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Age variation in the increase of hypothalamic and brain stem contents of phenylethanolamine m-octopamine and p-octopamine in spontaneously hypertensive rats (SH Kyoto).

Phenylethanolamine, m-octopamine and p-octopamine contents were determined as a function of age in the hypothalamus and brain stem of spontaneously hypertensive rats and controls Wistar Kyoto. In hypothalamus, the content of the 3 amines was 2--4-fold greater for the SH rats. In the brain stem, the phenylethanolamine and p-octopamine contents were 2--3-fold greater in SH rats but 5--6-fold higher in the case of m-octopamine. The difference appears at 3 weeks and correlates the blood pressure with the increase of age. The significance of these findings is discussed.

2-Hydroxyphenethylamine↗

Influence of phenylethanolamine on octopamine plasma determination in hepatic encephalopathy.

Octopamine and phenylethanolamine levels were measured by a radioenzymatic procedure in 30 cirrhotic patients with and without hepatic coma and in 15 normal controls. Octopamine data were obtained either by direct extraction with 40% isoamyl alcohol in toluene according to Molinoff et al. (Molinoff, P.B., Landsberg, L. and Axelrod, J. (1969) J. Pharm. Exp. Ther. 170, 253), or after pre-extraction of phenylethanolamine with 3% isoamyl alcohol in toluene. Phenylethanolamine was statistically correlated with the grade of hepatic encephalopathy. Octopamine levels also appeared to parallel the grade of coma, although the values obtained after pre-extraction were lower and less significant than those obtained with 40% isoamyl alcohol in toluene extraction. The higher values of directly extracted octopamine are due to contamination of other beta-hydroxylated phenylethylamines, among which is phenylethanolamine.

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Identification and quantitation of phenylethylene glycol in human and rat urine, and its elevation in phenylketonuria.

Phenylethylene glycol has been identified in rat and human urine using gas chromatography/chemical ionization/mass spectrometry. A method was developed for the quantitative analysis in urine of this phenylalanine metabolite and of p-hydroxyphenylethanol, a metabolite of tyrosine, by converting them to the pentafluoropropionyl derivatives and measuring them by selected ion monitoring. In human urine, about 90% of the phenylethylene glycol was present in a conjugated form (releasable by glusulase), but the reverse was true for rat urine, with about 90% being present in the unconjugated form. The excretion of free phenylethylene glycol (expressed as ng/mg creatinine) was 2.7-fold higher in a group of untreated phenylketonuric patients than in the control group, but the phenylketonuric patients excreted abnormally low amounts of 3-methoxy-4-hydroxyphenylethylene glycol. Intraperitoneal injections of L-phenylalanine in rats resulted in a small increase in the excretion of phenylethylene glycol. On the other hand, the injection of phenylethanolamine resulted in an 82-fold increase in the excretion of phenylethylene glycol, but phenylethylamine had no effect. These results indicate that the conversion of phenylethylamine to phenylethanolamine is the rate limiting step in this metabolic pathway.

2-Hydroxyphenethylamine↗

Plasma amino acids as predictors of the severity and outcome of sepsis.

Sepsis is a major catabolic insult resulting in a peripheral energy deficit which is made up in part by increased breakdown of lean body mass and oxidation of amino acids, principally the branched chain amino acids. The prognosis in any given case of sepsis is difficult to predict, but should theoretically be related to the degree of disturbance in peripheral energy deficit, which may in turn, be related to plasma amino acid pattern. In order to study whether this hypothesis was correct, plasma amino acids and some of their metabolic byproducts, the beta-hydroxyphenylethanolamines, were studied in 25 septic patients, and were used as discriminant variables in a series of computer performed discriminant analyses and multiple regressions. The two functions tested were the degree of metabolic septic encephalopathy as a determinant of the severity of sepsis and the final outcome in the septic patient. Plasma amino acid patterns exhibited elevated levels of the aromatic and sulfur containing amino acids, phenylalanine, tryosine, tryptophan, methionine, cysteine, and taurine, normal concentrations of alanine, and low normal concentrations of the branched chain amino acids, valine, leucine and isoleucine. Arginine levels, as previously noted, were very low. Patients not surviving the septic episode exhibited higher concentrations of aromatic and sulfur containing amino acids, while patients surviving sepsis had higher concentrations of the branched chain amino acids and arginine. When the degree of encephalopathy as a determinant of the severity of sepsis and step wise discriminant analysis with multiple crescent techniques were used, the best discriminant function between patients with and without encephalopathy was found to result from the interaction of cysteine, methionine, phenylalanine, isoleucine, leucine, and valine. These amino acids gave a correct classification in 82% of patients with no encephalopathy, and 80% of patients with septic encephalopathy. When the same amino acids were used for the discriminant analysis for patients dying of sepsis and patients surviving, the best discriminant function was achieved by using plasma concentrations of alanine, cysteine, methionine, isoleucine, arginine, tyrosine and phenylalanine resulting in 91% of the nonsurvivors, and 79% of the survivors correctly classified. The results suggest a close and significant relationship between the deranged energy metabolism and muscle protein breakdown in sepsis, and the outcome. This further suggests a central role for certain amino acids in perhaps predicting the severity of sepsis and its outcome.

2-Hydroxyphenethylamine↗

Plasma phenylethanolamine in hepatic encephalopathy.

It has been suggested that amines other than octopamine may be involved in the pathogenesis of hepatic encephalopathy. Plasma phenylethanolamine has been determined by a radioenzymatic method in twenty-six biopsy-proven cirrhotics with or without encephalopathy and in seven normal adults. Phenylethanolamine plasma levels correlated statistically with the presence of liver cirrhosis and severe coma. These results are consistent with the false neurotransmitter hypothesis of hepatic encephalopathy.

2-Hydroxyphenethylamine↗

An in vitro method for screening compounds for the effect on the rate of sickling of erythrocytes.

Since no practical animal model is available for the evaluation of compounds in vivo, we have developed an in vitro model for determining the effect of compounds on the rate of sickling of erythrocytes in whole blood taken from patients with sickle cell anaemia. RMI 6792 (a phenethanol-diamine derivative), procaine, and L-glutamine were tested in this in vitro system. RMI 6792 was tested at various concentrations in whole blood. The data indicate that RMI 6792 decreased the rate of sickling at and above 60 microgram/ml. Procaine slightly decreased sickling rate at 100 microgram/ml. L-glutamine at 555 had no inhibitory effect. RMI 6792 and procaine had no effect on the oxygen dissociation curve. RMI 6792 affected the calcium flux of the erythrocytes and the calcium concentration in the erythrocytes.

2-Hydroxyphenethylamine↗

[Increased contents of phenylethanolamine, m-octopamine and p-octopamine in the hypothalamus and brain stem of spontanously hypertensive rats (S.H.R. Kyoto)].

Phenylethanolamine, p-octopamine and m-octopamine contents were determined in the hypothalamus and the brain stem of spontaneously hypertensive Rats (S.H.R. Kyto) and the corresponding controls (Wistar Kyoto). In three-week-old Rats, phenylethanolamine and p-octopamine are found to be present in S.H.R. hypothalamus and brain stem at concentrations twice as high as compared to Wistar Kyoto Rats. The amount of m-octopamine is 5-fold higher in the brain stem of S.H.R. Rats as compared to Wistar Kyoto Rats.

2-Hydroxyphenethylamine↗

Structure activity relationships between catecholamines and the alpha-adrenergic receptor responsible for the aggregation of human platelets by epinephrine.

PEA is a potent inhibitor (Ki approximately 13 microM) of human platelet aggregation induced by epinephrine. This led us to perform an SAR study of a congeneric series of compounds in an effort to identify the molecular components of epinephrine critical to its aggregating effect upon human platelets. Phenylethanolamine was similar to PEA in inhibitory potency. However, hydroxylation of the phenyl ring diminished the inhibitory effect (Ki tyramine approximately 87 microM; Ki octopamine approximately 88 microM). Dopamine, the weakest inhibitor (Ki approximately 150 microM), was a partial agonist capable of inducing platelet aggregation in some samples of PRP. The order of potency of catecholamines as aggregating agents was epinephrine greater than norepinephrine greater than Epinine greater than dopamine. Phenylephrine, the prototype alpha-agonist, did not induce aggregation but was a potent inhibitor (Ki approximately 12 microM) of the aggregation induced by epinephrine. Isoproterenol, the prototype beta-agonist, was neither an aggregant nor an inhibitor of epinephrine-induced platelet aggregation. These findings suggest that the binding of epinephrine to the alpha-adrenergic receptor responsible for platelet aggregation is accomplished by the N-methyl amino group whereas intrinsic aggregating activity is a function of the catechol moiety.

2-Hydroxyphenethylamine↗

[The hypertensive effect of adyston and etilefrin. Comparative animal experimental studies].

According to the results obtained under the described conditions it can be stated that after i.v. administration Adyston induces a dose-dependent rise in systolic and diastolic blood pressure, in comparison with etilefrin the new product Adyston shows a greater potency in rising the systolic and diastolic blood pressure; Adyston induced rise of blood pressure is in general of longer duration in comparison with that induced by etilefrin, it is interesting that in the dose of 0.01 mg/kg Adyston increases the arterial blood pressure but at the same time slightly decreases the heart rate; this is not the case after administration of etilefrin which at the same dose increases both arterial blood pressure and heart rate.

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A selective radioenzymatic assay for the determination of octopamine and phenylethanolamine in plasma and cerebrospinal fluid. Preliminary results in human and experimental hepatic encephalopathy.

A sensitive radioenzymatic assay for the simultaneous determination of phenylethanolamine and octopamine in biological fluids is described. It is derived from the radioenzymatic assay originally described by Molinoff et al. (1969) and subsequently modified by Saavedra (1974). The enzymatic reaction is based upon the methylation of phenylethanolamine and octopamine by phenylethanolamine-N-methyl transferase using 14C-S-adenosylmethionine as the methyl donor. The N-methyl derivatives of the two amines are separately extracted and estimated. Selectivity is increased by optimization of extraction and evaporation and by subsequent extraction of the two compounds. Phenylethanolamine and octopamine levels were determined in plasma of human subjects and in plasma and CSF of dogs. The levels were found significantly elevated both in human and experimental hepatic encephalopathy.

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