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The effect of the introduction of a 2-methoxy substituent on the beta-adrenergic antagonistic properties of a series of 3- and 4-substituted phenylethanolamines (1) was studied. Both the series of bromo- and methyl-substituted compounds behaved similarly, indicating that electronic forces are not significant in determining beta-adrenergic antagonist activity. When compared with the corresponding phenylethanolamines without a 2-methoxy substitutent, the 2-methoxy-4-substituted derivatives (3a and 3d) had enhanced potency and selectivity but the 2,3- (3b and 3e) and the 2,5-disubstitution patterns (3c and 3f) showed a loss of activity. The inconsistent changes in activity prevented any firm conclusions being made about the effect of the ether oxygen and the beta-adrenoceptor antagonistic activity of phenoxypropanolamines.
J Med Chem 1978 Oct
PMID:2-Methoxyphenylethanolamines, potential beta-adrenergic blocking agents. 3 74

The oxidation of palmitoyl- and octanoylcarnitine in liver mitochondria from normal and clofibrate-treated male rats was studied by measuring the ADP-stimulated oxygen consumption and acetyl group production (the sum of formed ketone bodies, acetylcarnitine and citrate). In the absence of malate the treatment approximately doubled the rate of acylcarnitine oxidation. In normal mitochondria the acetyl groups consisted almost totally of ketone bodies. The clofibrate-induced increase in acetyl group production was attributable to enhanced rates of ketone body and acetylcarnitine formation. The observed increase in acylcarnitine oxidation was associated with an elevated beta-hydroxybutyrate: acetoacetate ratio, reflecting an increased mitochondrial NADH:NAD+ ratio. In normal mitochondria the addition of malate in the presence of fluorocitrate doubled the rate of beta oxidation by forming citrate. The beta oxidation in mitochondria from clofibrate-treated rats was virtually unresponsive to added malate. The clofibrate-induced increase in ketogenesis was confirmed in disintegrated mitochondria. The treatment approximately doubled the rate of ketone body production from acetyl-CoA in disrupted organelles. The enhanced capacity of ketogenesis was accompanied by increased activity of the specific acetoacetyl-CoA thiolase (EC 2.3.1.8), which is the first step enzyme of the pathway. Clofibrate administration also increased the activities of general oxoacyl-CoA thiolase (EC 2.3.1.16), palmitoyl-CoA dehydrogenase (EC 1.3.99.3), and butyryl-CoA dehydrogenase (EC 1.3.99.2), which all take part in the beta oxidation of fatty acids.
Med Biol 1979 Feb
PMID:Effect of clofibrate treatment on acylcarnitine oxidation in isolated rat liver mitochondria. 3 20

To accomplish the safe transport of ill newborns, various infant transport systems have been developed. One such unit, produced by Airborne Life Support Systems, has been tested by the authors. The parameters used to evaluate the system were: (1) temperature stability at 2 degrees C and -28 degrees C ambient; (2) rate of internal temperature fall-off when all power to the unit was interrupted; (3) degree of CO2 accumulation, and (4) internal sound levels. Without heat shield, temperature decrease at 2 degrees C ambient was 12 degrees C/h; with head shield, 2 degrees C/h for the first hour and 0.9 degrees C in the second hour. At -28 degrees C ambient, temperature decrease was 6.1 and 2.2 degrees C/h for the first and second hour, respectively. The rate of temperature fall-off was 15.6 degrees C in 45 min. Average CO2 accumulation was 0.24% after 2 h. Sound level for heater and fan was 16.5 dB. An additional 1 dB of noise was contributed to the system when air and oxygen were turned on.
Aviat Space Environ Med 1979 Feb
PMID:Evaluation of a life support module used for air transport of critically ill infants. 3 68

We measured rat brain cortex PO2 (PtO2) with gold microelectrodes (tip diameter 5--10 micron) for up to 2 hours after 16 min of transient global brain ischemia with and without thiopental 90 mg/kg infused iv over 60 min beginning at 5 min postischemia. Seventeen rats were immobilized and mechanically ventilated on 1% halothane in oxygen with continuous monitoring of PtO2, ECG, end-expiratory CO2, rectal temperature, and arterial blood pressure. Global ischemia was induced by trimethaphan hypotension to an MAP of about 50 torr and a neck tourniquet inflated to 1500 torr. Postischemia, nine control rats (11 PtO2 measurements) were untreated and eight rats (8 PtO2 measurements) received thiopental 90 mg/kg. Preischemia, PtO2 values in both groups ranged from less than 5--70 torr with values of greatest frequency between 10 and 15 torr. Postischemia, PtO2 in control rats peaked at 45 +/- 8 (SEM) torr at 20 min. In thiopental treated rats, peak PtO2 was 24 +/- 6 torr at 10 min postischemia. Relative frequency histograms of PtO2 revealed that PtO2 in thiopental treated rats was lower (p less than 0.05) between 15 and 30 min postischemia. The magnitude of the decrease in PtO2 between 105 and 120 min postischemia appeared to correlate directly with the absolute preischemic value (i.e., the higher the preischemic PtO2, the greater the decrease in PtO2 postischemia). These results suggest that thiopental administered in large doses in early postischemia does not improve brain oxygenation secondary to a reduction in brain oxygen consumption. The relevance of the correlation between the magnitude of the fall in PtO2 postischemia and the magnitude of the preischemic value is discussed.
Crit Care Med 1979 Aug
PMID:Postischemic brain oxygenation with barbiturate therapy in rats. 3 43

The Unicam Spectrophotometer, the IL 282 CO-Oximeter, and the Hemoscan were used to measure the in vitro P50 using 1, 20--45, and 50% hematocrit values of red blood cells suspended in autologous plasma or phosphate buffered saline at pH of 6.7--7.7. The relation between pH and P50 was a linear correlation for washed red blood cells by all three methods whereas the relation between pH and P50 was a log correlation for red blood cells in plasma. Multiple units of red blood cells with low 2,3 diphosphoglycerate (2,3 DPG) and increased affinity for oxygen, with normal 2,3 DPG and normal affinity for oxygen, and above normal 2,3 DPG and decreased affinity for oxygen, were frozen in 10 ml aliquots with 40% w/v glycerol and maintained at -80 degrees C. One tube of each level of 2.3 DPG was thawed, washed, and suspended in buffer daily to yield P50 values of 17.5 +/- 0.67, 29.7 +/- 0.92, or 41.2 +/- 0.72 torr at pH 7.2 in order to have a control of both instrumentation and personnel.
Crit Care Med 1979 Sep
PMID:In vitro measurement of P50--the pH correction, and use of frozen red blood cells as controls. 3 55

Ionic iron at physiological pH hydrolyzes into insoluble aggregates, which disperse on slight acidification. Uncontrolled ionic iron promotes autoxidation, which crosslinks biomolecules and produces destructive activated oxygen. Defenses against autoxidative crosslinking include: 1. ferritin, the macromolecular scavenger of iron; 2. metabolic turnover, which prevents irreversible crosslinking through early catabolic degradation and replacement; and 3. enzymatic deactivation of oxygen. I am proposing that the anticrosslinking defenses are defeated by transient actions of metabolic perturbations, toxicants, oxidants and "foreign bodies", which cause oxidative crosslinking of proteins and lipids into irreversible tissue imprint: indigestible bodies containing porous limited-access spaces (LASs). The pores exclude the macromolecular ferritin and the digestive and antiautoxidation enzymes but admit ionic iron which, sheltered from ferritin, accumulates into decontrolled-iron pathogen (DIP). DIP utilizes the energy of ambient pH fluctuations to erupt from the LAS, swamp the available ferritin, poison the surroundings, catalyze autoxidation and crosslink cell components into additional LAS carriers. With time and sufficient promotion by pH fluctuations or metal-complexing agents, DIP and LAS expand. DIP injures through heavy-metal inhibition of life processes and catalysis of autoxidation. Typically, carcinogenic initiators are protein denaturants, cell poisons, "foreign bodies" and autoxidation catalysts. These are DIP-initiating properties, and DIP may be a preneoplastic stage of carcinogenesis. A DIP-model interpretation is given for the growth of asbestos bodies. DIP is an inorganic parasite. It may envelope and attack phagocytized particles.
Med Hypotheses
PMID:Biological autoxidation. I. Decontrolled iron: an ultimate carcinogen and toxicant: an hypothesis. 3 81

An isolated mouse heart model has been developed to study the extracellular factors which influence the loss of myocardial enzymes. When added to a tris-HCl buffer/salt mixture at 25 degrees C, glucose, phosphate ion, increased osmolarity, oxygen exclusion and calcium reduced enzyme leakage. Of these, calcium effects on enzyme leakage and ultrastructure were assessed in detail. Concentrations less than or equal to 10(-4) M had no significant effect on enzyme efflux over a 5 hour period. At higher concentrations (10(-3) and 10(-2) M Ca2+), creatine kinase (CK) efflux was significantly altered in a time dependent fashion. In the first hour, 10(-3) and 10(-2) M Ca2+ reduced CK leakage to 33% and 25% of the control values, respectively; and to about 50% of the control values in the second and third hours. This protective effect was lost between the third and fifth hours, when an enzyme efflux 80% greater than control was observed. These studies indicated that CK leakage from mouse heart can be retarded for up to 3 hours by appropriate Ca2+ concentrations. The initial ultrastructural change, in the absence of Ca2+, was a dilatation of the transverse tubules, which gradually enlarged by coalescence. This was followed by a gradual disintegration and ultimate condensation of the myofibrils leaving altered mitochondria floating freely in an apparently intact sarcolemmal bag. These changes appeared to be delayed by Ca2+ for 3 hours, after which no protective effect was evident. Thus, CK leakage is a measure of myocardial autolysis, and numerous simple measures can retard this autolysis for several hours. This raises the possibility of prolonging the preservation of the normal heart in vitro.
J Med 1979
PMID:Factors influencing mouse heart creatine kinase efflux and ultrastructure. 3 67

The application of cytochrome P-450 in substrate conversion is complicated both due to the limited stability and the cofactor regeneration problems. To overcome the disadvantages of NADPH consumption the transfer of the reduction equivalents from an electrode into the cytochrome P-450-system was studied: 1. NADPH was cathodically reduced at a mercury pool electrode. By immobilization of NADP on dialdehyde Sephadex the reductive recycling was possible. 2. Different forms of reduced oxygen were produced by the cathode: a) The reaction of O2- with deoxycorticosterone yields a carboxylic acid derivative. In contrast the cytochrome P-450 catalyzed NADPH-dependent reaction with the same substrate gives corticosterone, O2- represents only an intermediate in the activation of oxygen and is not the "activated oxygen" species. b) Molecular oxygen was reduced to HO2- and H2O2, respectively. The interaction of adsorbed cytochrome P-450 on the electrode surface with the reduced oxygen species in the absence of NADPH was studied. The electrochemically generated peroxide seems to be more active than added H2O2. 3. In a model of electro-enzyme-reactor several substrates were hydroxylated by microsomal cytochrome P-450 with cathodically reduced oxygen which substitutes NADPH.
Acta Biol Med Ger 1979
PMID:Electrochemical investigations on the oxygen activation by cytochrome P-450. 4 52

The bradycardial response to the diving reflex, which occurs in man and in diving animals, is thought to be a physiologically protective oxygen-conserving mechanism whereby the animal is kept alive during submergence. The physiology and nervous pathways are not yet fully understood, but several investigators have pointed out the potentially fatal outcome of an accentuated diving reflex. the CO2 content of the peripheral venous blood has been proved variable and unpredictable during the hyperventilation-breath-hold dive cycle in man. A group of 8 male divers (average age 34 years) was investigated during breathhold dives to 3,3 m in a swimming pool. Heart rates were recorded and compared at various stages during breath-hold and SCUBA (self-contained underwater breathing apparatus) dives, viz. when resting on the surface, breath-holding, hyperventilating and swimming underwater. Two divers performed extreme breathhold endurance tests lasting 135 seconds underwater. All divers had a tachycardia after hyperventilation and a bradycardia after breathhold diving, lasting 80-100 seconds. Extrasystoles were recorded during some of the breathhold dives. Prolonged submergence caused extreme bradycardia (24/min) with central cyanosis. Bradycardia during diving may be a physiological )2-conserving reflex or the start of a pathophysiological asphyxial response.
S Afr Med J 1975 Apr 05
PMID:Bradycardia during human diving. 4 82

Preparation of analogs of 4-[N-(3-chlorophenyl) carbamoyloxy]-2-butynyltrimethylammonium chloride [1 (McN-A-343)], cis- and trans-4-[N-(4-chlorophenyl)carbamoyloxy]-2-butenyltrimethylammonium iodides (5 and 6), and the corresponding epoxides and cyclopropanes is reported. Pharmacological testing for ganglion-stimulating activity demonstrated that the trans olefin 6 and trans epoxide 8 have properties similar to 1, while the trans cyclopropane analog 10 was inactive. All cis compounds were inactive. The muscarinic ganglion-stimulating properties of the active compounds are interpreted in terms of similar fit at the receptor level by the alkyltrimethylammonium ion and the ether oxygen 5.7 A distant, as well as an electron-rich center midway between groups in the form of a double bond or unshared electron pairs. Comparison of smooth muscle and ganglion-stimulating properties of the compounds showed that trans epoxide 8 was the most selective for muscarinic ganglionic sites.
J Med Chem 1976 Jan
PMID:Stereochemical analogs of a muscarinic, ganglionic stimulant. 2. Cis and trans olefinic, epoxide, and cyclopropane analogs related to 4-[N-(3-chlorophenyl)carbamoyloxy]-2-butynyltrimethylammonium chloride (McN-A-343). 5 26


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