Modification of the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase of hen brain.

This study was aimed to investigate the possibility of modifying the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase (NTE) of hen brain. This reaction on NTE occurs with a half-time of 7.4 min. Atropine was effective in decreasing the rate of aging on DFP-inhibited NTE and this effect was time- and concentration-dependent. Atropine was also a weak but progressive inhibitor of NTE activity (I50 = 80 mM) and this reaction appears to be reversible at lower atropine concentrations. Among compounds containing oxime functional groups only OPAB, having longer methylene chain and being more lipophylic than other oximes usually used in acetylcholinesterase (AChE) reactivation studies, was effective in decreasing the rate of aging on DFP-inhibited NTE. However, when atropine and oximes were used together we have obtained a potentiating and/or synergistic effect which was most significant with combination of atropine and TMB-4 giving up to a 15-fold decrease in the rate of aging reaction. The efficacy of this particular combination was concentration-dependent. We have also discussed similarities and differences in aging reaction occurring on NTE and AChE.

Peutz-Jeghers' syndrome--juvenile intestinal polyposis--review of five cases.

During the past 30 years, authors observed and followed 5 patients with Peutz-Jeghers' syndrome. Four of them had diffuse polyposis of stomach, small bowel and colon. They also had severe clinical presentation of the disease, with recurring colicky pain, haemorrhage, anaemia and intussusception, all of which necessitated frequent surgical treatment. Excised polyps presented as benign hamartomas, without malignant alteration. Mucocutaneous pigmentations were present in 4 patients. Family history was revealing in only 2 cases. One patient, a girl aged 2 years, died due to the complications of the surgical intervention (intestinal obstruction). She has had the most severe form of the disease with diffuse polyposis.

Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain.

Phosphamidon (PSM) is an organophosphorus insecticide widely used in agriculture. This study was undertaken to examine the interaction of PSM with acetylcholinesterase (AChE) and neuropathy target esterase (NTE) of hen brain in vitro and in vivo. PSM was a potent inhibitor of AChE, with an I50 of 2.9 microM and second-order rate constant (ka) of 1.2 x 10(4) M-1 min-1 at 37 degrees C. PSM-inhibited AChE aged rapidly (t1/2 = 1.9 h). Pyridinium oximes pralidoxime, trimedoxime, obidoxime and HI-6 were effective reactivators of PSM-inhibited AChE, providing up to 75% reactivation. PSM was one of the weakest inhibitors of NTE among organophosphorus compounds, with an I50 of 19 mM and ka of 1.8 M-1 min-1 at 37 degrees C. Inhibited NTE did not reactivate spontaneously and KF-induced reactivation was not obtained even at the earliest tested moments, so it was not clear whether aging of PSM-inhibited NTE occurred very quickly or the KF molecule could not affect the stability of phosphoryl-NTE bond. From the ratio of kas for NTE and AChE (0.00015) it was predicted that delayed neuropathic effects of PSM in vivo would appear only at doses far above the acute LD50. The LD50 value of PSM p.o. for hens was 9 mg/kg. Hens were treated with a single oral dose of PSM, combined with standard antidotal treatment which included atropine, physostigmine, pralidoxime and anticonvulsant midazolam. Doses of 90 and 250 mg/kg caused up to 27% and 45% NTE inhibition 48 h after poisoning, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hartnup disease (report of 2 cases in one family)]. / Hartnupova bolest (prikaz dva bolesnika is jedne porodice).

INTRODUCTION: The Hartnup mutation affects the amino acid transport system of the intestine and kidney used by a large group of neutral amino acids (monoamino-monocarboxylic acids) resulting in a characteristic pattern of neutral aminoaciduria [2, 5, 6]. METHODS AND PATIENTS: In this research clinical and neurological methods and a great number of laboratory tests were used. Patient 1. A 16-year-old girl, born in 1972, was a full-term newborn. Her psychomotor development was normal. She is the eldest of three children in the family. Till the age of 10 the girl was healthy, except for the mild skin disorders on uncovered parts of the body, face and hands, occurring in springtime almost every year. She had had two exacerbations of the disease. The first exacerbation lasted between the end of April and August 22, 1982. The second began in the middle of November 1987 and finished on May 31, 1988. A changeable and severe clinical feature in this girl was characterized by polymorphic, transient mainly cerebral symptoms, papilloedema with peripapillary haemorrhage and pellagra-like skin rash. At the beginning of the disease the left spastic haemiplegia with bilateral Babinski's reflex and diffuse brain oedema were observed. Signs of the upper motor neurone lesion and myoclonic jerks of limbs and face were most persistent during the first and second exacerbation of the disease. Dysinhibition phenomenon: mandibular, snout and palmomental reflexes were sometimes positive. Mental states at the time of hospitalization were changed and characterized by bradypsychic, torpid, disoriented in time and confused at the beginning of the disease. She had severe psychotic episodes during the second relapse of the disease. The symptoms and signs of the disease as well as pellagra-like skin rash resolved with nicotinamide therapy. Patient 2. A 38-year-old man; clinically healthy, with no skin lesions. A gross aminoaciduria was found in this case. However, the amino acids pattern was atypical. DISCUSSION: This new, rare disease was described [1] with complex and variable clinical symptoms, intermittent course, permanent aminoaciduria and other biochemical features. In our symptomatic patient diagnosis of Hartnup disease was established during the second exacerbation of the disease. CONCLUSION: Two cases of Hartnup disease, one symptomatic and one asymptomatic, were diagnosed in a five member family. A child in this family died at the age of 3.5 probably from Hartnup disease.

Evidence that endothelium-dependent relaxation to histamine in the rat common carotid artery is mediated by EDRF.

The mechanism of histamine-induced relaxation in the isolated rat common carotid artery was analysed. Histamine (3 x 10(-7)-10(-4) mol/l) caused a concentration-dependent relaxation of the artery. Indomethacin, a cyclo-oxygenase inhibitor, and diethylcarbamazine, a lipoxygenase inhibitor, did not affect the relaxant response of the artery to histamine. After removal of the vascular endothelium the histamine-induced relaxation was strongly reduced. Moreover, hemoglobin and methylene blue, inhibitors of endothelium-derived relaxing factor (EDRF), prevented or reversed the relaxant effect of histamine. These findings confirm that the histamine-induced relaxation is to a greater extent endothelium dependent. It is concluded that the endothelium-dependent component in the relaxant response of the rat common carotid artery to histamine results from the release of EDRF.

Endothelium-dependent relaxations to histamine in the rat common carotid, renal and cranial mesenteric artery.

The effect of histamine on the isolated rat common carotid, renal and cranial mesenteric arteries was examined. Histamine (10(-8)-10(-4) M) caused concentration-dependent relaxations of the arteries during contractions induced with phenylephrine (10(-8)-10(-7) M). Removal of the vascular endothelium inhibited the histamine-induced relaxations. Pyrilamine (6 X 10(-6) M), but not metiamide (10(-6) M), abolished the relaxant effect of histamine. Moreover, pyrilamine (6 X 10(-6) M) did not affect endothelium-dependent relaxations of the arteries produced with acetylcholine. These results indicate that histamine causes endothelium-dependent relaxations of the rat peripheral large conduit arteries, which appeared to be mediated via H1-histaminergic receptors.

Endothelium-independent contractile and relaxant responses to histamine in the rabbit aorta and common carotid, mesenteric, renal, and femoral arteries.

1. The role of the vascular endothelium in the relaxant and contractile responses to histamine of the isolated rabbit aorta; common carotid, mesenteric, renal, and femoral arteries; as well as receptor types mediating these responses were analyzed. 2. Histamine (10(-8) to 10(-4) mol/l) contracted resting rings and caused a further concentration-dependent contraction of rings of the arteries precontracted by phenylephrine. 3. Pyrilamine abolished the contractile response to histamine in resting rings of the arteries, whereas it reversed that response into a concentration-dependent relaxant response in precontracted rings of the arteries. The relaxant effect of histamine was abolished by metiamide, but it was not affected by sotalol and atropine. Moreover, in control experiments, the phenylephrine-induced contractions and acetylcholine-induced relaxations were not changed by pyrilamine and metiamide, respectively. 4. Endothelial removal did not influence the contractile and relaxant responses of the arteries to histamine. 5. These findings indicate that, in the isolated rabbit aorta and common carotid, mesenteric, renal, and femoral arteries, the contractile effect of histamine resulting from the activation of H1 receptors overcomes its relaxant effect resulting from the activation of H2 receptors. The effects of histamine are neither mediated nor modulated by the endothelial cells.

Endothelium-independent relaxation of the rat femoral artery caused by activation of histamine H2-receptors.

The effect of histamine on the endothelial and smooth muscle cells of isolated rings of the rat femoral artery and the receptor type involved in its development were examined. Relaxed rings did not respond to histamine (10(-8)-10(-4) mol/l). However, when contraction had been produced by phenylephrine, histamine (3 x 10(-7)-10(-4) mol/l) caused a concentration-dependent relaxation. The relaxant effect of histamine on the rat femoral artery was abolished by metiamide, but it was not affected by removal of the vascular endothelium, pyrilamine, atropine, sotalol, hemoglobin or methylene blue. In contrast, under the same experimental conditions, the relaxant effect of histamine on the rat mesenteric artery was strongly reduced by removal of the vascular endothelium, hemoglobin or methylene blue. These findings indicate that, in the rat femoral artery, unlike in several other rat large peripheral arteries, the histamine-induced relaxation is endothelium-independent and results from the activation of smooth muscle histamine H2-receptors. It is tentatively suggested that histamine H1-receptors are not present on the endothelial and smooth muscle cells of the rat femoral artery.

Endothelium-dependent relaxation of the rat renal artery caused by activation of histamine H1-receptors.

The response of the isolated renal artery to histamine was analysed. The renal artery in relaxed state did not respond to histamine. However, in the precontracted renal artery with phenylephrine, histamine (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation. Removal of the vascular endothelium abolished the relaxant response to smaller concentrations of histamine (10(8)-3 x 10(-6) mol/l), and strongly reduced that to large concentrations of histamine (greater than 3 x 10(-6) mol/l). Mepyramine abolished the former response, and strongly reduced the latter response. The slight relaxant effect of histamine, resistant to mepyramine and removal of endothelium, was blocked only after combined treatment with mepyramine and metiamide. Sotalol, atropine, indometacin and diethylcarbamazine did not suppress the inhibitory effect of histamine. It is concluded that the relaxant effect of histamine on the rat renal artery is predominantly mediated by activation of H1-receptors on the endothelial cells. Only a slight component of the relaxant response to large concentrations of histamine results from activation of both H1- and H2-receptors in smooth muscle of the artery. Cyclo-oxygenase products of arachidonic acid metabolism are not involved in the mediation of the relaxant response to histamine.