Excitatory amino acid neurotransmission.
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Amino Acids↗
Biomedical subjects
R L Johnson
Publications and source records attributed to R L Johnson.
Dopamine receptor modulation by conformationally constrained analogues of Pro-Leu-Gly-NH2.
Two series of conformationally constrained analogues of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series of analogues, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the gamma-lactam residues 3(S)- and 3(R)-amino-2-oxopyrrolidineacetamide and the delta-lactam residue 3(S)-amino-2-oxopiperidineacetamide. The corresponding gamma-lactam analogues of less than Glu-Leu-Gly-NH2 were also synthesized. In a second series of analogues, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, 3(S)-amino-2-pyrrolidone, and 3(S)-amino-2-piperidone residues. The above analogues were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Of the conformationally constrained analogues of PLG synthesized in this study, only the gamma-lactam analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (3) was found to possess significant activity. This analogue was 10,000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concentrations of 10(-9) and 10(-10) M.
Animals↗
Interaction of L-prolyl-L-leucyl glycinamide with dopamine D2 receptor: evidence for modulation of agonist affinity states in bovine striatal membranes.
The role of the hypothalamic tripeptide L-prolyl-L-leucyl-glycinamide (PLG) in modulating the agonist binding to bovine striatal dopamine D2 receptor was investigated using a selective high-affinity agonist, n-propylnorapomorphine (NPA). PLG caused an enhancement in [3H]NPA binding in striatal membranes in a dose-dependent manner, the maximum effect being observed at 10(-7)-10(-6) M concentration of the tripeptide. The Scatchard analysis of [3H]NPA binding to membranes preincubated with 10(-6) M PLG revealed a significant increase in the affinity of the agonist binding sites. In contrast, there was no effect of PLG on the binding pattern of the antagonist [3H]spiroperidol. The antagonist versus agonist competition curves analyzed for agonist high- and low-affinity states of the receptor displayed an increase in the population and affinity of the high-affinity form of the receptor with PLG treatment. The low-affinity sites concomitantly decreased with relatively small change in the affinity for the agonists. Almost similar results were obtained when either NPA or apomorphine was used in the competition experiments. A partial antagonistic effect of PLG on 5'-guanylylimidodiphosphate [Gpp(NH)p]-induced inhibition of high-affinity agonist binding was also observed, as the ratio of high- to low-affinity forms of the receptor was significantly higher in the PLG-treated membranes compared to the controls. Direct [3H]NPA binding experiments demonstrated that PLG attenuated the Gpp(NH)p-induced inhibition of agonist binding by increasing the EC50 of the nucleotide (concentration that inhibits 50% of the specific binding). No effect of PLG on high-affinity [3H]NPA binding, however, could be observed when the striatal membranes were preincubated with Gpp(NH)p.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Rapid in vivo determinations of instantaneous right ventricular pressure and volume in dogs.
We have developed a method for measuring in vivo canine right ventricular (RV) volume at a frequency of 60 Hz. In six dogs (17-22 kg), under pentobarbital anesthesia, 18 radiopaque markers were surgically implanted in the RV myocardium to maximally represent the RV shell. The xyz-coordinates of the markers were obtained from biplane cineradiographic recordings. RV volume was calculated from the polyhedron created by the markers by decomposing the polyhedron into 24 tetrahedrons, each of whose volumes could be solved from the xyz-coordinates of markers. RV volume was obtained each 16.7 ms, permitting detailed representation if RV volume dynamics. RV end-diastolic volume, end-systolic volume, and ejection fraction averaged 41.3 +/- 10.9, 23.0 +/- 5.8, and 0.44 +/- 0.05 ml, respectively. By simultaneously measuring RV pressure, RV pressure-volume loops were constructed that demonstrated that RV ejection occurred without significant isovolumic contraction, although isovolumic relaxation occurred at end systole. RV systolic elastance was determined in two dogs by imposing four levels of RV afterload. Maximal systolic elastance averaged 4.14 mmHg/ml under control conditions and 9.20 mmHg/ml during dobutamine infusion.
Animals↗
Ventricular ejection fractions of linear transformation and ellipsoid models.
Eigenvolumes calculated from a linear transformation model were found previously to be linearly related to balloon volumes in excised hearts. The present study analyzed endocardial marker kinematics in intact, contracting left ventricles by biplane cinefluorography. Ejection fractions of the linear transformation model were compared by linear regression analysis with those of an ellipsoidal model, whose ejection fractions had been documented previously in closed and open-chest dog preparations. Data from 10 dogs indicated a correlation coefficient of 0.98 and a regression equation with close similarity to the line of identity. Ejection fractions calculated from the linear transformation model are concluded to be proportional to actual ejection fractions in intact, beating left ventricles.
Algorithms↗
Effects of metabolic blockade on distribution of blood flow to respiratory muscles.
Sublethal inhibition of citrate metabolism in the tricarboxylic acid (TCA) cycle with monofluoroacetate (MFA) has been shown to cause a fivefold increase in myocardial blood flow without any change in cardiac output, blood pressure, or O2 consumption (C. Liang, J. Clin. Invest. 60: 61-69, 1977); however, blood flow did not increase to any organs examined other than the heart, including resting limb skeletal muscle. Preferential inhibition of glycolysis with iodoacetate (IA) failed to cause similar changes in distribution of blood flow. This unique response of myocardium to TCA cycle inhibition suggested a unique metabolic control of cardiac vasodilation. An alternate explanation is that MFA is preferentially concentrated in active muscle. After MFA, tissue citrate accumulates behind the block and the highest levels are reported in the heart and diaphragm, suggesting enhanced blockade or enhanced compensation in these two continuously active muscles. To test the hypothesis that vasodilation in the heart after MFA is not unique and that similar vasodilation will be evoked in active respiratory muscles, we measured blood flow to the myocardium, kidney, diaphragm, intercostals, transverse abdominals, and triceps brachii in anesthetized dogs using radionuclide-labeled microspheres, before and after MFA, and in another set of dogs before and after IA. Before MFA or IA, inspiratory loading significantly increased blood flow to active muscles of breathing in proportion to the added load. After MFA, blood flow to active muscles of breathing as well as to the heart became abnormally elevated with respect to mechanical work, and loading evoked no further increase in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Abdominal Muscles↗
Quantification of pulmonary vascular occlusion in dogs by use of the diffusing capacity.
The purpose of these experiments was to quantify stagnant intrapulmonary blood caused by a pulmonary arterial occlusion (PAO). The hypothesis was that the diffusing capacity of the lung for CO (DLCO) would be altered little by PAO when measured with the usual inspired concentrations (0.3%) of CO, since stagnant blood distal to the occlusion takes up CO for 20 s or more before significant CO backpressure would develop. However, higher levels of CO (i.e., greater than or equal to 3%) would equilibrate faster with capillary blood (within 5-10 s), and DLCO measured 10-20 s subsequent to the high CO exposure would reflect only the DLCO in the unoccluded regions. Thus the fractional reduction in DLCO measured with 3% CO, with respect to that measured with 0.3% CO, should be related to the fractional occlusion of the pulmonary artery in a predictable way. We occluded the right pulmonary artery (RPAO), the left pulmonary artery (LPAO), or the left lower lobar artery (LLPAO) and found that DLCO measured during rebreathing a 0.3% CO mixture was 80, 87, and 94%, respectively, of the preocclusion value, whereas the DLCO measured during rebreathing a 3.3% CO mixture was 59, 73, and 87% of the preocclusion value. A computer model was developed to predict the reduction in DLCO at different levels of CO exposure that would be caused by varying fractions of PAO. Our data indicated that RPAO corresponded to a 42% vascular occlusion, LPAO a 35% occlusion, and LLPAO a 20% occlusion. Measurement of DLCO using low and high concentrations of CO might be useful in assessing the fraction of vascular bed occluded and in following noninvasively the course of vascular occlusion in a variety of pulmonary diseases.
Animals↗
Cardiac output and O2 consumption during inspiratory threshold loaded breathing.
In this study, noninvasive measurements of cardiac output and O2 consumption were performed to estimate the blood flow to and efficiency of the respiratory muscles that are used in elevated inspiratory work loads. Five subjects were studied for 4.5 min at a respiratory rate of 18 breaths/min and a duty cycle of 0.5. Studies were performed at rest without added respiratory loads and at elevated inspiratory work loads with the use of an inspiratory valve that permitted flow only when a threshold pressure was maintained. Cardiac output and O2 consumption were calculated using a rebreathing technique. Respiratory muscle blood flow and O2 consumption were estimated as the difference between resting and loaded breathing. Work of breathing was calculated by integrating the product of mouth pressure and volume. Increases in cardiac output and O2 consumption in response of 4.5 min loaded breathing averaged 1.84 l/min and 108 ml/min, respectively. No increases were seen in response to 20-s loaded breathing. In a separate series of experiments on four subjects, though, cardiac output increased for the first 2 min then leveled off. These results indicate that the increase in cardiac output was a metabolic effect of the increased work load and was not caused primarily by the influence of the highly negative intrathoracic pressure on venous return. Efficiency of the respiratory muscles during inspiratory threshold loading averaged 5.9%, which was similar to measurements of efficiency of respiratory muscles using whole-body O2 consumption that have been reported previously in humans and in dogs.
Adult↗
A mouthpiece face mask for the exercising dog.
To develop a rebreathing method for lung volumes, cardiac output with acetylene, and CO diffusing capacity in awake exercising dogs, we have modified and adapted the low-dead-space mask of Montefusco et al. (Angiology 34: 340-354, 1983). We have simplified the fabrication procedure, allowing the physiologist to make the device from parts that can be prefabricated before each dog is custom fitted with the mouthpiece. This decreases the anesthesia time required to custom fit the mouthpiece to each dog. We have also reduced the weight of the mask, making it more tolerable during exercise. We have validated that the mask is leak-free by having the dog rebreathe an inert insoluble gas, He, until equilibration is achieved between the bag and lung. Preliminary measurements of lung volume, cardiac output with acetylene, and CO diffusing capacity have been made during exercise.
Animals↗
Noninvasive diffusing capacity and cardiac output in exercising dogs.
We have developed a rebreathing procedure to determine diffusing capacity (DLCO) and pulmonary blood flow (Qc) in the awake, exercising dog. A low dead space, leak-free respiratory mask with an incorporated mouthpiece was utilized to achieve mixing between the rebreathing bag and the dog's lung. The rebreathing bag was initially filled with approximately 1.0 liter of gas containing 0.6% C2H2, 0.3% C18O, 9% He, and 35-40% O2. End-tidal gas concentrations were measured with a respiratory mass spectrometer. The disappearance of C2H2 and C18O was measured with respect to He to calculate Qc and DLCO. Values for DLCO in dogs, expressed per kilogram of body weight, were much larger than those reported in humans. However, at a given level of absolute O2 consumption, measurements of absolute DLCO in dogs were comparable to those reported in humans by both rebreathing and steady-state methods at rest and near-maximal exercise. These results suggest that DLCO is more closely matched to the metabolic capacity (i.e., maximal O2 consumption) than to body size between these two species.
Animals↗
Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude.
It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.
Altitude↗
Uterine metabolism of the pregnant guinea pig as a function of gestational age.
During the last half of pregnancy, the fetal guinea pig grows exponentially at 7.1%/day. In order to define the metabolic requirements of the gravid uterus during this period of rapid growth, catheters were placed in the femoral artery and uterine vein of guinea pigs at gestational ages ranging from 40 days to term (68 days). The animals were studied in the unstressed state after full recovery from surgery and anesthesia. Arterial and venous concentrations of oxygen, glucose, lactate, acetoacetate, beta-hydroxybutyrate, and acetate were measured, and metabolic quotients and coefficients of extraction were calculated. The glucose/oxygen quotient did not change significantly in the last half of pregnancy averaging 1.26, while the lactate/oxygen quotient remained unchanged at -0.42, and the (glucose + lactate)/oxygen quotient remained unchanged at 0.82. Coefficients of extraction of glucose and oxygen increased linearly with gestational age. The increase in supply of substrates for the rapid growth of the conceptus toward the end of gestation is accounted for by increasing extraction of substrate and by greatly increasing blood flow with increasing gestation. While glucose remains the major metabolic fuel of the guinea pig conceptus and acetate is consistently taken up by the uterus, these substrates alone cannot account for the metabolic fate of the oxygen taken up and fall far short of the predicted nutritional requirements of the fetus for both oxidative metabolism and growth.
3-Hydroxybutyric Acid↗
Physician income and education.
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Education, Medical↗
Is another change in healthcare reimbursement about to occur?
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Costs and Cost Analysis↗
Radiology information systems are worth their cost.
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Capital Expenditures↗
Growing pains: twelve lessons from corporate restructuring.
Corporate reorganization is a realignment of resources to enhance competitive strength and can follow one of two lines, vertical or horizontal. Whichever strategy is used, the reason for it remains unchanged: to provide a structural hierarchy through which strategic market niches are acquired and resources are economically deployed throughout the system. Healthcare corporate restructuring, however, is encountering growing pains, some of which were inevitable and others avoidable. When the healthcare organizational landscape is surveyed, 12 lessons can be learned about corporate reorganization: 1. Reorganization should be based on anticipated market and environmental conditions. 2. Form follows function. 3. Interdependence among multiple corporate units must be clearly acknowledged. 4. Reorganization is much more costly and politically charged than it appears at first. Reserved rights must be clearly defined. 6. The purpose and composition of the parent governing board must be distinguished from those of subsidiary boards. 7. Clarification of roles and relationships between the parent and subsidiaries is critical. 8. Unrealistic expectations of success should be confronted through up-front planning, negotiation, and creative problem solving. 9. False assumptions about corporate staffing needs create internal system warfare. 10. Physician support is crucial for success. 11. Hospital-based management skills and understanding may be inadequate for making personnel decisions in subsidiaries other than the hospital. 12. Competitive strategies must be strategically determined and must not be taken gamesmanship.
Economic Competition↗
Identification of progesterone and cortisol as immunoreactive plasma digitalis like factors in pregnancy.
Plasma values for immunoreactive digitalis like factors (DLF) in 3 women during the third trimester of pregnancy were 0.13, 0.13 and 0.40 ng digoxin equivalents/ml. Progesterone accounted for 39%, 35% and 19% of the total DLF in the three women respectively, and cortisol 4%, 18% and 7% based on HPLC analysis. Both progesterone and cortisol displaced [125I]-digoxin from digoxin antibody and [3H]-ouabain from hog brain Na,K-ATPase in a concentration-dependent manner, but only progesterone in the plasma concentrations found in these patients would appreciable influence Na,K-ATPase. HPLC separation of the plasma DLF from two of the women showed several peaks. Two of these were identified as progesterone and cortisol by retention time, immunoassay and by GC-mass spectrometry.
Blood Proteins↗
Uncompensated care.
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Delivery of Health Care↗