Sex-related Differences in Rat Liver Microsomal Enzymes and Their Induction by Doxapram

Abstract— The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10–120 mg kg^?1 day^?1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg^?1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg^?1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg^?1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b₅ content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.     

In-situ Ocular Absorption of Ophthalmic β-Blockers through Ocular Membranes in Albino Rabbits

Ocular membranes have been characterized by in-situ absorption of the ophthalmic β-blockers carteolol (hydrophilic) and timolol and befunolol (lipophilic) using a cylindrical cell. After introduction of drug solution into the cell on the cornea, sclera (bulbar conjunctival and scleral layer) or palpebral conjunctiva, the disappearance of the drug from the cell was determined as in-situ absorption. The ophthalmic drugs disappeared from the conjunctival and scleral membranes although disappearance from the cornea was hardly observed. The conjunctival membrane showed the highest permeability. Lipophilic drugs were more permeable than hydrophilic. In-situ apparent permeability coefficients of the ophthalmic drugs through the conjunctiva and sclera correlated with the lipophilicity of drugs. A high drug concentration in the aqueous humor was observed after corneal application. There is a relationship between concentrations of drugs in the aqueous humor and previously reported in-vitro apparent permeability coefficients of the drugs in the cornea. This in-situ method using a cylindrical cell is a useful method of investigating the ocular absorption of ophthalmic drugs.     

Anticardiolipin Antibodies in Patients With Pregnancy Loss Induce Factor Xa Production in the Presence of (β2-Glycoprotein I

PROBLEM : Anticardiolipin antibodies (aCL) are commonly associated with recurrent pregnancy loss, though the mechanism is uncertain. Some investigators have indicated that aCL may be directed at a complex made up of cardiolipin and a blood anticoagulant, β2-glycoprotein I (β2GPI). We therefore investigated the effects of β2GPI-dependent aCL IgG enriched fractions, isolated from sera of patients with pregnancy losses, on blood coagulation. METHOD : β2GPI-dependent aCL were prepared from sera of three women with second trimester pregnancy losses, by cardiolipin affinity column chromography, following by anti-β2GPI affinity column chromatography. The effects of β2GPI and β2GPI-dependent aCL on the activation of factor X in vitro were examined. RESULTS : β2GPI inhibited the activation of factor X and β2GPI-dependent aCL blocked this inhibitory effect in a dose dependent manner. CONCLUSION : These results imply the possibility of β2GPI-dependent aCL induce hypercoagulation or thrombus by blocking the inhibitory effect of β2GPI on activation of factor X, which may result in pregnancy loss.     

Difficulty in estimating localized bowel contraction by colonic manometry: a simultaneous recording of intraluminal pressure and luminal calibre

To examine whether or not intraluminal pressure changes at a site in the human colon reflect with fidelity the local bowel wall contractions or relaxation, endoscopic recording of the changes in colonic calibre as a parameter of the motor events with simultaneous manometry was performed at a fixed site in a prepared sigmoid colon during the interdigestive state. In four of the 12 subjects, a total of 20 phasic pressure waves with an amplitude of 13–22 mmHg and a duration of 13–18 sec were obtained in a 20 min recording session. Eighteen of the 20 phasic pressure waves (90%) were associated not with a decrease (contraction) but with an increase in the calibre (relaxation). The pressure change began 0.2–8.4 sec (mean: 4.5 sec) behind and ended ? 1.8 to 8 sec (mean: 3.5 sec) ahead of the calibre change. In the other eight subjects, no phasic pressure change was recorded in the presence of an overt calibre change. We conclude that manometric phasic pressure change recorded at a site in the empty human colon is not necessarily correlated with the localized contractile activity. Extrapolation of pressure profiles in the colon to motor events at the manometric site should be cautious.     

Contractile Action of Mn2+ via Ca2+ Channels Activated by Bay K 8644 in Guinea-pig Taenia Coli

Mn²⁺ has been shown to inhibit K+-induced contraction of smooth-muscle, to induce contraction of smooth-muscle in Ca²⁺-free, K+ medium and to activate the contractile proteins of skinned fibres of smooth muscle cells. Further work has suggested that Mn²⁺ penetrates the cytoplasm through voltage-dependent Ca²⁺ channels when the cell membranes of smooth muscles are depolarized with K+. We have investigated whether in Ca²⁺-free medium, Mn²⁺ enters the cytoplasm through Ca²⁺ channels and induces contraction of guinea-pig taenia coli in the presence of Bay K 8644, a dihydropyridine Ca²⁺-channel agonist which prolongs the open state of the voltage-dependent Ca²⁺ channels in smooth-muscle cells. In Ca²⁺-free medium the application of 5 mM Mn²⁺ in the presence of Bay K 8644 caused contraction of and concomitant increase in Mn²⁺ uptake in guinea-pig taenia coli smooth muscle. In the presence of Bay K 8644 nifedipine, a dihydropyridine Ca²⁺ channel antagonist, dose-dependently inhibited both manganese uptake and the contraction induced by Mn²⁺. These results suggest that Mn²⁺ enters the cytoplasm through dihydropyridine-sensitive, voltage-dependent Ca²⁺ channels activated by Bay K 8644 and then induces contraction in taenia coli.     

Apolipoprotein E ε4 allele distribution in alcoholic dementia and in Alzheimer's disease in Japan

The apolipoprotein E ε4 allele has been associated with both familial and sporadic Alzheimer's disease (AD). Given its possible role in nerve repair and growth, it is plausible that apolipoprotein E may be a common denominator in the pathogenesis of several dementing diseases. Therefore, we investigated ε4 frequencies in demented and nondemented alcoholics, as well as in patients with sporadic AD and controls in Japan. No significant difference in allele frequencies was found between demented and nondemented alcoholics and controls, while a significant association was demonstrated between AD and the ε4 allele. These results support a specific role of ε4 in the pathogenesis of AD, rather than a more general role for ε4 in dementing illnesses.     

Electrophysiologic Effects of Sodium Channel Blockade on Anisotropic Conduction and Conduction Block in Canine Myocardium: Preferential Slowing of Longitudinal Conduction by Flecainide Versus Disopyramide or Lidocaine

Objectives. The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle.

Background. Anisotropic ventricular conduction—electric conductivity dependent on the myocardial fiber direction—is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown.

Methods. In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions.

Results. High dose flecainide (100 μg/kg body weight per min) delayed the AT along the L direction markedly (mean [±SE] 227 ± 38%, p < 0.02) and mildly (121 ± 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs.

Conclusions. A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.

(J Am Coll Cardiol 1997;29:1639–44)