Effects of two methylxanthines, pentoxifylline and propentofylline, on arachidonic acid metabolism in platelets stimulated by thrombin

[3H]Pentoxifylline and [3H]propentofylline were taken up by human platelets in a dose-dependent manner probably involving a passive diffusion through the plasma membrane. In vitro, the two drugs were able to inhibit platelet activation induced by thrombin. serotonin secretion was reduced from 57% to 38% and 28% in the presence of 1 mM pentoxifylline and 1 mM propentofylline, respectively. Platelet aggregation was inhibited in the same way. Modifications of [14C]arachidonic acid metabolism in human platelets stimulated by thrombin were then measured in the presence of drugs. Preincubation of platelets with 1 mM pentoxifylline or propentofylline inhibited the production of [14C]arachidonic acid metabolites, without any accumulation of free arachidonic acid, suggesting an action at a step preceding its conversion. Phosphatidylinositol and phosphatidylcholine hydrolysis measured upon thrombin treatment as well as phosphatidic acid production were reduced or suppressed in the presence of the drugs. A dose-dependence study showed that phosphatidylcholine hydrolysis was totally inhibited at 5.10(-4) M propentofylline, while phosphatidic acid formation was reduced by only 40%. Propentofylline was in general more efficient than pentoxifylline in inhibiting events occurring upon thrombin stimulation. Our results suggest that the two methylxanthines inhibit both phospholipase A2 and phospholipase C, the former displaying a greater sensitivity to the two drugs.     

Metabolism and DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in fetal tissues of the Syrian golden hamster

The nicotine derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent respiratory tract carcinogen in adult Syrian golden hamsters. In this study, the metabolism and genotoxicity of NNK was investigated in fetal hamster trachea and lung tissues. Fetal lung and tracheal explants were cultured in vitro with [5-3H]NNK, and metabolites released into the culture medium were assayed by high-performance liquid chromatography-scintigraphy. Activation of NNK by alpha-carbon hydroxylation and deactivation by pyridine N-oxidation increased from Day 12 to 15 of fetal development. In lung tissues, at Day 12 of fetal development, carbonyl reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol was the major metabolic pathway. When adult and fetal lung explants were cultured in vitro with [methyl-3H] NNK, explant DNA was methylated at the O6- and N-7 guanine sites. When hamsters were injected i.p. with NNK (0-200 mg/kg) on Day 14 of gestation, chromosome aberrations were observed in epithelial cells established from lung and tracheal explant outgrowths. Most aberrations in lung and tracheal cells were of chromatid types. High frequency of chromatid exchange was observed in tracheal cells. After injection of NNK (200 mg/kg) to 14-day pregnant hamsters, NNK was detected in lung (0.39 +/- 0.16 nmol/mg), placenta (0.72 +/- 0.48 nmol/mg protein) and amniotic fluids (34.07 +/- 7.62 nmol/ml). These results demonstrated that NNK can cross the placental barrier in pregnant hamsters and be activated to genotoxic intermediates in tracheal and lung tissues and suggest that NNK is a transplacental carcinogen in this species.     

Congenital long QT syndrome in newborns]

The perinatal manifestations of the long QT syndrome are rare, but early diagnosis and therapy are necessary to prevent sudden death. CASE REPORTS: A long QT syndrome was diagnosed in two neonates who presented with foetal bradycardia. In one case, a mutation in the gene KCNQ1 was identified, and a long QT syndrome was diagnosed in the mother and two brothers of the neonate. On beta-blocker therapy, one infant became free of long QT syndrome related symptoms, but a sudden death of the second infant occurred. CONCLUSION: The long QT syndrome should be considered in the differential diagnosis of foetal bradycardia. Early treatment of the neonate and his family may prevent ventricular arrhythmias and sudden death.     

Variations in HDL and VLDL levels chronic alcoholics. Influence of the degree of liver damage and of withdrawal of alcohol

Changes in plasma HDL and VLDL levels were investigated in 284 chronic alcoholics staying in a Detoxification Centre where they initiated or continued abstinence. The data show that the variations in plasma HDL are modulated by the degree of liver injury. In severe hepatic damage HDL levels are sharply decreased. An alcohol-induced rise in HDL can occur in the only subjects with no signs of hepatic insufficiency. This elevation is rapidly reversible after withdrawal of alcohol. Such a rise might reflect enhanced synthesis and release by liver but might also be due to an accelerated turnover of the VLDL.     

A study of jaw reflexes of the awake cat during mastication and locomotion

This paper reports on experiments on the jaw opening reflex carried out while awake unrestrained cats were eating or walking on a treadmill. It is shown that the jaw opening reflex response to low intensity stimulation diminished in all phases of the masticatory cycle. The response to higher threshold afferents, however, is phase modulated so that the largest responses occur during the jaw closing phase. This is in accord with the need for increased protection of the soft tissues in this phase of the movement. In contrast, the digastric reflex amplitude does not change when the cat passes from quiet standing to walking on the treadmill. Evidence is presented that the electromyographic activity of the jaw closing muscles increases during upwards movement of the head during walking and decreases as the head falls. These data support the hypothesis that the myotatic reflex in the elevator muscles plays a role in stabilizing the mandible during locomotion.     

Effect of carbachol on 45Ca uptake and protein secretion in rat lacrimal gland.

Carbachol stimulates 45Ca uptake and protein secretion in rat lacrimal glands. At low concentration (10-8 M) atropine inhibits these effects but phentolamine and propranolol (10-5 M) are ineffective. The optimum response in both processes is obtained at the same concentration (10-6 M) of the cholinergic agonist. Vinblastine (10-4 M) reduces protein discharge induced by carbachol without modifying the uptake of 45Ca stimulated by the parasympathetic mediator. Calcium influx is proposed as the primary effect of cholinergic inducers in secretory processes.     

Unitary discharges in dorsal and ventral roots after the administration of 4-aminopyridine in the cat

The administration of 4-aminopyridine (4-AP) in decerebrate paralyzed cats induces centrifugal rhythmic discharges in both ventral and dorsal roots. This study describes the mode of discharge of individual primary afferents as well as some ventral root fibers. Several patterns of antidromic discharge have been observed in primary afferents after the administration of 4-AP. A large proportion of the units (n = 96; 53%) showed rhythmic bursts of discharge related (n = 41) or not (n = 55) to the ongoing rhythmic activity in the peripheral nerves. Other units (n = 86; 47%) discharged either tonically, sporadically or had no antidromic activity at all. The conduction velocity of the non-bursting units was significantly higher (89.7 +/- 18.4 m/s) than that of the bursting units (70.6 +/- 15.4 m/s; P less than 0.01). Ventral roots showed rhythmic activity although less intense than that of the dorsal roots. As in dorsal roots, some fibers showed a rhythmical pattern of discharge related to the mass activity recorded from whole dorsal roots or peripheral nerves, while other units were not related. It is concluded that bursting activity which occurs in peripheral nerves after the administration of 4-AP is mainly the result of the antidromic activation of medium to small size primary afferent fibers.