Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels.

The effects of Brazilian scorpion Tityus serrulatus toxin gamma (TiTx gamma) were studied on voltage-gated Na+ channels from human heart (hHl) and rat skeletal muscle (rSkM1). The Na+ channels were expressed in Xenopus laevis oocytes, and Na+ currents were recorded using two-microelectrode voltage-clamp techniques. In control experiments, the threshold of activation of hH1 is more negative than that of rSkM1 by approximately 20 mV.

Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells.

Antimalarials are beneficial therapeutic agents in systemic lupus and rheumatoid arthritis. These autoimmune diseases have abnormally low apoptosis of inflammatory cells. Both disorders have an abnormal angiogenesis.

The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

Background: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both.

Okadaic acid enhances prepulse facilitation of cardiac alpha 1-subunit but not endogenous calcium channel currents in Xenopus laevis oocytes.

Xenopus laevis oocytes can be selected to express relatively high levels of endogenous Ca currents. These currents are facilitated by prepulses. Facilitated endogenous Ca currents are unaffected by okadaic acid, RpcAMPS or the dihydropyridine (DHP) antagonist (+) PN 200-110.

Electrophysiological characteristics of cloned skeletal and cardiac muscle sodium channels.

The alpha-subunit encoding for voltage-gated sodium channels rSkM1 (rat skeletal muscle subtype 1) and hH1 (human heart subtype 1) has been cloned and expressed by various groups under various conditions in Xenopus oocytes and the tsA201 (HEK 293) mammalian cell line derived from human embryonic kidney cells. In this study, we have expressed hH1 and rSkM1 in tsA201 cells for comparison under the same conditions using patch-clamp methods. Our results show significant differences in the current-voltage (I-V) relationship, kinetics of current decay, voltage dependence of steady-state inactivation, and the time constant for recovery from inactivation.

Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel alpha-subunits expressed in tsA201 cells.

We have expressed recombinant alpha-subunits of hH1 (human heart subtype 1), rSkM1 (rat skeletal muscle subtype 1) and hSkM1 (human skeletal muscle) sodium channels in human embryonic kidney cell line, namely the tsA201 cells and compared the effects of ATX II on these sodium channel subtypes. ATX II slows the inactivation phase of hH1 with little or no effect on activation. At intermediate concentrations of ATX II the time course of inactivation is biexponential due to the mixture of free (fast component, taufasth) and toxin-bound (slow component, tauslowh) channels.

Left ventricular intramyocardial pressure determination using two different solid-state micromanometric pressure sensors.

Intramyocardial tissue pressure can influence distribution of ventricular blood flow and dynamics during the cardiac cycle. Left ventricular ventral wall subepicardial and subendocardial tissue pressures were measured simultaneously using two different types of solid-state micromanometers (5F Millar model SPR-230 and Konigsberg Instruments model P19 pressure transducers) and compared with left ventricular cavity pressure. Systolic pressures recorded by Millar and Konigsberg transducers were similar when the sensor surfaces faced the left ventricular cavity either in the endocardium or epicardium.

Biliopancreatic Diversion with a New Type of Gastrectomy: Some Previous Conclusions Revisited.

BACKGROUND: In 1990, we modified Scopinaro's billopancreatic diversion (BPD); instead of a distal gastrectomy and gastroileal anastomosis, a parietal gastrectomy was performed with nutrients diverted through a duodenal switch. Also, the length of the common channel (50 cm) was doubled to 100 cm, while the nutrient limb remained 250 cm. In 1991, we reported initial results after 16 months, weight loss was as expected following BPD, but patients reported fewer side-effects and the prevalence of excessive malabsorption was less.

Influence of indapamide and chlorthalidone on reperfusion-induced ventricular fibrillation in isolated guinea pig hearts.

The delayed rectifier potassium current (IK) is a major repolarizing current in guinea pig ventricular myocytes. Blockade of IK or other repolarizing currents is of increasing interest for development of antiarrhythmic drugs; however, these interventions may also be proarrhythmic. In the present study, we compared the potential antiarrhythmic properties of indapamide and chlorthalidone, two structurally related sulfonamide diuretics which differ in their ability to block the slow component of the delayed rectifier (IKs) in isolated, buffer-perfused guinea pig hearts.

Biliopancreatic Diversion, with Distal Gastrectomy, 250 cm and 50 cm Limbs: Long-term Results.

BACKGROUND: Since 1984, biliopancreatic diversion (BPD) has been our procedure of choice in the treatment of morbid obesity. Better understanding of long-term outcome following BPD is needed. METHODS: We report the results of our first consecutive 92 patients who underwent BPD more than 5 years ago.

Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes.

Background: Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia. The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K+ currents involved in cardiac repolarization.

Methods And Results: A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms.

Angiotensin II modulates the delayed rectifier potassium current of guinea pig ventricular myocytes.

Amplitude of the delayed rectifier (IK) tail current measured following long (5000msec) depolarizing pulses (-10 to +50mV) was decreased 19 +/- 3% (P < 0.05) in a voltage-independent manner by angiotensin II (AII) 100nM. In contrast, amplitude of tail current measured following short (250msec) depolarizing pulses to potentials > +10mV was increased 13 +/- 3% (P < 0.

Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.

In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hypokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiarrhythmics and K(+)-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K(+)-sparing properties, exhibits other pharmacological effects.

An innovative technical approach for repetitive intratracheal instillation without anesthesia in small animals.

Intratracheal instillation in small laboratory animals often involves repeated anesthesia and upper airway intubation. To facilitate this approach, we developed an indwelling system for repeated intratracheal administrations that was assembled from widely available simple components. Its installation can be considered a minor surgical procedure and is done under sterile surgical conditions.

Role of polymorphic debrisoquin 4-hydroxylase activity in the stereoselective disposition of mexiletine in humans.

It was reported previously that mexiletine undergoes stereoselective disposition in humans and that formation of three of its major metabolites co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-mediated oxidation pathways of mexiletine are responsible for the stereoselective disposition of the racemate in humans. Fourteen healthy subjects (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) participated in this study.

Biliopancreatic Diversion with a New Type of Gastrectomy.

In an attempt to improve the results of biliopancreatic diversion in the treatment of morbid obesity, two aspects of the procedure performed at Laval Hospital were modified to reduce adverse physiological consequences. The distal gastrectomy was replaced by a parietal gastrectomy which preserves vagal continuity along with the lesser curvature, and leaves intact the antro-pyloroduodenal pump. The duodenum was stapled shut and nutrients were diverted through a duodeno-ileal anastomosis.

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg).

Influence of low-flow infusion and magnesium on tissue necrosis during regional ischemia in the canine myocardium.

Passive intracoronary perfusion of therapeutic agents has been used in the clinical setting to attenuate the effects of brief episodes of myocardial ischemia. The objective of this study was to assess the effects of low-flow coronary infusion with or without Mg2+ on tissue necrosis and cardiac hemodynamics after prolonged regional ischemia. In 33 anesthetized dogs (5 excluded during study), the left anterior descending coronary artery was occluded for 6 h.

Biliopancreatic Diversion with Gastrectomy as Surgical Treatment of Morbid Obesity.

The best procedure for the treatment of morbid obesity has not yet been defined. Biliopancreatic diversion is one of the techniques available, but its results have not been sufficiently documented and the addition of a subtotal gastrectomy to the diversion so as to avoid leaving a blind non-functioning stomach, is still questionable. The purpose of this paper is to report our experience with our first 149 consecutive patients who were treated by biliopancreatic diversion with subtotal gastrectomy for morbid obesity.

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine.

Differential modulation of carbonic anhydrase (CA III) in slow- and fast-twitch skeletal muscles of rat following denervation and reinnervation.

Carbonic anhydrase III (CA III) is influenced by neuronal factors in skeletal muscles of the rat. CA III protein and its mRNA levels were assessed in slow- and fast-twitch muscles after short-term denervation by ligature of the sciatic nerve and reinnervation following removal of the sheath tightly fixed around the nerve. Significant elevations in the CA III mRNA content of fast-twitch muscles were recorded after denervation, but they were cancelled following spontaneous muscle reinnervation.

Modulation of Mycobacterium avium growth in vivo by cytokines: involvement of tumour necrosis factor in resistance to atypical mycobacteria.

The protective mechanisms associated with resistance to atypical mycobacteria infections are not clear. In an effort to broaden our understanding of the mechanisms involved, susceptible mice were infected with a virulent strain of M. avium and various treatments were applied so as to modify the course of the disease.

Effect of N-acetylcysteine on tissue necrosis during acute myocardial infarction in rabbits.

This study examined whether N-acetylcysteine, a low molecular weight compound used clinically to replenish glutathione, could limit tissue necrosis during acute myocardial infarction in hearts with minimal coronary collateral flow. Fifty rabbits underwent 45 mins ischemia with and without coronary reperfusion for 3h. Four groups were studied.

Pulmonary function and airway responsiveness during long-term therapy with captopril.

Angiotensin-converting enzyme inhibitors sometimes cause cough; the mechanism is unknown. We therefore studied the effects of ambulatory treatment with captopril on pulmonary function and on nonspecific bronchial responsiveness to methacholine in 15 hypertensive subjects. Lung volumes, expiratory flows and nonspecific bronchial responsiveness to methacholine using doses up to 64 g/L were measured before and four and eight weeks after captopril treatment was started.