Some cocaine-like actions of 3-phenoxypropylguanidine

In anaesthetized cats 3-phenoxypropylguanidine caused a contracture of the nictitating membrane, a dilatation of the pupil and a fall followed by a rise in the arterial blood pressure. In spinal preparations of cats the initial fall in blood pressure was usually absent and the rise in blood pressure subsided to a steady level, which was about 10 mm Hg above the initial pressure. The pressor action and the contracture of the nictitating membrane were inhibited by phenoxybenzamine and by previous treatment with reserpine, but were not abolished by adrenalectomy and bretylium. 3-Phenoxypropylguanidine potentiated the actions of adrenaline and noradrenaline, increased the blood glucose concentration of the rabbit and decreased the appetite of the cat. The action of tyramine on the cardiovascular system was inhibited by 3-phenoxypropylguanidine, but the stimulant action of tyramine on the nictitating membrane of the cat was not abolished by this substance. Although 3-phenoxypropylguanidine produced a local anaesthesia of long duration in guinea-pig skin, it failed to anaesthetize the rabbit cornea. The responses to stimulation of the preganglionic cervical sympathetic nerve of the cat and the great auricular nerve of the rabbit ear were not abolished by 3-phenoxypropylguanidine; neither did this substance abolish the nicotinic action of acetylcholine in atropinized cats. Contractions of the rat fundus to tryptamine and 5-hydroxytryptamine were antagonized by 3-phenoxypropylguanidine, but were potentiated by cocaine.     

Vasodepression induced by acetylcholine in the atropinized dog

The pressor response to acetylcholine in the atropinized dog resulted from an increase in cardiac output. The pressor response was attributed solely to the release of adrenaline from the adrenal medulla. After giving compound P-286 (N-diethylaminoethyl-N-isopentyl-N'N'-di-isopropylurea) to these dogs, acetylcholine lowered blood pressure, owing to a decrease in total peripheral resistance in the absence of an increase in cardiac output. P-286 presumably blocked the liberation of adrenaline from the adrenal glands by acetylcholine. The blood vessels contributing to the fall in peripheral resistance were not in the intestines. The fall in blood pressure was not blocked by dichloroisoprenaline and it was still present in dogs treated with reserpine. It is suggested that the fall in blood pressure was due to stimulation of ganglion cells subserving vasodilatation.     

The actions of bretylium: adrenergic neurone blocking and other effects

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare-like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. Adrenergic nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5-hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea-pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.     

The pre-junctional site of action of Enhydrina schistosa venom at the neuromuscular junction

The venom of Enhydrina schistosa abolishes the contractile response caused by intra-arterial acetylcholine in the cat anterior tibialis muscle, without affecting the contractile response to indirect stimulation. From the results obtained with facilitatory drugs and the effects observed with chronic denervation, it is suggested that the venom probably produces this phenomenon by blocking acetylcholine action at a pre-junctional site of the motor endplate.     

Contractility of human gallbladder muscle in vitro

This study examined the effects of transmural nerve stimulation, acetylcholine, adrenoceptor agonists and several peptides on the contractility of strips of human gallbladder in vitro. Acetylcholine caused concentration-related contractions of the tissues and the sensitivity to acetylcholine was similar in gallbladders with mild and severe chronic cholecystitis. Noradrenaline and adrenaline relaxed gallbladder strips, probably via beta 2-adrenoceptor stimulation. Transmural nerve stimulation always caused contractions, but in the presence of atropine inhibitory responses were demonstrable and these were antagonized by propranolol. There was no evidence of non-adrenergic inhibitory neural responses. Of the peptides tested, only cholecystokinin octapeptide (CCK-OP), gastrin, pentagastrin, substance P and caerulein caused contractions. Responses to CCK-OP, gastrin and pentagastrin were antagonized by dibutyryl cyclic GMP. Hormones which had no effect upon human gallbladder strips included motilin, secretin, bombesin, neurotensin, glucagon, vasopressin, VIP and somatostatin. Considerable differences therefore exist between human tissues and those from experimental animals with respect to the direct actions of neural and hormonal stimuli on gallbladder contractility.     

Mechanism of action of Jameson's mamba venom on the superior cervical ganglion of cat.

Dendroaspis jamesoni snake venom administered intra-arterially into the superior cervical ganglion, inhibits contraction of the cat nictitating membrane to supramaximal electrical stimulation of preganglionic nerve, when given in large doses, and facilitates it if administered in small doses. The block is at the superior cervical ganglion. The venom did not block the contraction of nictitating membrane to intra-arterial injections of direct depolarizers of the ganglion (1,1-dimethyl-4-phenylpiperazinium, methacholine, potassium chloride) whereas it blocked the contraction of the nictitating membrane to indirect depolarizers of the ganglion (acetylcholine, carbachol) and electrical stimulation of the preganglionic nerve followed by injection of neostigmine intra-arterially during stimulation. Radioactive studies with ⁴⁵Ca showed that the percentage of injected radioactivity in the first effluent blood sample (1 min) was greater in cats treated with venom (74%) than in control cats (35%). The venom blocks the process, probably involving calcium, concerned in the release of acetylcholine. The venom itself, as judged by chromatographic separation and guinea pig ileal testing, contains acetylcholine or an acetylcholine-like material.     

Factors influencing the adrenergic neurone blocking action of propranolol

1. The reversal by propranolol of its own adrenergic neurone blocking effect in the cat can be prevented by cutting the splanchnic nerves or by ligating the adrenal veins.2. In the absence of secretion from the adrenal medulla the nerve blocking action of propranolol is more complete, but can still be reversed by repeated injections or a constant infusion of adrenaline.3. Prior treatment with adrenaline or noradrenaline also prevents the development of the blocking action of propranolol in the cat and in the isolated guinea-pig vas deferens.4. It is suggested that in the cat, propranolol stimulates the release of catecholamines from the adrenal medulla which antagonize its nerve blocking effect.     

Peripheral Effects of Tityus serrulatus Scorpion Venom

Abstract

In this review we describe the peripheral effects induced by Tityus serrulatus scorpion venom and two of the most important toxins-tityustoxin and toxin Ts-γ purified from the crude venom. The complex cardiac arrhythmias elicited by the venom or the toxins were explained by the release of catecholamines and acetylcholine. In isolated rat atria, toxin Ts-γ induced mainly cholinergic effects of long duration. Arterial hypertension was mostly due to release of catecholamines from postganglionic nerve endings and adrenal glands with subsequent stimulation of alpha-adrenergic receptors. The pulmonary edema was related to an adrenergic discharge with stimulation of alpha-adrenergic receptors, leading to an increase of preload and afterload and subsequent heart failure (cardiogenic factor) and also release of permeability factors in lungs, such as the platelet-activating factor (non-cardiogenic factor). The complex respiratory arrhythmias elicited by scorpion toxins in rats were mainly due to stimulation of afferent visceral receptors, being therefore reflex in nature. The scorpion toxin (tityustoxin) also induced pre- and postsynaptic actions at the neuromuscular junctions. The purified scorpion toxins evoked, in anesthetized rats, the appearance of acute gastric injuries in the glandular mucosa (ulcers), simultaneously with an increase in volume, acidity and pepsin output of the rat stomach, explained mostly by the release of acetylcholine and histamine.     

The effects of adrenaline, noradrenaline and isoprenaline on inhibitory α- and β-adrenoceptors in the longitudinal muscle of the guinea-pig ileum

1. Two preparations, a segment of the ileum and the myenteric plexuslongitudinal muscle preparation, have been used for an analysis of the inhibitory effects of adrenaline, noradrenaline and isoprenaline on the contractor responses of the longitudinal muscle to acetylcholine or to electrical, coaxial or field, stimulation.2. Since the inhibitory effects of adrenaline, noradrenaline and isoprenaline on the acetylcholine-induced contractions were not affected by phenoxybenzamine but were antagonized by propranolol, it is concluded that beta-adrenoceptors are present on the muscle cells.3. The responses to electrical stimulation were suppressed by adrenaline or noradrenaline but only partly inhibited by isoprenaline. Propranolol antagonized the effect of isoprenaline and, to some extent, that of noradrenaline, but scarcely affected the action of adrenaline. Phenoxybenzamine, on the other hand, antagonized most of the effect of adrenaline and, to some extent, that of noradrenaline; it usually potentiated the effect of isoprenaline.4. The output of acetylcholine evoked by electrical stimulation was diminished by adrenaline or noradrenaline but was not affected by isoprenaline. The depressant effect on acetylcholine release was antagonized by phenoxybenzamine but not affected by propranolol; therefore these effects of adrenaline and noradrenaline are mediated by alpha-adrenoceptors.5. It may be assumed that alpha-adrenoceptors in situ are stimulated mainly by circulating adrenaline and possibly noradrenaline and thus cause a prejunctional inhibition at the nerve-smooth muscle junction.     

Adenosine and the bradycardiac response to vagus nerve stimulation in rats.

The effects of intracardiac infusions of adenosine on the changes in heart rate (HR), electrocardiogram (ECG) and arterial blood pressure (BP) induced by both vagal stimulation and exogenous acetylcholine (ACh) were studied in anesthetized rats. Adenosine inhibited the bradycardia induced by vagal nerve stimulation, an effect antagonized by theophylline, decreased the elongation caused by vagal stimulation of the R-R intervals of the ECG, and caused a small but consistent decrease in the hypotensive effect of vagus nerve stimulation. At the dose that reduced the bradycardiac responses to vagal stimulation, adenosine enhanced the bradycardiac effect of exogenous ACh, increased R-R intervals and the number of P waves not followed by the ECG and had little or no effect on the inhibition induced by ACh on BP. The effects of adenosine on the bradycardiac responses to vagal nerve stimulation or to ACh administration were similar in both non-reserpinized and reserpinized animals. These results suggest that exogenous adenosine can modify the vagal influences on the heart by exerting pre-junctional inhibition of the vagus nerve and post-junctional enhancement of the ACh actions, and that the adrenergic system does not contribute to these effects of adenosine.     

The effect of adrenal demedullation on cardiovascular responses to environmental stimulation in conscious rats.

Circulating plasma adrenaline has been implicated in the facilitation of neurogenic pressor responses and development of hypertension. Bilateral adrenal demedullation in rats did not affect body weight, urine output, urinary electrolyte (Na+, K+ and Cl-) excretion, nor plasma corticosterone concentration, indicating the selective nature of the demedullation procedure. Adrenal demedullation did induce significant reductions in adrenal catecholamine content, plasma adrenaline levels, resting blood pressure and heart rate in conscious rats, but did not affect alerting-induced increases in blood pressure. The adrenal medulla and circulating plasma adrenaline appear to contribute to the maintenance of resting cardiovascular parameters, but would not appear to be involved in nor facilitate the cardiovascular responses to environmental stimulation.     

The reversal by metoclopramide of apomorphine-induced inhibition of responses to stimulation of the cardioaccelerator nerves in the cat

The effect of metoclopramide on presynaptic dopamine receptors was investigated in the cat cardioaccelerator nerve preparation. Metoclopramide, a substituted benzamide derivative, antagonized inhibitory action of apomorphine on positive chronotropic responses induced by sympathetic nerve stimulation in cat hearts, in vivo. Neither phentolamine, an alpha-adrenergic blocking agent, nor indomethacin a prostaglandin synthesis inhibitor, antagonized the effect of apomorphine. Apomorphine did not alter the positive chronotropic effects of intravenously administered noradrenaline. Metoclopramide potentiated stimulation-induced positive chronotropic responses. These results suggest that metoclopramide blocks the presynaptic dopamine receptors at the cat heart.     

Muscarinic component of splanchnic-adrenal transmission in the dog

1. The effect of atropine on catecholamine release evoked by stimulation of the splanchnic nerve was studied in the adrenal medulla of the dog. The magnitude of the catecholamine release was estimated biologically on the basis of the pressor response occurring in the perfused and acutely sympathectomized hindquarters of the same dog by comparing it with responses elicited by intravenous injection of adrenaline.2. Atropine reduced the responses to nerve stimulation, and appeared to have a more prominent effect on the responses elicited by stimulation at moderate frequency (10 pulses/sec).3. Hexamethonium or nicotine caused a more powerful, but not complete, blockade of transmission; the subsequent injection of atropine caused a further inhibition of the residual responses, leading to a complete, or near complete, abolition of the release by nerve stimulation.4. The data were taken as evidence that transmission of impulses through muscarinic receptors occurs in normal conditions in the adrenal medulla of the dog, though this type of transmission is less prominent than that through nicotinic receptors.     

An eserine-like action of chloral hydrate

The intra-arterial injection of chloral hydrate potentiated the transmission of nerve impulses through the cat superior cervical ganglion, antagonized the ganglionblocking action of hexamethonium, and greatly enhanced the ganglion-stimulant action of acetylcholine. Effects on the ganglion-stimulant actions of carbachol, nicotine, tetramethylammonium and potassium chloride were slight or absent. Chloral hydrate itself usually had no direct stimulant action. The neuromuscular-blocking action of tubocurarine on the isolated rat diaphragm preparation was completely and rapidly reversed by chloral hydrate. This reversal was prevented by previoustreatment of the muscle with neostigmine. Chloral hydrate potentiated the actions of acetylcholine and nicotine on the isolated rabbit duodenum, and, in concentrations exceeding 1 mg/ml., produced a spasm which was abolished by hyoscine but not by mepyramine. It was concluded that these eserine-like effects were manifestations of an anticholinesterase action of chloral hydrate. Neither chloralose nor trichlorethanol showed evidence of this property.     

The adrenaline and noradrenaline content of the adrenal gland of the cat following depletion by acetylcholine

This paper describes the attempts that were made to obtain a replacement of adrenaline and noradrenaline in the adrenal gland of the atropinized cat, subsequent to the depletion of the gland by repeated intravenous doses of acetylcholine. In the anaesthetized animal, there was no replacement of adrenal amines within 15 hours of the depletion. The further loss of amine that occurred during this time was prevented by the de nervation of the gland. If the animal was allowed to recover from the anaesthetic there was some replacement of amines within 2 to 3 days, provided that the condition of the animal was satisfactory. By 6 to 7 days the total amine content had returned to its initial level, but there was now an alteration in the relative proportions of the two amines. Although the adrenaline was still well below the resting level, the noradrenaline was several times its initial value. By one month, the noradrenaline had decreased and the adrenaline had increased to their initial amounts and proportions. Thus this work gives evidence for the formation of adrenaline from noradrenaline.     

Reflex activation of the adrenal medulla during hypoglycemia and circulatory dysregulations is regulated by capsaicin-sensitive afferents

Summary 1. Catecholamines were measured in the adrenal venous outflow during hypoglycemia, hypotension, hypovolaemia and efferent splanchnic nerve stimulation in anaesthetized capsaicin-pretreated rats and their vehicle controls. In control rats, efferent splanchnic nerve stimulation caused a marked rise in adrenaline and noradrenaline levels. In contrast, the other stimuli mainly elicited adrenaline release. 2. The release of adrenaline and noradrenaline evoked by splanchnic nerve stimulation was of the same magnitude in capsaicin-pretreated rats (whose afferent C-fibres were destroyed by this pretreatment) as in their untreated controls. 3. Capsaicin-pretreatment of rats resulted, however, in a reduced adrenaline release during insulin-induced hypoglycemia for up to 30 min and, as a consequence, generated a greater fall in blood glucose. The adrenal response to hypoglycemia in the first 30 min was also reduced by bilateral vagotomy indicating the existence of glucoreceptors on peripheral vagal terminals. 4. Adrenaline secretion following central glucopenia induced by 2-deoxy-d-glucose remained unaffected by capsaicin-pretreatment, indicating an intact function of the central regulation of adrenaline release. 5. Hypotension evoked either by sodium nitroprusside or by haemorrhage resulted in a pronounced increase in adrenaline release which was almost absent in the capsaicin-pretreated rats. 6. It is concluded that the stimulation of the adrenal medulla during hypoglycemia, hypotension, and hypovolaemia is based on a reflex mechanism initiated by capsaicin sensitive afferents.This work was supported by the Austrian Scientific Research Funds, grant No. P6646, the Austrian National Bank (grant No. 2811) and the Pain Research Commission of the Austrian Academy of Sciences Send offprint requests to J. Donnerer at the above address     

Pharmacological properties of AR-C239, 2-[2-[4(o-methoxyphenyl)-piperazine-1-Yl]-ethyl]4,4-dimethyl-1,3(2H-4H) isoquinolinedione, a new alpha-adrenoceptor blocking drug

In pentobarbital-treated dogs and rats, AR-C239, a new and potent alpha-adrenoceptor blocking drug, competitively antagonized pressor responses to adrenaline and inhibited pressor responses to noradrenaline, phenylephrine, tyramine, and dimethylphenylpiperazinium. Injected intravenously into closed-chest dogs, AR-C239 (3-50 micrograms/kg) induced a progressive fall in blood pressure, heart rate, and sympathetic nerve activity. The drug appears to be devoid of direct vasodilator action, and the fall in blood pressure results from the peripheral alpha-blockade. AR-C239 did not change the tachycardia induced by stimulation of the cardiac nerve in dogs and, at least in this preparation, seems to be a specific alpha 1-adrenoceptor blocking drug. When administered into the cisterna magna of dogs, AR-C239 did not have any centrally mediated cardiovascular actions and heart rate. AR-C239 did not modify the functioning of the baroreflex arc. Due to its specificity for alpha 1-Adrenoceptors, AR-C239 may be useful for characterizing alpha-adrenoceptors.     

The effects of cholinomimetic drugs on responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery

1. The effects of infusions of the cholinomimetic drugs acetylcholine, methacholine, muscarine, carbachol, arecoline and pilocarpine were examined on vasoconstrictor responses of the perfused rabbit ear artery to sympathetic nerve stimulation and to injections of noradrenaline.2. The first effect of very low concentrations of acetylcholine or muscarine was a slight enhancement of responses to sympathetic nerve stimulation, but when higher concentrations of acetylcholine, methacholine, muscarine, carbachol and arecoline were infused, these vasoconstrictor responses were decreased. With still higher concentrations the responses tended to increase in size during the infusion. After stopping an infusion, the depressed vasoconstrictor responses rapidly recovered and became enhanced.3. Infusions of pilocarpine in a wide range of concentrations generally caused enhancement of responses.4. The depressant effects of cholinomimetic drugs on the responses to sympathetic nerve stimulation were antagonized by atropine. Larger concentrations of the drugs overcame the blockade by atropine.5. The effects of acetylcholine, methacholine and muscarine on the responses to sympathetic nerve stimulation were more pronounced at low than at high frequencies of stimulation.6. Vasoconstrictor responses to injected noradrenaline were enhanced by acetylcholine or methacholine, whereas responses to sympathetic nerve stimulation were decreased by the same concentrations of these choline esters.7. It is suggested that cholinomimetic drugs may act on receptor sites associated with the adrenergic terminal axon and that they may facilitate or impair the release of noradrenaline and impair noradrenaline uptake.     

The ganglion blocking action of procainamide

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 μg) 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 (0.5×10^-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.     

Comparison of bretylium and guanethidine: tolerance, and effects on adrenergic nerve function and responses to sympathomimetic amines

Bretylium depresses the slope of regression lines relating frequency of sympathetic nerve stimulation to magnitude of contractions of the cat nictitating membrane. In contrast, guanethidine and reserpine preferentially abolish responses to low rates of nerve stimulation and cause a roughly parallel shift of the regression lines. The hypersensitivity of the nictitating membranes of cats to intravenous adrenaline or noradrenaline is far greater after a series of small daily doses of bretylium or guanethidine than after single large doses. The maximal sensitivity produced was similar to that after postganglionic sympathetic nerve section and exceeded that produced by ganglion blockade. The development of hypersensitivity to catechol amines is accompanied by some return of responses of the nictitating membranes to sympathetic nerve stimulation despite continued daily administration of bretylium or guanethidine. In cats given bretylium daily, responses to low rates of nerve stimulation become greater than in controls unless the dose of bretylium given subcutaneously is 50 mg/kg or more. When marked hypersensitivity to catechol amines has been produced by giving bretylium or guanethidine daily for 7 or 14 days, the sympathomimetic effects of these compounds are greater. Responses to intravenous dimethylphenylpiperazinium are also increased and the results suggest that even large daily doses of adrenergic neurone blocking agents do not appreciably impair the functioning of the adrenal medulla. The pressor effects of intravenous adrenaline, noradrenaline and dimethylphenylpiperazinium iodide increase less than the corresponding nictitating membrane responses. These results are discussed in relation to tolerance to adrenergic neurone blockade, and differences between the effects of bretylium and guanethidine found in man. Bretylium and guanethidine depress the slopes of the dose-response curves for the pressor and nictitating membrane contracting effects of tyramine. When single doses or a short series of daily doses were given, guanethidine caused more depression of the slopes than did bretylium, but nevertheless large depressions of slope were found after giving bretylium daily for several weeks. The magnitude of the responses can be greater or less than in controls depending on the dose of the sympathomimetic amine, the dose of the adrenergic neurone blocking agent and the duration of its administration. The results suggest that injection of tyramine produces a progressively smaller release of adrenaline or noradrenaline during the daily administration of bretylium (or guanethidine) but that in some test situations this is more than compensated for by the development of hypersensitivity to the catechol amine released. Some corresponding changes in responses to amphetamine and ephedrine are also described.