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We estimated the activity of pulmonary capillary endothelium-bound (PCEB) angiotensin converting enzyme (ACE) in the rabbit in vivo, before and at 20 min and 2 h postadministration of the ACE inhibitors trandolaprilat (8 μg/kg) and enalaprilat (10 μg/kg), alone and in combination with the calcium channel blocker verapamil (100 μg/kg). PCEB ACE activity was assessed from the single-pass transpulmonary hydrolysis of the synthetic substrate 3H-benzoyl-Phe-Ala-Pro (BPAP). We then calculated the modified kinetic parameter Amax/Km and the dissociation constants (k-1) of the two inhibitors from PCEB ACE. Trandolaprilat reduced PCEB ACE activity less than enalaprilat, but its action was more sustained. Verapamil did not influence the immediate inhibitory action of either inhibitor. Enalaprilat exhibited more than a threefold higher k-1 than trandolaprilat from PCEB ACE (77.9 ± 9.2 vs. 25.2 ± 4.3 × 10–5&sol/sec). Co-injection of verapamil did not significantly affect the k-1 of enalaprilat (86.3 ± 5.2 × 10–5/sec) but moderately increased that of trandolaprilat (45.2 ± 6 × 10–5/sec). We conclude that 1) trandolaprilat confers a longer-lasting enzyme inhibition than enalaprilat, and 2) although the trandolaprilat-verapamil treatment moderately reduces the duration of the trandolaprilat-induced inhibition, it still offers a longer enzyme inhibition than enalaprilat alone or in combination with verapamil. Drug Dev. Res. 44:80–86, 1998. © 1998 Wiley-Liss, Inc.

The purpose of the present study was to contrast a commonly used ACE inhibitor (enalaprilat) with a novel ACE inhibitor (trandolaprilat) in their ability to inhibit 1) pulmonary capillary endothelial-bound ACE activity in vivo, 2) arterial pressure responses to i.v. angiotensin I and bradykinin, and 3) selected tissue ACE activity ex vivo, in rabbits. Pulmonary capillary endothelium-bound ACE activity in vivo was estimated via the single pass transpulmonary hydrolysis of the substrate 3 H-Benzoyl-Phenylalanyl-Alanyl-Proline (BPAP). Doses of acutely administered trandolaprilat (8 μg/kg) or enalaprilat (10 μg/kg) were equieffective in reducing the pressor response to angiotensin I. At these doses, trandolaprilat produced a greater inhibition of pulmonary capillary endothelial-bound ACE activity (66.5 ± 4.7% reduction of baseline BPAP metabolism vs. 52.7 ± 4.2% by enalaprilat, P < 0.05). Chronically administered trandolaprilat (8 μkg/ day for 8 days) was more effective than enalaprilat (either 8 μg/kg/day or 10 μg/kg/day for 8 days) in reducing the angiotensin-1 induced increase in mean arterial pressure (increases of 9.7 ± 1.4 mmHg vs. 20.3 ± 2.3 mmHg and 19.1 ± 5.7 mmHg respectively; P< 0.01), as well as in reducing BPAP metabolism. In agreement with in vivo data, trandolaprilat was 5.5-, 3.6-, and 2.5-times more effective than enalaprilat in reducing ACE activities in the aorta, left ventricle, and lung, respectively. We conclude that trandolaprilat is a more potent, longer acting, and more tissue-selective ACE inhibitor than enalaprilat, and that the method outlined here can be used to aid in the development of tissue-specific ACE inhibitors.

As a follow-up to the phenomena identification and ranking table (PIRT) studies conducted recently by NRC on next generation nuclear plant (NGNP) safety, a study was conducted to identify the significant 'gaps' between what is needed and what is already available to adequately assess NGNP safety characteristics. The PIRT studies focused on identifying important phenomena affecting NGNP plant behavior, while the gap study gives more attention to off-normal behavior, uncertainties, and event probabilities under both normal operation and postulated accident conditions. Hence, this process also involved incorporating more detailed evaluations of accident sequences and risk assessments. This study considers thermal-fluid and neutronic behavior under both normal and postulated accident conditions, fission product transport (FPT), high-temperature metals, and graphite behavior and their effects on safety. In addition, safety issues related to coupling process heat (hydrogen production) systems to the reactor are addressed, given the limited design information currently available. Recommendations for further study, including analytical methods development and experimental needs, are presented as appropriate in each of these areas.

An accident, thermal fluids, and reactor physics phenomena identification and ranking process was conducted by a panel of experts on the next generation nuclear plant (NGNP) design (consideration given to both pebble-bed and prismatic gas-cooled reactor configurations). Safety-relevant phenomena, importance, and knowledge base were assessed for the following event classes: (1) normal operation (including some reactor physics aspects), (2) general loss of forced circulation (G-LOFC), (3) pressurized loss-of-forced circulation (P-LOFC), (4) depressurized loss-of-forced circulation (D-LOFC), (5) air ingress (following D-LOFC), (6) reactivity transients - including anticipated transients without scram (ATWS), (7) processes coupled via intermediate heat exchanger (IHX) (IHX failure with molten salt), and (8) steam/water ingress. The panel's judgment of the importance ranking of a given phenomenon (or process) was based on the effect it had on one or more figures of merit or evaluation criteria. These included public and worker dose, fuel failure, and primary (and other safety) system integrity. The major phenomena of concern that were identified and categorized as high importance combined with medium to low knowledge follow: (1) core coolant bypass flows (normal operation), (2) power/flux profiles (normal operation), (3) outlet plenum flows (normal operation), (4) reactivity-temperature feedback coefficients for high-plutonium-content cores (normal operation andmore » accidents), (5) fission product release related to the transport of silver (normal operation), (6)emissivity aspects for the vessel and reactor cavity cooling system (G-LOFC), (7) reactor vessel cavity air circulation and heat transfer (G-LOFC), and (8)convection/radiation heating of upper vessel area (P-LOFC).« less

We investigated pulmonary endothelial function in vivo in 12- to 18-mo-old male Watanabe heritable hyperlipidemic (WHHL; n = 7) and age- and sex-matched New Zealand White ( n = 8) rabbits. The animals were anesthetized and artificially ventilated, and the chest was opened and put in total heart bypass. The single-pass transpulmonary utilizations of the angiotensin-converting enzyme (ACE) substrate [3H]benzoyl-Phe-Ala-Pro (BPAP) and the 5′-nucleotidase (NCT) substrate [14C]AMP were estimated, and the first-order reaction parameter A max/ K m, where A max is the product of enzyme mass and the catalytic rate constant and K m is the Michaelis-Menten constant, was calculated. BPAP transpulmonary utilization and A max/ K m were reduced in WHHL (1.69 ± 0.16 vs. 2.9 ± 0.44 and 599 ± 69 vs. 987 ± 153 ml/min in WHHL and control rabbits, respectively; P < 0.05 for both). No differences were observed in the AMP parameters. BPAP K m and A max values were estimated separately under mixed-order reaction conditions. No differences in K m values were found (9.79 ± 1 vs. 9.9 ± 1.31 μM), whereas WHHL rabbit A max was significantly decreased (5.29 ± 0.88 vs. 7.93 ± 0.8 μmol/min in WHHL and control rabbits, respectively; P < 0.05). We conclude that the observed pulmonary endothelial ACE activity reduction in WHHL rabbits appears related to a decrease in enzyme mass rather than to alterations in enzyme affinity.

The chief problems in glazing alumina bodies at high temperatures are (1) high porosity of the body with high capacity for absorption at the glaze-fusion temperature, (2) difference in thermal expansion between body and glaze, and (3) chemical activity of body and glaze materials. It is preferable to use feldspathic glazes with the RO group composed of alkalis from high-potash feldspars augmented if necessary by small amounts of potash frits. The effects of varying alumina and silica, with the RO group composed entirely of alkali, are illustrated for a typical glaze field. The glazes were applied to four alumina bodies containing 0 to 30% clay. The specimens were fired to cone 18, one-fire and two-fire. The results show that the area of best glazes was centered around 1.0 RO, 1.5 Al2O3, 15.0 SiO2 and 1.0 RO, 1.75 Al2O3, 15.0 SiO2 for one-fire and two-fire glazing, respectively.

An on-line computer can be very valuable for data acquisition and reduction in atomic flame spectroscopy (AFS). When the computer is also used to control the sampling process, this total system offers the advantages of ease of sample handling, repeated standardizations, and multiple analyses with averaging and randomization of the sampling sequence.1 Therefore, a solution sampler that is capable of rapid response and dependable operation and can be simply programmed for computer control has been designed and constructed.