Diadenosine-5-phosphate exerts A1-receptor-mediated proarrhythmic effects in rabbit atrial myocardium.

(1) Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. (2) Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I(K(ACh/Ado))) and ATP-sensitive potassium current (I(K(ATP))) were measured by using the whole-cell voltage clamp method. (3) Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 micro M; n=6; P<0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n=6). Ap(5)A>/=1 micro M reduced AERP (100 micro M, 58+/-11 ms; n=6). (4) Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>/= micro M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 micro M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. (5) The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 micro M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. (6) Ap(5)A (

Pharmacokinetics of polychlorinated biphenyl components in swine and sheep after a single oral dose.

Single-dose oral administration of a commercial polychlorinated biphenyl product containing 54% chlorine provided data with which to plot the time course of total polychlorinated biphenyl and individual components in the blood of swine and sheep. Pharmacokinetic parameters describing absorption from the gut and elimination from a two-compartment body system were determined for the components in swine and sheep. The absorption half-time for total polychlorinated biphenyl in swine was 1.13 hr while that for sheep was 3.83 hr. The half-time for disposition of total polychlorinated biphenyl from the central compartment was 4.4 hr in swine and 7.7 hr in sheep; the apparent biological half-life was 62.4 hr in swine and 78.8 hr in sheep. Individual components varied significantly from each other and from total polychlorinated biphenyl in all parameters.

Experimental lead toxicosis in ponies: comparison of the effects of smelter effluent-contaminated hay and lead acetate.

Grass hay produced in the Coeur d'Alene River Basin of northern Idaho was fed to a group of 4 ponies. The hay contained Pb in concentration of 423 +/- 82 mg/kg and Cd in concentration of 10.8 +/- 1.4 mg/kg, resulting in daily exposures of the ponies to approximately 7.4 mg of Pb/kg and 0.19 mg of Cd/kg/day. The results in this group of ponies were compared with those from a group fed noncontaminated grass hay and given a daily dose of 10 mg of Pb/kg of body weight, in the form of lead acetate. Clinical toxicologic signs, hematologic changes, and blood and tissue Pb concentrations were similar in the 2 groups. However, the severity of the disease process appeared to be greater in the ponies fed the Pb- and Cd-contaminated hay. This was shown clearly by the shorter interval between onset of clinical changes and death in the ponies fed contaminated hay. The possibility of multiple heavy metal effects is discussed. Clinical toxicologic signs observed include incoordination, labial paresis, pharyngeal paresis, CNS depression, anorexia, and body weight loss. Anemia or marginal anemia was common and was often accompanied by the appearance of nucleated RBC and Howell-Jolly bodies in peripheral blood. Neither the hematologic response nor the blood Pb concentrations were reflective of the severity of poisoning, although blood Pb concentrations were greater than 0.35 micrograms/ml once clinical signs of toxicity were observed. Liver, kidney, spleen, brain, and bone Pb concentrations and liver, kidney, and brain Cd concentrations were increased in both the ponies fed contaminated hay and the ponies given lead acetate.

Preparation of autogenous bone grafts in two different bone mills.

The purpose of this study was to evaluate the performance of two bone mills (R Quetin Bone Mill and Micro Knochenmühle, Aesculap) for the grinding of autogenous bone (intraoral, cortical) according to the following criteria: (1) loss of bone during the grinding process, (2) particle size of the chips, (3) variability in chip size, (4) technical handling, and (5) cost-benefit ratio. The amount of material loss was determined by harvesting 30 bone cores from the mandibular symphysis of a pig. Each specimen was weighed before and after the grinding procedure on scales with an accuracy of 0.1 mg. The size and variability of the bone particles were determined histomorphometrically. Twenty-seven bone specimens from different patients were analyzed. Eight were ground with the Aesculap and 12 with the Quetin mill. Seven specimens harvested with a Brånemark implant bur served as controls. A histologic section was prepared from each specimen, and 10 bone particles per section were subjected to histomorphometric analysis. The Quetin mill was superior in all points to the Aesculap mill for the requirements of a periodontal practice.

Long-term clinical results of galvano-ceramic and glass-ceramic individual crowns.

STATEMENT OF PROBLEM: Alternatives to metal-ceramic restorations should possess clinical durability before being recommended to the dentist. Longitudinal clinical studies are required for evaluation so innovative types of restorations can meet the expectations of dentists and patients. PURPOSE: This study compared the performance of galvano-ceramic restorations (Auvo Galvano Crown [ACG]) and glass-ceramic individual crowns (Dicor) based on longitudinal clinical trials. MATERIAL AND METHODS: A total of 769 galvano-ceramic single crowns (AGC) in 322 patients and 173 glass-ceramic individual crowns (Dicor) in 88 patients were reviewed for 8 years and a maximum of 11 years, respectively, after cementation. Risk of fracture was determined with use of a survival analysis (Kaplan and Meier). RESULTS: Partial ceramic cracking was observed at the time of the last recording of data in 11 galvano-ceramic crowns, 8 of the units remained in place. Two crowns became dislodged and 1 tooth exhibited a fractured root, despite an intact crown. One restoration was removed because of hypersensitivity and 1 with partial ceramic fracture. Forty-two of the glass-ceramic crowns were completely fractured. After a comparable 7 years under risk, 96.5% (+/-3.4; 95% confidence interval) of the galvano-ceramic premolar and molar crowns and 92% (+/- 8.5) of crowns placed on incisors and canines crowns were intact. The corresponding data for the glass-ceramic restorations were only 70% (+/- 10.6) in posterior and 82.7% (+/- 8. 1) in anterior quadrants. CONCLUSION: Long-term results of electroformed individual crown restorations were superior to glass-ceramic restorations.

Pharmacokinetics of ketamine HCl and metabolite I in the cat: a comparison of i.v., i.m., and rectal administration.

Ketamine HCl [2-(o-chlorophenyl)-2-(methylamino) cyclohexanone HCl] concentrations in whole blood were used to study the pharmacokinetics of i.v., i.m., and rectal administrations, at a dose of 25 mg/kg, in normal domestic cats. Absorption was rapid with both the i.m. and rectal routes. Systemic availability was 51% (SEM 10) for the i.m. dose and 43.5% (SEM 6.1) for the rectal dose. The first-pass effect had a minimal influence on the metabolism of ketamine HCl administered rectally. The elimination rate constant (beta) of the drug was statistically similar in the i.v., i.m., and rectal groups, at a 95% level of significance (P less than 0.05). At the dosage rates studied, ketamine HCl produced an anesthetic effect in the cat following i.v., i.m. and rectal administration.

Effect of diuretics on ketamine and sulfanilate elimination in cats.

Rate constants of elimination were used to evaluate potential effects of diuretic agents on the elimination of ketamine from the blood of cats. Furosemide, mannitol, and aminophylline did not significantly alter the ketamine elimination rate constants, although the diuretics had a tendency to prolong elimination. This tendency of furosemide was further substantiated by observing the effect of furosemide on glomerular filtration. The rate of sulfanilate elimination, used as an indicator of glomerular filtration, was significantly decreased in the cats that were administered furosemide. Possible mechanisms for the influence of furosemide on the renal excretion of ketamine are discussed.

Propranolol inhibits IK(Ado) by competitive A1-receptor interaction.

OBJECTIVES: Betablocking agents are known to exert anti-arrhythmic effects in ischemic myocardium due to blockade of myocardial beta-1-receptors. Since adenosine (Ado) induced muscarinic potassium current (IK(Ado)) and ATP sensitive potassium current (IK(ATP)) are discussed to be activated during ischemia we studied the effect of propranolol on IK(Ado) and IK(ATP). METHODS AND RESULTS: The effect of propranolol on muscarinic potassium current and IK(ATP) was studied in isolated rat atrial myocytes by means of the whole-cell voltage clamp tech- nique. Propranolol (50 microM) completely inhibited IK(Ado). IC50 was 7 microM. Inhibition of acetylcholine induced current (IK(ACh)) and GTP-gamma-S induced muscarinic potassium current was less potent (IC50 29 microM and 31 microM respectively). Propranolol was active from the outside only. Intracellular application did not significantly affect muscarinic potassium current. (+)-propranolol, an isomer without beta-blocking properties, was as effective as (+/-)-propranolol. The inwardly rectifying potassium current IK(ATP) showed minor sensitivity to the compound (10% current reduction, propranolol 50 microM). CONCLUSIONS: Propranolol inhibits IK(Ado). Inhibition is not due to beta-receptor blockade. Predominantly an interaction with A1-receptors seems to be involved. The observations in part might explain the anti-arrhythmic properties of the drug in ischemic/fibrillating myocardium based on the prolongation of refractoriness.

Apparent pharmacokinetics of PCB components in growing pigs and lambs when fed a ration containing Aroclor 1254.

Young growing lambs and pigs were fed a ration containing 200 ppm of Aroclor 1254 for 35 days and then switched to "clean" feed. Blood and fat samples were collected periodically throughout the experiment and analyzed for components of Aroclor 1254 and total PCB. Several components are apparently accumulated and eliminated at different rates within each species, as seen by comparing gas chromatograph tracings, accumulation ratios and apparent rate constants of elimination. Differences in accumulation and elimination of Aroclor components, some of which were apparently caused by differences in growth rates, were also seen between pigs and lambs. Variable growth rates of different species of food producing animals are an important factor to consider when dealing with tissue distribution and residues of polychlorinated biphenyls for determination of carcass disposition, as well as accumulation of toxic concentrations in the animal body.

Tissue distribution of PCB components in swine and sheep fed three different rations containing Aroclors 1242 and 1254.

Growing swine and sheep were fed three dietary variations containing 20 ppm of Aroclors 1242 or 1254 for 13 to 15 weeks. Generally, Aroclor 1254 residues were higher; higher 1242 residues in swine blood, spleen, and ovary are attributed to persistent major components of this Aroclors. Some minor differences in total PCB were observed with varying diets, but peak composition did not vary. Some lower chlorinated components maintained higher levels in the blood relative to other components; other components were selectively accumulated in tissues such as fat and muscle. Blood and fat residues in sheep declined during the last weeks of feeding. Microsomal oxidase levels were elevated in response to PCB and diet in both species, but the response was greater in sheep. Sheep liver microsomes were capable of metabolizing pure analogs and components of Aroclor 1242. Major differences in Aroclor profiles can be demonstrated between swine and sheep residues and total residues can be estimated by measuring selected peaks in blood and backfat. The peaks which provide the most reliable estimate of total PCB residue vary with species and Aroclor.

Inhibition of G protein-coupled and ATP-sensitive potassium currents by 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015), an amiodarone derivative.

2-Methyl-3- (3,5-diiodo-4-carboxymethoxybenzyl) benzofuran (KB130015; KB), a novel compound derived from amiodarone, has been proposed to have antiarrhythmic properties. Its effect on the G protein-coupled inward rectifying K+ current [IK(ACh) or IK(Ado)], ATP-sensitive K+ current [IK(ATP)], and background inward rectifying current (I(K1)) were studied in guinea pig atrial and ventricular myocytes by the whole-cell voltage-clamp technique. Receptor-activated IK(ACh/Ado), induced in atrial myocytes by the stimulation of either muscarinic or Ado receptors was concentration dependently (IC50 value of approximately 0.6-0.8 microM) inhibited by KB. Receptor-independent guanosine 5'-O-(3-thio)triphosphate-induced and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC50 value of approximately 0.9 microM). IK(ATP) induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas IK1 measured in ventricular myocytes was insensitive to the drug (KB < or =50 microM). Although being effective when applied from the outside, intracellular application of KB via the patch pipette affected neither IK(ACh) nor IK(ATP). 3,3',5-triodo-L-thyronin, which shares structural groups with KB, did not have an effect on the K+ currents. Consistent with the effects on single myocytes, KB did not depolarize the resting potential but antagonized the shortening of action potential duration by carbamylcholine-chloride or by DNP in multicellular preparations and antagonized the shortening of action potential duration by acetylcholine in single myocytes. It is concluded that KB inhibits IK(ACh) and IK(ATP) by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane.