Albert Sjoerdsma

Effects of drugs on human blood platelet and plasma amine oxidase activity in vitro and in vivo.

Abstract A method employing radioactive substrates has permitted sensitive assay of monoamine oxidase (MAO) activity in blood platelets and plasma. Kinetic studies indicate that while platelet and plasma MAO are distinct from that of liver mitochondria, the platelet and liver enzymes are quite similar, particularly in the characteristics of their response to inhibitors. Administration of six different MAO inhibitors including furazolidone to human subjects resulted in marked inhibition of platelet MAO, accompanied by expected changes in urinary tryptamine excretion. Effects of these drugs on plasma MAO were variable; an additional drug, isoniazid, in therapeutic dose was found to inhibit markedly plasma, but not platelet, MAO. Use of platelet MAO assay in the direct assessment of the MAO-inhibitory potency of drugs in man is suggested.

ALTERED URINARY KALLIKREIN EXCRETION IN HUMAN HYPERTENSION

Abstract Measurements of urinary kallikrein using an esterolytic assay revealed lower levels in patients with essential hypertension than in a control population, normal levels in renal-artery stenosis, and raised levels in phaeochromocytoma and primary aldosteronism. Values in three cases of primary aldosteronism were among the highest encountered. Coupled with recent findings in animals, these results suggest a role for the kallikrein-kinin system in abnormal elevations of blood-pressure.

Decarboxylase Inhibition and Blood Pressure Reduction by α-Methyl-3,4-Dihydroxy-DL-phenylalanine

α-Methyl-3,4-dihydroxy-DLphenylalanine has been found to be an effective inhibitor of aromatic amino acid decarboxylation in man. This was shown by decreased formation of serotonin, tryptamine, and tyramine from the precursor amino acids. Reduction of amine biosynthesis is associated with lowering of blood pressure in hypertensive patients and a transient sedative effect.

Chemotherapeutic implications of polyamine biosynthesis inhibition

Clinical Pharmacology and Therapeutics (1984) 35, 287–300; doi:10.1038/clpt.1984.33

Further studies on tryptophan hydroxylase in rat brainstem and beef pineal

Abstract Soluble tryptophan hydroxylating enzymes have been obtained from both the beef pineal gland and rat brainstem. The enzymes have a pH optimum of 7.5 and appear to be typical aromatic ring hydroxylases. Although aniron requirement of the enzymes can be demonstrated by iron chelators, exogenous iron is not absolutely required for activity. Tetrahydrobiopterin was more effective than 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8 tetrahydropteridine as a cofactor for the enzymes. The beef pineal enzyme hydroxylates phenylalanine at approximately the same rate as it does tryptophan, whereas the brain enzyme showed no detectable activity toward phenylalanine. Finally, catechol compounds are effective inhibitors of the enzymes, presumably because of their ability to chelate iron.

Physiologically active amines in common fruits and vegetables

Abstract 5-Hydroxytryptamine, tryptamine, tyramine, 3,4-dihydroxyphenylethylamine and norepinephrine have been identified and assayed in a large number of fruits and vegetables. The significance of these findings with respect to plant physiology and to dietary effects in animals is discussed.

Tryptophan Hydroxylation in Mammalian Systems

Publisher Summary The development of a quantitative assay system and appropriate assay conditions for mammalian tryptophan hydroxylase has permitted a preliminary characterization of this enzyme. Tryptophan hydroxylase from brainstem and pineal tissue is either soluble or easily solubilized from mitochondrial fraction and exhibits the characteristics of a typical aromatic ring hydroxylase. This rate-limiting enzyme is extremely useful in understanding the hydroxyindole pathway of tryptophan metabolism and eventually the role of 5-HT in tissues. Hydroxylation of tryptophan at the 5-position is the first step in the hydroxyindole pathway of tryptophan metabolism. This pathway leads to the formation of physiologically active substances such as 5-HT and melatonin. The tryptophan hydroxylating enzyme activity shows complete dependence on the presence of oxygen, a reduced pteridine, and ferrous iron. Relatively high levels of 2-mercaptoethanol (0.05 M) are also required for optimal in vitro enzyme activity. With the availability of this reproducible source of tryptophan hydroxylating enzyme, it has been possible to develop a sensitive radioassay, which now has been successfully applied to normal mammalian tissues.

The cardiac disease associated with the carcinoid syndrome (carcinoid heart disease)

Abstract The clinical and pathologic features of seventeen patients with the carcinoid syndrome are reviewed. Nine had carcinoid heart disease. The only clinical feature which distinguished those patients with carcinoid heart disease from those without was the presence of a precordial systolic murmur suggestive of tricuspid regurgitation or pulmonic stenosis. Urinary excretion of 5-hydroxyindoleacetic acid was similar in the two groups. The chest roentgenogram and the electrocardiogram was of no help in determining presence or absence of carcinoid heart disease. Cardiac catheterization in patients with carcinoid heart disease has shown that tricuspid regurgitation and pulmonic stenosis are the most frequent valvular alterations. Cardiac output appears to be increased in some patients who do not have carcinoid cardiac involvement. The cardiac lesions associated with the carcinoid syndrome were pathognomonic and bore little resemblance to lesions found in other cardiac diseases. Cardiac involvement in the carcinoid syndrome consisted of focal or diffuse collections of a peculiar type of fibrous tissue, which was free of elastic fibers and which was deposited on the endocardium of the valvular cusps, on the endocardium of the cardiac chambers and on the intima of the great veins, coronary sinus and occasionally great arteries. The valvular cusps per se remained normal as did the mural endocardium, and each was clearly separated from the fibrosing process by the elastic membrane which covered its surface. Left-sided cardiac lesions were commoner in the carcinoid syndrome than previously thought and were found in the absence of a right to left shunt or a pulmonary carcinoid tumor. The pathogenesis of the carcinoid cardiac lesions (carcinoid fibrous plaques) remains unknown. The morphologic appearance of the endocardial lesion suggests that it might be the result of the deposition of a material, possibly collagen, from the blood, but the identity of the substance which either directly or indirectly produced the endocardial fibrosis is unknown. The inability to produce these cardiac lesions in animals with serotonin and the present observation that the urinary excretion of 5-hydroxyindoleacetic acid was similar in the patient with carcinoid heart disease irrespective of the presence or absence of cardiac involvement suggest that mechanisms other than that involving serotonin should be considered.

Urinary excretion of catecholamines and their metabolites in pheochromocytoma.

Abstract Twenty-four-hourspecimens of urine from 23 patients with pheochromocytoma and a large group of hypertensive subjects were assayed for free catecholamines (norepinephrine plus epinephrine), total metanephrines (metanephrine plus normetanephrine), and 3-methoxy-4-hydroxymandelic acid. Twenty of the 23 patients with tumors had a diagnostic increase in the urinary excretion of all catecholamine metabolites. In the other 3 patients the assay of free catecholamines was the single most reliable test. Because of its over-all reliability and ease of performance, the assay of total metanephrines is favored for screening hypertensive patients for the presence of pheochromocytoma. In the occasional patient whose value is equivocal by this assay, the determination of free catecholamines is considered to be the most helpful test in confirming or excluding the diagnosis.

Biochemical and clinical effects of γ‐vinyl GABA in patients with epilepsy

Article abstract-In a pilot single-blind study, γ-vinyl GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase (GABA-T), was administered orally to 10 epileptic patients who were refractory to conventional anticonvulsant therapy. Daily doses of 1 g and 2 g for 2 weeks each as add-on therapy were followed by 2 weeks of placebo treatment. CSF obtained from suboccipital and lumbar punctures demonstrated dose-related increases in concentrations of free and total GABA and homocarnosine with treatment, but no changes in 5-hydroxyindoleacetic acid or homovanillic acid levels, indicating effective and selective CNS GABA-T inhibition. These biochemical changes were associated with decreased seizure frequency in seven patients, decreased seizure severity in one, no change in one, and possible worsening in one. γ-Vinyl GABA may be useful in the therapy of epilepsy.