. The results support the hypothesis that histamine stimulates the myocardium by a direct action on specific receptors.
Topics: Diphenhydramine; Ganglionic Blockers; Guinea Pigs; Heart; Hexamethonium; Hexamethonium Compounds; Histamine; Isoproterenol; Myocardium; Nicotine; Pempidine; Piperidines; Reserpine; Sympatholytics
PubMed: 13766225
DOI: 10.1111/j.1476-5381.1960.tb00270.x -
British Journal of Pharmacology and... Feb 1964In cats and rabbits procainamide (20 to 50 mg, intravenously) produced a fall of blood pressure of 20 to 50 mm Hg which reached a maximal effect within 1 min and lasted...
In cats and rabbits procainamide (20 to 50 mg, intravenously) produced a fall of blood pressure of 20 to 50 mm Hg which reached a maximal effect within 1 min and lasted for about 5 min. Procainamide reduced the pressor responses to nicotine and to carotid arterial occlusion and reduced the depressor response to vagal stimulation, but did not antagonize the actions of adrenaline or noradrenaline on blood vessels. The contractions of the nictitating membrane to stimulation of the preganglionic cervical sympathetic nerve were partially or completely blocked by 20 to 50 mg of procainamide given intravenously. The ganglion blocking effect was more abrupt in onset and more slow to recover than that due to hexamethonium and had about 1/250th of the activity of the latter. Procainamide (1 mg) reduced the acetylcholine output of the perfused superior cervical ganglion to below 30% of the control value and blocked transmission completely. Small doses (10 mug) reduced the acetylcholine output but hardly affected ganglionic transmission. Procainamide, injected into the perfused superior cervical ganglion, blocked contractions elicited by stimulation of the preganglionic cervical sympathetic nerve for a longer period than those produced by acetylcholine injected into the perfusion circuit to the ganglion; the reverse was true for hexamethonium. Procainamide reduced the size of action potentials recorded from the superior cervical ganglion without altering the resting potential of the ganglion. The ganglion blocking activities of procainamide and hexamethonium often potentiated each other, especially when the preparation had been set up for several hours. On the guinea-pig isolated ileum preparation, procainamide (0.5x10(-4) g/ml.) antagonized responses due to acetylcholine, histamine and, most effectively, to nicotine. On the isolated heart, procainamide (1 mg) almost abolished the bradycardia produced by acetylcholine; 10 mg slowed and weakened the heart, while 100 mg stopped it. We conclude that procainamide, like procaine, blocks ganglionic transmission by (1) depressing the release of acetylcholine from preganglionic nerve endings; and (2) competing, with the acetylcholine which is released, for receptor sites on the ganglion cells. The amounts required to produce significant effects in vivo and in vitro are comparable. The methods available for detecting this type of ganglion blocking action are discussed.
Topics: Acetylcholine; Animals; Blood Pressure; Cats; Electrophysiology; Ganglia; Ganglionic Blockers; Guinea Pigs; Heart; Hexamethonium; Hexamethonium Compounds; Histamine; Ileum; Nicotine; Nictitating Membrane; Norepinephrine; Pharmacology; Procainamide; Procaine; Rabbits; Research
PubMed: 14126044
DOI: 10.1111/j.1476-5381.1964.tb01552.x -
British Journal of Pharmacology Nov 1983The actions of pancuronium, a selective antagonist of acetylcholine (ACh) at nicotinic cholinoceptors at motor endplates, and hexamethonium, a selective antagonist of...
The actions of pancuronium, a selective antagonist of acetylcholine (ACh) at nicotinic cholinoceptors at motor endplates, and hexamethonium, a selective antagonist of ACh at nicotinic cholinoceptors in autonomic ganglia, have been studied in rat phrenic nerve diaphragm preparations. The effects on paraoxon-induced twitch potentiation and antidromic firing (ADF) in the phrenic nerve, were compared with the effects on normal twitch tension and intracellularly recorded miniature endplate potentials (m.e.p.ps) and endplate potentials (e.p.ps.) In preparations exposed to paraoxon, pancuronium was found to be approximately 10 times more effective in reducing the potentiated component of the twitch than the component which corresponded to the pre-paraoxon twitch. A similar result was obtained with hexamethonium. Pancuronium and hexamethonium, in concentrations which reduced paraoxon-induced twitch potentiation but had no effect on the twitch tension of preparations not treated with paraoxon, reduced paraoxon-induced ADF. The lowest concentrations of pancuronium and hexamethonium required for this also reduced the amplitude of m.e.p.ps and e.p.ps. Dithiothreitol, a disulphide bond reducing agent which reduces the affinity of ACh for nicotinic cholinoceptors, enhanced the potency of pancuronium 2 to 3 fold. The same also applied for hexamethonium. It is concluded that the experiments failed to provide evidence for an action of ACh on prejunctional nicotinic cholinoceptors of the ganglionic-type being involved in the initiation by paraoxon of twitch potentiation and ADF. Furthermore, the results obtained can be explained by pancuronium and hexamethonium reducing the action of ACh at the postjunctional membrane.
Topics: Animals; Hexamethonium Compounds; In Vitro Techniques; Male; Membrane Potentials; Motor Endplate; Neuromuscular Junction; Pancuronium; Paraoxon; Rats; Rats, Inbred Strains
PubMed: 6640203
DOI: 10.1111/j.1476-5381.1983.tb10720.x -
British Journal of Pharmacology and... Jun 1964Acetylcholine, in the presence of atropine, has an action like that of sympathetic stimulation. When injected into the splenic artery it causes contraction of the...
Acetylcholine, in the presence of atropine, has an action like that of sympathetic stimulation. When injected into the splenic artery it causes contraction of the spleen, but this action is blocked by hexamethonium; stimulation of the splenic nerves, however, is still effective. Thus hexamethonium distinguishes between sympathetic nerve stimulation and the action of acetylcholine. If bretylium is used instead of hexamethonium, there is no such distinction, for bretylium blocks the response to nerve stimulation as well as that to acetylcholine. It appeared that hexamethonium might block the action of acetylcholine by preventing its entry into the sympathetic fibre. Acetylcholine has some structural similarity to bretylium, since acetylcholine is a derivative of trimethylammonium and bretylium is a derivative of dimethylethylammonium. It has been found that hexamethonium, pentolinium and hemicholinium (HC-3), which are all bis-quaternary compounds, block the action of bretylium, presumably by preventing its entry into the fibre. Consistent with the view that ability to enter the fibre is important is the observation that mecamylamine and pempidine, which are ganglion-blocking agents, but not either mono- or bis-quaternary compounds, often abolish the response to stimulation of the sympathetic postganglionic fibre.
Topics: Acetylcholine; Animals; Atropine; Autonomic Nerve Block; Biphenyl Compounds; Bretylium Compounds; Ganglionic Blockers; Hexamethonium; Hexamethonium Compounds; Mecamylamine; Pempidine; Pentolinium Tartrate; Pharmacology; Rabbits; Research; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System
PubMed: 14211685
DOI: 10.1111/j.1476-5381.1964.tb01709.x -
British Journal of Pharmacology Oct 19891. The action of hexamethonium has been studied at a range of muscarinic receptors in vitro by use of both functional and radioligand binding studies. 2. In functional...
1. The action of hexamethonium has been studied at a range of muscarinic receptors in vitro by use of both functional and radioligand binding studies. 2. In functional studies, hexamethonium exhibited little or no significant (P less than 0.05) antagonism of contractile responses to carbachol at muscarinic receptors in the guinea-pig ileum, oesophageal muscularis mucosae, urinary bladder and trachea. However, antagonism was observed at muscarinic receptors in the guinea-pig left atria mediating negative inotropic responses and the calculated pKB value was 3.80. Hexamethonium also antagonized contractile responses to carbachol in the canine saphenous vein. The pKB value at these receptors was 3.75. 3. In the presence of 3.2 mM hexamethonium, the pA2 value for methoctramine at atrial muscarinic receptors was reduced by approximately 10 fold (control pA2 value was 7.81 +/- 0.05; pA2 value in hexamethonium was 6.73 +/- 0.04). In contrast at tracheal muscarinic receptors, the pA2 values for methoctramine were unaffected in the presence of 3.2 mM hexamethonium (control pA2 = 5.58 +/- 0.07; pA2 value in hexamethonium was 5.63 +/- 0.12). All values quoted are mean +/- s.e. mean, n = 8. 4. In competition radioligand binding studies, hexamethonium exhibited a higher affinity for cardiac M2 receptors (pKi = 3.68) than for cerebrocortical M1 receptors (pKi = 3.28) or for submaxillary gland M3 receptors (pKi = 2.61). At M2 receptors hexamethonium at concentrations of 0.1-10 mM, increased the half life of the dissociation rate of [3H]-N-methylscopolamine 1.6-4.3 fold. This was observed at M3 receptors only at 10 mM, when the half life was increased 1.7 fold. 5. We conclude that hexamethonium, in addition to its well characterized nicotinic antagonist properties, can act as a weak muscarinic antagonist and differentiates between cardiac M2 receptors and glandular/smooth muscle M3 receptors. However, hexamethonium differentiates less clearly between M1 and M2 receptors. The selectivity between M2 and M3 receptors observed in the present study with hexamethonium is comparable to other M2 selective antagonists such as AF-DX 116 and himbacine. 6. Caution should be exercised with regard to the inclusion of hexamethonium in functionsal studies of M2 muscarinic receptor subtypes at concentrations of 0.1 mm and above.
Topics: Animals; Carbachol; Diamines; Guinea Pigs; Hexamethonium Compounds; In Vitro Techniques; Kinetics; Muscle Contraction; Muscle, Smooth, Vascular; Myocardium; N-Methylscopolamine; Pirenzepine; Potassium Chloride; Receptors, Muscarinic; Scopolamine Derivatives; Submandibular Gland
PubMed: 2819331
DOI: 10.1111/j.1476-5381.1989.tb12623.x -
The Journal of Physiology May 19731. A preparation is described whereby the responses of the two anococcygeus muscles can be recorded in vivo in the pithed rat and the autonomic outflows to the muscle...
1. A preparation is described whereby the responses of the two anococcygeus muscles can be recorded in vivo in the pithed rat and the autonomic outflows to the muscle selectively stimulated in the spinal canal.2. Motor responses are obtained from stimulation at two levels; an upper extending from T 11 to L 3 and a lower from L 6 to S 2. Stimulation between these levels, i.e. between L 3 and L 6, produces no response. The response to stimulation at both upper and lower levels is abolished by phentolamine. The response to stimulation in the upper region is abolished by hexamethonium and is, therefore, presumably preganglionic; the response to stimulation at the lower level is resistant to hexamethonium and presumably post-ganglionic. Stimulation at levels above T 11 causes contraction after a delay, by liberating catecholamines from the adrenal medulla. This effect is blocked by both phentolamine and hexamethonium.3. If the adrenergic motor nerves are blocked and the muscle tone raised by a combination of guanethidine and tyramine, stimulation between L 5 and S 2 produces inhibition. The inhibitory outflow, therefore, overlaps the motor outflow but extends one segment more rostral (L 5). Stimulation restricted to this L 5 segment even in the presence of a normal unblocked motor innervation causes inhibition. The inhibitory response is blocked by hexamethonium or mecamylamine but desensitization and ;escape' occurs. This desensitization is less than that observed in the vas deferens when its motor nerves are similarly stimulated in the spinal cord.4. It is concluded that inhibitory fibres to the anococcygeus arise in the spinal cord and are organized in the pattern of the autonomic nervous system with a peripheral synapse. The site of origin of these inhibitory fibres is different from the motor adrenergic fibres to the muscle.
Topics: Anal Canal; Animals; Atropine; Blood Pressure; Coccyx; Electric Stimulation; Guanethidine; Hexamethonium Compounds; Male; Mecamylamine; Motor Neurons; Muscle Tonus; Muscles; Neural Inhibition; Phentolamine; Rats; Spinal Nerves; Tyramine
PubMed: 4717154
DOI: 10.1113/jphysiol.1973.sp010210