Some pharmacologic properties of levo- and dextro-nordefrin.
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Ephedrine↗
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Comparative circulating serum levels of mepivacaine with levo-nordefrin and lidocaine with epinephrien.
Expected blood levels of common local anesthetics have been reported for numerous types of injections. Comparative levels of mepivacaine and lidocaine after dental injection have been only partially evaluated. A study was designed to compare the circulating serum level of 36 mgs. of mepivacaine with 1:20,000 levonordefrin (M) and 36 mgs. of lidocaine with 1:100,000 epinephrine (L) in 1.8 cc dental cartridges after standardized's bilateral maxillary infiltrations. Each of five subjects received 1.8 cc of (L) to the left maxillary second bicuspid and 1.8 cc of (M) to the right maxillary second bicuspid at a rate of one cc per minute. The serum was sampled before the injections and at 5, 15, 30, 60, 90, 120 and 240 minute intervals after the injections and analyzed by gas liquid chromatography. The results indicated that the serum level of (M) peaked at 30 minutes, 0.37 μg/ml of serum and (L) had peaks at 15 and 30 minutes, 0.22 μg/ml of serum. This difference was statistically significant, (p <.01) at all times sampled with (M) always resulting in a higher serum level. Serum levels persisted throughout the four hour test period.
Adult↗
Quantitative and qualitative analysis of the pressor effects of levonordefrin.
Levonordefrin, a common alternative to levoepinephrine as a vasoconstrictor in dental local anesthetic preparations, is usually used in fivefold higher concentrations, and, as such, is generally considered equivalent to epinephrine. We used anesthetized dogs that had autonomic reflexes blocked by mecamylamine to reevaluate the cardiovascular actions of intravenously administered nordefrin with respect to those of epinephrine and norepinephrine over a 100-fold dose range (0.1-10.0 micrograms/kg). Epinephrine caused a significantly greater pressor effect than nordefrin only at the highest dose studied; at low to moderate doses there was no significant difference between the two drugs. Blockade of alpha-adrenoceptors with phentolamine attenuated the peak pressor effects of all three agents. The epinephrine dose-response curve was suppressed more than the curves for norephinephrine and nordefrin, which were not significantly different from each other. Nordefrin was indistinguishable qualitatively from norepinephrine in that neither agent showed any evidence of beta 2-adrenoceptor vasodilation as seen with epinephrine. These findings suggest that nordefrin resembles norepinephrine rather than epinephrine in the receptor profile through which it produces its cardiovascular effects, and that the true potency difference between nordefrin and epinephrine with respect to pressor activity may be somewhat less than the fivefold difference commonly assumed.
Adrenergic alpha-Antagonists↗
Liquid chromatographic separation of enantiomers of adrenergic agonists.
Many established and experimental adrenergic agonists are derivatives of 2-aminoethanol with a phenol or catechol moiety in the 1-position. There is considerable interest in the stereochemical aspects of the actions of such chiral drugs. Surprisingly, however, little has been published on the chromatographic separation of the enantiomers of these compounds, and what has been published involved nearly exclusively capillary gas-liquid chromatography. In this report, the resolution of the racemates of ten adrenergic agents using reversed-phase liquid chromatography is described. The procedure is based on derivatizing the racemic mixture of each agent with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate, followed by separation of the resulting diastereomers on octadecylsilane columns using methanol-aqueous ammonium acetate mixtures as mobile phase. Detection was at 254 nm. The separation of the enantiomers of norphenylephrine and of octopamine was less than complete; the resolution of the other agents, i.e., synephrine, N-ethylnorphenylephrine, p-hydroxyephedrine, p-hydroxynorephedrine, metanephrine, normetanephrine, isoproterenol, and nordefrin, was complete. The derivative of (-)-isoproterenol eluted before that of its antipode. The procedure may be applicable to other similar agents.
Adrenergic Agonists↗
Steroid potentiation of responses to sympathomimetic amines in aortic strips.
1. Responses to catecholamines (adrenaline, noradrenaline, nordefrine) were enhanced by 17beta-oestradiol, progesterone and desoxycorticosterone in untreated and reserpine pretreated aortic strips. Responses to tyramine, believed mediated via endogenous catecholamines, were enhanced only in untreated strips.2. Responses to sympathomimetic amines lacking the catechol nucleus (phenylephrine, synephrine, methoxamine) were potentiated inconsistently by the steroids and reserpine pretreatment reduced markedly the frequency of potentiated responses.3. Known inhibitors of catechol-O-methyl transferase (tropolone, U-0521, pyrogallol) potentiated responses to catecholamines and abolished the enhancing effects of the steroids-when the steroids were given first, there was no further increase in response to catecholamines on adding inhibitors of catechol-O-methyl transferase.4. Experiments with the oil-immersion technique, to eliminate diffusion of drug from the tissue, indicated that 17beta-oestradiol, progesterone and desoxycorticosterone decreased the rate at which aortic strips inactivated adrenaline by O-methylation.5. It is concluded that 17beta-oestradiol, progesterone and desoxycorticosterone potentiate responses to catecholamines in aortic strips by inhibiting a major mechanism for their inactivation.
Animals↗
Effects of reserpine on the disposition of sympathomimetic amines in vascular tissue.
1. The effects of reserpine pretreatment on the intrinsic inactivation of low concentrations of phenylephrine and noradrenaline in strips of rabbit thoracic aorta were assessed by measuring the rates of relaxation, after oil immersion to prevent loss of active amine by diffusion into the surrounding medium.2. Reserpine pretreatment considerably augmented the amplitude of responses to low concentrations of phenylephrine, noradrenaline and nordefrine (Cobefrine).3. Reserpine pretreatment did not reduce the overall rate of inactivation of either phenylephrine or noradrenaline, but it did appear to decrease the contribution of uptake and storage, measured as an increased effect of enzyme inhibition and a decreased effect of cocaine on the rate of inactivation.4. The role of catechol-O-methyl transferase (COMT), but not that of monoamine oxidase (MAO), in terminating the action of noradrenaline was increased in strips from animals pretreated with reserpine. Thus it appears that interference with intraneuronal storage diverts active amine to inactivation by COMT in vascular tissue, rather than by MAO as has been previously suggested.5. As in preparations not treated with reserpine, inhibition of MAO alone had little effect on the rate of inactivation of noradrenaline, and this enzyme appears to function predominantly as an alternate pathway of little importance as long as COMT activity is unimpaired. Enzymatic processes accounted for about 85 and 70% of the inactivation of a low concentration of noradrenaline in reserpine pretreated and untreated preparations, respectively.6. Cocaine potentiated responses to noradrenaline and phenylephrine as effectively in reserpine pretreated as in untreated preparations, and inhibition of the pathways of enzymatic inactivation did not appreciably decrease the potentiation produced by this agent.7. The present results cannot be explained by the hypothesis that interference with amine inactivation by nerve uptake and storage is responsible for the potentiation of responses to noradrenaline or phenylephrine by either reserpine or cocaine, and emphasize the unrealiability of potentiation as an index of interference with mechanisms involved in terminating the action of sympathomimetic amines.
Animals↗
Anticoccidial activities of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine and other alpha 2 adrenergic agonists.
Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among alpha 2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional alpha 2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, alpha 1 agonists and alpha antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate alpha 2 adrenoceptor. alpha 2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.
Adrenergic alpha-Agonists↗
Ketamine potentiates catecholamine responses of vascular smooth muscle by inhibition of extraneuronal uptake.
Effects of ketamine on responses to sympathomimetic amines were studied using isolated aortic and pulmonary artery strips from the rabbit. Ketamine (1.1 x 10(-5) to 3.7 x 10(-4) M) potentiated adrenaline-contracted strips. Potentiation was not impaired in tissues from animals pretreated with reserpine, with 6-hydroxydopamine, or its tissues pretreated with cocaine. Pretreatment of the strips with the catechol O-methyltransferase (COMT) inhibitors tropolone or pyrogallol or the inhibitor of extraneuronal uptake 17 beta-estradiol blocked the potentiation by ketamine; in addition, potentiation by the COMT and extraneuronal uptake inhibitors was abolished or greatly reduced by ketamine. In rabbit aorta, ketamine potentiated responses to the catecholamines (adrenaline greater than nordefrine greater than noradrenaline) but not to the noncatecholamines phenylephrine, methoxamine, and synephrine; instead a slight relaxant effect was observed. Ketamine potentiated, whereas cocaine inhibited, responses to tyramine Experiments using the technique of oil immersion demonstrated that ketamine reduced the rate at which aortic strips inactivate adrenaline even when monoamine oxidase (MAO) and neuronal uptake processes were fully inhibited. Uptake studies showed that ketamine and 17 beta-estradiol reduced extraneuronal accumulation of [3H]adrenaline in aortic strips. We conclude that ketamine is an inhibitor of extraneuronal uptake in the vascular smooth muscles studied and the importance of this mechanism in producing its known cardiovascular effect is discussed.
Animals↗
Immediate complications of local anesthetic administered to 1,007 consecutive patients.
BACKGROUND: Probably the most common procedure in dentistry is the administration of local anesthetic, or LA. Immediate complications of LA administration include positive blood aspiration, blanching of the tissue and burning sensation on impingement of the nerve. Because studies about the immediate complications of LA administration were conducted before 1980, more recent data regarding this procedure are needed. MATERIALS AND METHODS: In this prospective study, an experienced dentist administered, 2,528 LA injections to 1,007 consecutive patients with 1-inch 27-gauge needles, using a solution of 2 percent lidocaine and 1:100,000 nordefrine hydrochloride. RESULTS: The authors observed positive blood aspiration in 73 injections (2.9 percent) without any further complications. The most severe immediate complication-syncope-occurred only in one case. In 63 injections (2.5 percent), the dentist touched the nerve, and the patient reported feeling an electric current sensation (40 times with inferior alveolar nerve blocks, 18 times with lingual nerve blocks, four times with mental nerve blocks and one time with a second injection to the same site) without any further complications. CONCLUSIONS: The results confirm that LA injections that are properly carried out appear to be safer today than they were in the past. CLINICAL IMPLICATIONS: LA is a safe procedure when the appropriate technique is used. It is even safer when an inferior alveolar nerve block is administered.
Adolescent↗
Endocrinological and biophysical responses to further reduction in oxygenation following sustained hypoxemia in fetal goats.
OBJECTIVE: The purpose of this study was to determine fetal endocrinological and biophysical responses to the further reduction in oxygenation following prolonged nonacidemic hypoxemia in fetal goats. METHODS: Seven further hypoxic experiments were performed after prolonged (24-h) nonacidemic hypoxemia, caused by an infusion of nitrogen into the maternal trachea and by reducing uterine arterial blood flow in four chronically instrumented goat fetuses at 123-131 days' gestation. We measured arginine vasopressin, adrenocorticotropic hormone, cortisol, and catecholamines as endocrinological parameters. Fetal heart rate, fetal blood pressure, and fetal breathing movement were observed as biophysical parameters. RESULTS: Fetal arterial pO2 was significantly decreased from 27.0 +/- 1.2 mmHg (control) to 18.0 +/- 0.7 mmHg and 11.3 +/- 1.3 mmHg at the end of the prolonged hypoxemia and the further hypoxia, respectively. The further hypoxia induced reductions in fetal heart rate, increases in fetal blood pressure, and a series of gasping. Arginine vasopressin and catecholamines were elevated significantly by the further hypoxia. Although adrenocorticotropic hormone and cortisol were increasingly elevated, they did not reach a significant level. CONCLUSIONS: Some specific fetal responses-excessive elevations of fetal catecholamines, arginine vasopressin, accompanied with fetal gasping-were observed during further severe hypoxia.
Adrenocorticotropic Hormone↗
Characterization of the monoaminergic innervation of immature rat neocortex: a histofluorescence analysis.
In the neocortex of 6-day-old rat, abundant axon terminals which exhibit specific catecholamine fluorescence are found in all regions and throughout all cortical layers. The overall density of axons in 6-day-old cortex is similar to the density in the adult cortex. In immature cortex, there are two distinct fluorescent plexuses, both presumably noradrenergic, one in the molecular layer and another in the lower half of the cortex. The superficial plexus is composed primarily of horizontal fibers, and the deep plexus of a dense feltwork of obliquely oriented fibers suggestive of a terminal field. The cortical plate itself is traversed by a few vertical processes. Following lesions of the midbrain tegmentum no fluorescent axons are seen in cortex, providing evidence that the fluorescent axons in cortex arise from brain stem neurons. The deep and superficial plexuses can be differentially visualized depending on the histochemical techniques employed and on pharmacological treatment, such as loading with a monoamine congener. Both deep and superficial axons are shown to contain endogenous catecholamines but those fibers in the deep plexus are filled to far less than their maximum capacity. The pharmaco-histochemical differences between axons in the two plexuses suggest that there may exist two distinct catecholaminergic projections to lateral neocortex. The demonstration of an extensive cortical monoamine innervation early in ontogeny supports the possibility that monoamine neurons play an important role in information processing and/or developmental interactions in the immature brain.
Age Factors↗
Rapid and reversible desensitisation of vascular and platelet alpha 2 adrenoceptors.
The effects of intravenous infusion with the alpha2 adrenoceptor selective agonist alpha methylnoradrenaline on pressor responses to alpha adrenoceptor agonists, alpha2 adrenoceptor mediated platelet aggregation and adenylate cyclase were examined in conscious rabbits. Pressor responses to alpha methylnoradrenaline but not phenylephrine were decreased in a dose dependent manner during methylnoradrenaline infusion at all times examined. Recovery of these responses after stopping infusion was dependent on both the dose infused and the duration of the infusion. Alpha methylnoradrenaline infusion resulted in a dose and time dependent decrease in the pro-aggregatory response of platelet to adrenaline without any significant change in the response to ADP or in the number of [3H]yohimbine binding sites. The ability of PGE1 to stimulate adenylate cyclase was not influenced by alpha methylnoradrenaline infusions. However, reversal of this stimulation by adrenaline was decreased by relatively long (30 min) infusions of the highest dose of alpha methylnoradrenaline examined. It is concluded that alpha methylnoradrenaline infusions resulted in desensitisation of all the alpha2 adrenoceptor mediated responses examined. However the time course for the desensitisation apparently differed according to the response examined.
Adrenergic alpha-Agonists↗
Effects of imidazolines on noradrenaline release in rat isolated kidney.
The aim of the present study was to investigate whether or not activation of imidazoline receptors modulates noradrenaline release in the rat isolated kidney. Kidneys were pre-exposed to 3H-noradrenaline and the renal nerves were stimulated with 6 pulses at 100 Hz. The stimulation induced (S-I) outflow of radioactivity was taken as an index of endogenous noradrenaline release. The imidazoline derivatives clonidine (1-1000 nmol/l) and moxonidine (10-1000 nmol/l) inhibited S-I outflow of radioactivity with an EC50 of 6.8 nmol/l and 62.5 nmol/l and a maximum of 88% and 97%, respectively. The concentration response curves for clonidine and moxonidine were shifted to the right by the selective alpha 2-adrenoceptor antagonist rauwolscine (0.1 mumol/l) in a parallel manner with identical pKB's of 8.52 and 8.46, respectively. Furthermore, the alpha-adrenoceptor agonist (-)-alpha-methylnoradrenaline (0.1-30 nmol/l), which has no affinity for imidazoline binding sites, inhibited S-I outflow of radioactivity with and EC50 of 2.4 nmol/l and a maximum of 94%. Rauwolscine (0.1 mumol/l) again shifted the concentration response curve for this alpha-adrenoceptor agonist to the right with a pKB of 8.40. Moreover, the selective alpha 2-adrenoceptor antagonist 2-[2-(2-methoxy-1,4- benzo-dioxanyl)]imidazoline HCl (RX821002, 0.01 mumol/l) shifted the concentration response curves for clonidine and moxonidine to the right with pKB's of 9.46 and 9.18, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-2 Receptor Antagonists↗
Presynaptic alpha 2-autoreceptors in mouse heart atria: evidence for the alpha 2D subtype.
Presynaptic alpha 2-autoreceptors in mouse atria were characterized in terms of the alpha 2A, alpha 2B, alpha 2C and alpha 2D subtypes. Segments of the atria were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The affinity of up to 16 antagonists for the autoreceptors was assessed as (1) pEC30% values. i.e. concentrations that increased previously autoinhibited release of 3H-noradrenaline (120 pulses, 3 Hz) by 30%, and (2) pKd values against the release-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under conditions of no or little autoinhibition (2 trains of 20 pulses, 50 Hz, train interval 120 s). The pKd values correlated well with the pEC30% values (r = 0.98; P < 0.001; slope of regression line 0.93), indicating that UK 14,304 and released noradrenaline modulated the release of noradrenaline through pharmacologically identical receptors. Comparison with antagonist affinities for (1) prototypic native alpha 2 radioligand binding sites, (2) radioligand binding sites in COS cells transfected with alpha 2 subtype genes, and (3) previously classified presynaptic alpha 2-autoreceptors-all taken from the literature-indicated that the mouse atrial autoreceptors corresponded to the alpha 2D subtype. For example, the pKd values at mouse atrial auto-receptors correlated closely with pKd values at native alpha 2D binding sites in the bovine pineal gland (r = 0.96; P < 0.001); with pKd values at alpha 2D binding sites in COS cells transfected with the rat alpha 2D gene (r = 0.85; P < 0.01); and with pKd values at guinea-pig cerebral and atrial and mouse cerebral alpha 2D-autoreceptors (r = 0.96-0.98; P < 0.001). The antagonist pKd values at mouse atrial autoreceptors correlated less with pKd values at alpha 2A, alpha 2B and alpha 2C sites. It is concluded that the presynaptic alpha 2-autoreceptors in mouse atria are alpha 2D. This identification supports the hypothesis that at least the majority of alpha 2-autoreceptors belong to the alpha 2A/D pair of orthologous alpha 2-adrenoceptors.
Adrenergic alpha-Agonists↗
Adrenergic innervation of the mouse heart revealed at an early stage using alpha-methylnoradrenaline.
The development of noradrenergic innervation was studied in the mouse heart using fluorescence histochemistry. Following incubation of hearts with alpha-methylnoradrenaline fluorescent nerve fibres were seen as early as 13 days in utero. It is suggested that the neuronal uptake mechanism for noradrenaline is functional at an early stage.
Adrenergic Fibers↗
A catecholaminergic neuron connecting the first two optic neuropiles (lamina ganglionaris and medulla externa) of the crayfish pacifastacus leniusculus.
The crustacean optic neuropiles, the lamina ganglionaris and especially the medulla externa, show a specific pattern of green fluorescence with the fluorescence histochemical method of Falck-Hillarp. Normally, only the terminals and the cell bodies fluoresce, but in reserpine-treated animals exogenous catecholamines are taken up by the whole adrenergic neuron and are thus visualized as a whole. Incubating crayfish optic neuropiles in dopamine or alpha-methylnoradrenaline after reserpine treatment demonstrated a tangential neuron connecting the lamina and the medulla externa. The morphology of this tangential neuron differs from the two types of tangential neurons, Tan1 and Tan2, previously characterized with Golgi techniques. The catecholaminergic neuron thus constitutes, a third tangential neuron type.
Animals↗
Brain tissue transplanted to the anterior chamber of the eye: 3. Substitution of lacking central noradrenaline input by host iris sympathetic fibers in the isolated cerebral cortex developed in oculo.
Fetal parietal cerebral cortex was homologously transplanted to the anterior chambers of the eyes of adult rats. The transplants got vascularized, proliferated, as measured by in vivo stereoscopic inspections, and differentiated into brain tissue similar to cortex cerebri in situ and survived for long times, greater than 41/2 months. Fibers from the intact sympathetic adrenergic ground plexus of the iris were able to innervate the transplants in an organotypic way regarding fluorescence morphology, pattern of distribution of the nerve terminals and, to a certain extent, density of innervation, the only variable parameter being density of innervation. Thus, in unpretreated or MAO inhibited transplants only rather few to scattered terminals could be found, while after preincubation in 10(-5)M alpha-methyl-noradrenaline the number of visible terminals was normal or slightly less than normal, as compared to cortex cerebri in situ. When superior cervical ganglia (SCG) were transplanted together with fetal cortex tissue to sympathetically denervated eyes the ingrowth in the cortex tissue was similar to that after single cortex transplantation combined with 5 day old SCG, while a marked hyperinnervation was encountered when combined with adult SCG. It is concluded that the developing cortex cerebri, deprived of its normal CNS source of adrenergic nerves, is able to receive sympathetic adrenergic nerves from the iris in an organotypic way upon transplantation to the anterior chamber of the eye.
Animals↗
Absence of indoleamine-accumulating neurons in the retina of humans and cynomolgus monkeys.
Indoleamine-accumulating neurons have previously been detected in cats, rabbits, goldfish, chicken, pigeons, and Cebus monkeys, and were therefore also looked for in humans and in Old World monkey. Cynomolgus irus. The monkey eyes were injected intravitreally with 50 microgram 5,6-dihydroxytryptamine, 5 microgram alpha-methylnoradrenaline, or both drugs simultaneously. The human retinas were incubated in either drug. Previous observations on the distribution of dopaminergic neurons were confirmed in the two species, but no indoleamine-accumulating neurons were detected. The result emphasizes the similarity between human and Old World monkey retinas and contrasts them with the retina of the New World monkeys.
5,6-Dihydroxytryptamine↗