The presence of an alpha-adrenoceptor--mediated coronary vasoconstrictor reflex during acute systemic hypoxia was examined in thirteen chloralose-anesthetized dogs. Local vasodilator effects were avoided by perfusing the left common coronary artery (LCC) with normoxic blood, while the dogs were ventilated with 5% 02-95% N2 . Left ventricular afterload was held constant and positive cardiac inotropic responses and beta two-adrenoceptor-mediated coronary vasodilation were blocked by propranolol. Parasympatheticmediated bradycardia and coronary vasodilation were blocked with atropine. Systemic hypoxia decreased LCC flow to normoxic myocardium by 19.4+2.6 %. Although myocardial oxygen extraction increased 9.7+2.9 %, myocardial oxygen consumption decreased 16.5+2.6 %. Intracoronary prazosin prevented the reflex vasoconstriction during repeated hypoxia.

The muscarinic agonist carbachol stimulates a rapid increase in ^32Pi incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI) in calcium tolerant myocytes prepared from heart tissue. The density of muscarinic receptors, determined by [^3H]-QNB binding, is greater in the atria than in the ventricles. 250 uM carbachol decreased specific [^3H]-QNB binding to muscarinic receptors on myocyte membranes by fifty percent. Trifluoperazine, also a phospholipase C inhibitor, inhibited the carbachol stimulated increase in ^32Pi incorporation into PA and PI and did not interfere with muscarinic receptor binding. Therefore, isolated canine myocytes provide a suitable model system to further study the muscarinic receptor stimulated phospholipid effect, and its role in mediating biochemical processes and physiological function in the heart.

An investigation of the ratio of free to bound phenytoin in overdose cases was accomplished by three studies to answer these questions: 1. Will the free to bound ratio change with increasing total phenytoin concentration? 2. Will the free to bound ratio be altered with decreasing total protein concentration? 3. Do these results correlate with overdose cases? The results demonstrated that the ratio of free to bound phenytoin remains constant throughout the therapeutic range as long as a person has a normal total protein concentration. However, the free to bound ratio changes significantly when the total protein decreases by 25 per cent. This substantiates the importance of monitoring free and total phenytoin concentrations in hypoproteinemia.

Cigarette smoke condensates from all cigarettes tested were found to be potent inducers of AHH enzyme in cultured human lymphocytes and, with the exception of Kent Lights and Carlton CSC's, all were found to be toxic under the experiment conditions. Most of the AHH inducing activity was found in basic and neutral fractions of the lAl standard cigarettes. A radiometric assay of BP metabolites in cultured human lymphocytes was developed in which we were able to separate the primary metabolites and the secondary metabolites from the parent compound (BP) by neutral alumnia HPLC. The primary metabolites were further separated by a selective enzyme hydrolysis and/or reverse phase HPLC.

Rats were trained to discriminate an injection of cocaine, 5.0 mg/kg, from an injection of saline, using a two-lever choice paradigm: one lever was correct after cocaine injection, the other lever was correct after a saline injection. After training, cocaine and methamphetamine were generalized to the cocaine lever, but phenethylamine (PEA) was only partially generalized. Cocaine was injected every 8 hrs, 20.0 mg/kg, and the discriminability of 5.0 mg/kg was tested every other day. Redetermination of the cocaine generalization curve after 6 days of chronic administration showed a shift to the right, from an ED50 of 4.1 mg/kg in the pre-chronic condition to 10.0 mg/kg. Tolerance did not develop to the behavioral effects of cocaine, measured by time to the first reinforcement and response rate. There was cross-tolerance to methamphetamine; however, no evidence for cross-tolerance to PEA was obtained. Following the acquisition of tolerance, chronic administration of cocaine was terminated, and the discriminability of 5.0 mg/kg was tested every other day for loss of tolerance. After 8 days the ED50 returned to 5.0 mg/kg.

The high concentrations of amitriptyline found in blood at autopsy, indicating a large amount of ingested drug, is often contradictory to the prescription available. Using dogs as the animal model it was found that there was a large variance between the dose given and its plasma amitriptyline concentration during the acute phase of absorption. Factors that were found to be important were the amitriptyline to nortriptyline (as metabolite) ratio, the nature of the specimen, and the collection site. The calculation of the dose from an acute ingestion of amitriptyline resulting in death cannot be accurately determined from a single specimen collected at autopsy.

A model was developed to predict the increased physiological effort of wearing a respiratory protective device. Specifically, the model was designed to predict the effects of varying ventilatory demands on eleven respiratory variables of the man-respirator system, breath frequency (f_b), tidal volume (V_t), inspiratory flow (dvi/dt), expiratory flow (dve/dt), inspiratory mask pressure (P_mi), expiratory mask pressure (P_me), inspiratory intrathoracic pressure (P_ii), expiratory intrathoracic pressure (P_ie), inspiratory mask work (W_mi), expiratory mask work (W_me), and mask leakage index (L_i). The model was tested by experiment in which three male subjects underwent maximal exercise testing with and without the "pressure-demand" respirator. The eleven variables were determined for each thirty second period utilizing on-line computer analysis. Application of the model to these experimental conditions resulted in significant (p<.001) relationships between each of the predicted and observed variables.

Cytoplasmic 15-hydroxyprostaglandin dehydrogenase from swine kidney was purified to specific activity of 1.2 U per mg protein, by chromatographic techniques. Native molecular weight of enzyme was estimated at 45,000. Enzyme was inhibited by sulfhydryls, diuretics, and various fatty acids. Substrate studies indicated NAD+ specificity and ability to catabolize prostaglandins, except prostaglandin B and thromboxane B. Initial velocity studies gave intersecting plots conforming to a sequential mechanism. 15-keto-prostaglandin exhibited linear noncompetitive production inhibition with respect to either prostaglandin or NAD+; NAD yielded linear competitive production inhibition with respect to NADH. Results, and those of dead-end inhibition and alternated substrate studies, are consistent with an ordered Bi-Bi mechanism: NAD+ is added first, then prostaglandin; then 15-keto-rostaglandin is released, then NADH.

Male Fischer rats (n=43) were used in a diet-diet/ exercise design to investigate the apparent protein sparing effects of exercise. The animals were divided into five groups: INITIAL (baseline), SEDENTARY (control), DIET, DIET/EXERCISE, and EXERCISE. Carcasses were analyzed for body composition, the blood for plasma alanine concentration and the urine for urea nitrogen concentration. The results showed no significant differences between groups in urinary urea nitrogen, plasma alanine, body weight, or carcass weights. The EXERCISE group had a significant increase in percent protein and a significant decrease in percent fat and grams of fat when compared to all other groups (p <.05).

Wretlind, Heden, and Wadstrom found ammonium sulfate to be inhibitory for the formation of extracellular protease in Aeromonas hydrophila grown in Brain Heart Infusion medium. They demonstrated by manipulating the iron and zinc content within their medium that it is possible to differentially affect the accumulation of hemolysin and protease by A. hydrophila grown in batch culture. Further manipulation of the composition of this medium was done in the present study to determine the effect of other components on the production of protease. The purpose of this study was to determine the factors affecting the level of A. hydrophila protease produced in a chemically defined medium.

Two separate experiments were designed to measure urinary cyclic AMP and renal papillary cyclic AMP, respectively, Results suggest that urinary cyclic AMP excretion rate is unchanged and cannot be used as an index of tubular sensitivity to either vasopressin or fluoride. However, renal papillary tissue cyclic AMP increased significantly (p<0.05) at plasma fluoride concentrations which result in polyuric renal failure. Further, it appears that fluoride independently stimulates cyclic AMP in the papilla, demonstrated by the additive effect with vasopressin. It was postulated that the defect in water reabsorption induced by fluoride must be at a step subsequent to the generation of cyclic AMP, because one would expect to see an antidiuresis, not a diuresis with increased tissue cyclic AMP.

Histamine is present in the central nervous system and is believed to be derived from neurons (50 percent) and mast cells (50 percent). This experiment was designed to analyze histologically the numbers and distribution of brain-associated mast cells in normal (+/+), mast cell deficient (W/W^v) and heterozygote (W/+, W^v/+) mice of the WBB6F_1 /J strain. Significant variations in the number and distribution of mast cells between the various genotypes were found. Based on the results, a hypothesis is proposed to account for the observed genotypical differences in mast cell numbers and distribution. Based on the total number of mast cells and the content of histamine in a typical mast cell, it is apparent that the mast cell is not a major source of brain histamine, suggesting that another non-neuronal pool of histamine must be present in the brain.

A modified ascending thin layer chromatographic technique has been developed which resolves the major phospholipid and neutral lipid classes of five common fluids and tissues. A one-half milliliter sample is extracted with n-butanol:diisopropylether (40:60 by volume, cholesteryl acetate = 100 ng/ul) for thirty minutes and the organic phase is spotted onto a thin layer chromatography plate and carried through three successive chromatographic developments. The lipids are then visualized either by charring with ammonium bisulfate or staining with phosphomolybdic acid. The use of cholesteryl acetate as an internal standard enables quantitation of the phospholipids and neutral lipid classes. This method may be a very valuable, new technique for research and clinical laboratories.

Ten caucasian male quadriplegics were compared with eight sedentary caucasian male controls in regards to left ventricular dimensions and mass obtained from echocardiograrns. The interventricular septum (IVS), left ventricular posterior wall (LVPW) and left ventricular internal diameter (LVII) were within normal limits for both groups. However, the INS in the SCI were significantly thicker than controls (p <0.05). Myocardial thickness was larger in SCI subjects (p <0.05). Absolute left ventricular mass (LVM) and total left ventricular volume was not different ( p > 0.05), but SCI subjects had significantly greater LVM to lean body mass ratios. Echocardiographically, SCI patients demonstrate concentric hypertrophy. This suggests adaptive response to chronic increase in afterload pressure secondary to their daily activities and muscle spasticity.

Mice were exposed to diesel exhaust for 9 months prior to evaluation for benzo(a)pyrene disposition. On the last day of exposure the mice were instilled intratracheally with tritiated-benzo(a)pyrene ([3H]BP). The mice were sacrificed at intervals of 2, 24, and 168 hours. Disappearance of radioactivity from lungs and liver was rapid and essentially linear with time. In lungs, liver, and testes; [3H]BP metabolites were found mainly as conjugates, a form readily excretable. Clearance of the hydrocarbon from liver and testes in exposed mice was not markedly different from that in nonexposed mice. However, mice exposed to diesel exhaust had delayed [3H]BP clearance from lungs, possibly due to [3H]BP adsorption to diesel smoke particles.

Thirty-one rats were trained on a differential reinforcement of low rate schedule. After responding had stabilized, animals were injected with methylphenidate, twice weekly, presession. Methylphenidate produced dose-dependent increases in response rates and decreases in reinforcements. Repetition of these doses produced a reduced drug effect, and a third administration of the 10 mg/kg dose further reduced the drug effect. Subsequently, the effects of daily and intermittent administration were determined for this dose. Daily methylphenidate, pre-session, produced tolerance to the behavioral effects of methylphenidate and cross-tolerance to the amphetamines. Twice-weekly methylphenidate, pre-session, produced partial tolerance to methylphenidate and partial cross-tolerance to the amphetamines. Thus, periodic exposure to the behaviorally disruptive effects of a drug of the amphetamine class reduces the effects of subsequent exposure.

Early function of a temperature-sensitive mutant of staphylophage 44A HJD was examined during the twenty-five-minute period following infection. Host cell and phage DNA were labeled with C and3H respectively. DNA was separated into linear and covalently closed circular (CCC) forms by density-gradient centrifugation. The host, S. aureus, shows no CCC DNA, and apparently carries no plasmid. Following infection with wild type phage, CCC DNA forms occur in tritiated and 1 C DNA fractions 10 to 15 min after infection. Infection with mutant at permissive temperature also demonstrates CCC DNA with both labels. Infection with mutant at nonpermissive temperature produced no CCC DNA during the first 25 min after infection. The impaired function in this mutant may be a linker protein.

A method for purification and radiolabelling phosphoglucose isomerase was devised in order to develop a sensitive quantitative radioimmunoassay for the detection of the enzyme irrespective of its catalytic activity. For four genetic variants of PGI no difference in the molecular specific activity was observed. In one variant (PGI-Denton), liver and heart tissue extracts, and in mature erythrocytes (as compared to normal erythrocytes), a decreased molecular specific activity was observed which initially may imply that these samples contain cross-reactive material which is not catalytically active.