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An isolate of Serratia marcescens that produced both an inducible chromosomal and a plasmid-mediated TEM-1 beta-lactamase was resistant to ampicillin and amoxicillin and also demonstrated decreased susceptibility to extended-spectrum beta-lactam antibiotics (ESBAs). Clavulanic acid did not lower the MICs of the ESBAs, but it decreased the MICs of the penicillins. The TEM-1-producing plasmid was transferred to a more susceptible S. marcescens strain that produced a well-characterized inducible chromosomal beta-lactamase. The MICs of the ESBAs remained at a low level for the transconjugant. Ampicillin and amoxicillin which were good substrates for the plasmid-mediated enzyme, were not well hydrolyzed by the chromosomal enzymes; the ESBAs were hydrolyzed slowly by all the enzymes. When each of the S. marcescens strains was grown with these beta-lactam antibiotics, at least modest increases in chromosomal beta-lactamase activity were observed. When organisms were grown in the presence of clavulanic acid and an ESBA, no enhanced induction was observed. The increases in the MICs of the ESBAs observed for the initial clinical isolate may have been due to a combination of low inducibility, slow hydrolysis, and differences in permeability between the S. marcescens isolates. When clavulanic acid and a penicillin were added to strains that produced both a plasmid-mediated TEM and a chromosomal beta-lactamase, much higher levels of chromosomal beta-lactamase activity were present than were observed in cultures induced by the penicillin alone. This was due to the higher levels of penicillin that were available for induction as a result of inhibition of the TEM enzyme by clavulanate.

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1. In dogs anaesthetized with chloralose and artificially ventilated, the carotid sinuses were vascularly isolated and perfused with arterial blood. Mean aortic pressure was held constant at 111 +/- 2 mmHg (mean +/- S.E.M., n = 18) by means of a pressure bottle connected to the aorta and a Starling resistance. Both vagus nerves were sectioned in the neck and propranolol hydrochloride (1 mg kg-1 h-1) or atenolol (0.5-4 mg kg-1 h-1) was administered. The left and right renal blood flows were measured by electromagnetic flowmeters (wrap-round probes), glomerular filtration rate by creatinine clearance, urinary sodium by flame photometry and solute excretion by osmometry. 2. In six dogs decreasing pressure in the isolated carotid sinuses from 119 +/- 4 to 78 +/- 3 mmHg (n = 9) resulted in significant decreases in renal blood flow by 18 +/- 3% (P less than 0.01), glomerular filtration rate by 41 +/- 9% (P less than 0.01), filtration fraction by 30 +/- 11% (P less than 0.05), urine flow by 46 +/- 6% (P less than 0.001), sodium excretion by 46 +/- 9% (P less than 0.001) and osmolar excretion by 44 +/- 6% (P less than 0.001). Fractional sodium excretion did not change significantly. Increasing carotid sinus pressure back to 120 +/- 4 mmHg (n = 6) resulted in increases in all the variables to values not significantly different from those at initial high carotid pressure. 3. Ligation of left renal nerves at low carotid sinus pressure (83 +/- 3 mmHg, n = 5) caused significant increases in all of the variables in the left kidney. After ligation, changes in carotid sinus pressure produced no effect on the denervated left kidney, but in the three dogs in which the responses of the right kidney were also tested, the usual responses after denervation of the left kidney were seen. 4. The results show that changes in carotid sinus pressure around the normal range can result in significant reflex effects on renal haemodynamics and function and that these effects are mediated solely by renal sympathetic nerves. The influence of any extrarenal humoral factors seems to be minimal.

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1. Dogs were anaesthetized with chloralose and artificially ventilated. Localized stimulation of left atrial receptors for 23-25 min was achieved by distension of three small balloons at the pulmonary vein-atrial junctions and one in atrial appendage. Renal blood flows were measured by electromagnetic flow probes, glomerular filtration rate by creatinine clearance, urinary sodium excretion by flame photometry and solute excretion by osmometry. The mean aortic pressure was held constant at 92.2 +/- 2.4 mmHg (mean +/- S.E.M., n = 27) by means of a pressure bottle connected to the aorta and beta-adrenergic receptor activity was blocked by continuous infusion of propranolol (17 micrograms kg-1 min-1, I.V.). 2. In twelve dogs stimulation of left atrial receptors resulted in significant increases of 11.8 +/- 2.4% (P less than 0.001) in renal blood flow; 32.5 +/- 7.2% (P less than 0.001) in glomerular filtration rate; 19.5 +/- 5.0% (P less than 0.005) in filtration fraction: 36.3 +/- 9.0% (P less than 0.001) in urine flow: 32.7 +/- 9.2% (P less than 0.005) in sodium excretion: 36.6 +/- 9.9% (P less than 0.005) in osmolar excretion and a decrease of 31.3 +/- 11.2% (P less than 0.025) in free water clearance. Left atrial pressure and heart rate did not change significantly. In eight of the dogs ligation of the renal nerves resulted in similar changes in all of the renal variables; subsequent stimulation of atrial receptors did not cause significant changes in the renal variables. 3. In five additional dogs, in which heart rate and aortic pressure were allowed to change, stimulation of left atrial receptors for the same period resulted in significant increases in heart rate (4.3 +/- 0.7%. P less than 0.001) and mean aortic pressure (2.0 +/- 0.6%, P less than 0.025). Under this condition both the intact right kidneys and the denervated left kidneys showed significant responses in urine flow, sodium excretion, osmolar excretion and free water clearance. 4. The results show that the renal sympathetic nerves mediate the primary renal responses to atrial receptor stimulation, at least in the short term. The influence of any humoral factor in this reflex seems to be secondary to changes in heart rate and systemic blood pressure, possibly via arterial baroreceptors.

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1. Dogs were anaesthetized with chloralose and artificially ventilated. The carotid chemoreceptors were stimulated by changing the perfusion of vascularly isolated carotid sinus regions from arterial to venous blood. The mean carotid sinus pressure and the mean arterial blood pressure were held constant at 124 +/- 3 and 122 +/- 3 mmHg, respectively. Both vagosympathetic trunks were sectioned in the neck and propranolol (17 micrograms kg-1 min-1 I.V.) and gallamine triethiodide (0.2-2.0 mg kg-1 30 min-1 I.V.) were infused. Renal blood flow was measured by an electromagnetic flow probe, glomerular filtration rate by creatinine clearance, sodium excretion by flame photometry and solute excretion by osmometry. 2. In sixteen tests in thirteen dogs perfusion of the carotid sinus regions with venous blood resulted in significant decreases in renal blood flow from 271 +/- 24 to 198 +/- 21 ml min-1 100 g-1 renal mass; glomerular filtration rate from 41.0 +/- 4.8 to 22.1 +/- 3.1 ml min-1 100 g-1; filtration fraction from 0.25 +/- 0.02 to 0.19 +/- 0.02; urine flow from 0.48 +/- 1.0 to 0.21 +/- 0.03 ml min-1 100 g-1; sodium excretion from 18.1 +/- 4.1 to 12.9 +/- 4.2 mumol min-1 100 g-1; and osmolar excretion 327 +/- 42 to 171 +/- 26 mu osmol min-1 100 g-1. The right atrial pressure did not change significantly from 4.6 +/- 1.2 cmH2O. 3. In seven dogs, tying renal sympathetic nerves abolished all the responses except that of sodium excretion which was now reversed; sodium excretion increased from 68 +/- 19 to 116 +/- 38 mumol min-1 100 g-1 without significant change in right atrial pressure from 7.4 +/- 1.9 cmH2O. Crushing the carotid bodies, however, abolished all the responses. 4. The results show that carotid chemoreceptor stimulation can cause significant reflex effects on renal haemodynamics and function which are mediated via renal sympathetic nerves. They also show that the chemoreceptor stimulation can cause natriuresis in the absence of haemodynamic changes, in the denervated kidney, presumably via a humoral factor.

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Tigemonam, a novel, orally administered monobactam, exhibited potent and specific activity in vitro against members of the family Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae. Its activity was variable to poor against gram-positive bacteria, Acinetobacter spp., Pseudomonas aeruginosa, and anaerobes. Within its spectrum of activity, tigemonam was far superior to oral antibiotics currently available, including amoxicillin-clavulanic acid, cefaclor, and trimethoprim-sulfamethoxazole. In addition, tigemonam was superior to cefuroxime, which is under development as an oral pro-drug, and more active than cefixime against several genera of the Enterobacteriaceae. The activity of tigemonam against the enteric bacteria, Haemophilus species, and Neisseria species was, in general, comparable to that of the quinolone norfloxacin. The excellent activity of tigemonam against beta-lactamase-producing bacteria reflected its marked stability to hydrolysis by isolated enzymes. The expanded spectrum of activity against gram-negative bacteria observed with tigemonam thus extends oral beta-lactam coverage to include members of the Enterobacteriaceae that are intrinsically or enzymatically resistant to broad-spectrum penicillins and cephalosporins.

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When normal conscious dogs were given small doses of (NH4)2HPO4 by stomach tube to increase their plasma PO4, the rate of excretion of PO4 increased without change in creatinine clearance. After eating meat, increased PO4 excretion was accompanied by increase in both creatinine clearance and plasma PO4. The calculated rate of tubular reabsorption of PO4 did not change significantly after (NH4)2HPO4 administration, but there was a significant increase in PO4 reabsorption after meat; in comparison there was no change in SO4 reabsorption. Similarly, administration of certain amino acids, which caused an increase in creatinine clearance, also caused a significant increase in PO4 reabsorption. Administration of SO4 with PO4 had no significant effect on PO4 reabsorption. It appears from the results, that PO4 has an apparent tubular maximum rate of reabsorption (Tm) when plasma PO4 alone is varied; but this Tm is not a real maximum because PO4 reabsorption increases above this value after the administration of meat or amino acids, both of which cause an increase in glomerular filtration rate. There is no evidence to suggest that there is any inhibition of PO4 reabsorption by SO4 or amino acids.

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In chloralose-anaesthetized and artificially ventilated dogs, the carotid sinuses were vascularly isolated and perfused with arterial blood. Mean aortic pressure was held constant at 100 +/- 2 mmHg (mean +/- S.E. of mean, n = 19) by means of a pressure bottle connected to the aorta. Both vagus nerves were sectioned in the neck and propranolol hydrochloride (0.5 mg kg-1) was administered every 30 min. The left renal blood flow was measured by an electromagnetic flowmeter (wrap-round probe), glomerular filtration rate by creatinine clearance and urinary sodium by flame photometry. Decreasing pressure in the isolated carotid sinuses from 186 +/- 10 to 63 +/- 5 mmHg resulted in significant decreases in renal blood flow from 281 +/- 35 to 177 +/- 30 ml min-1 100 g-1 renal mass; glomerular filtration rate from 40.0 +/- 7.8 to 12.3 +/- 4.4 ml min-1 100 g-1; urine flow from 0.31 +/- 0.05 to 0.12 +/- 0.03 ml min-1 100 g-1 and sodium excretion from 21.7 +/- 7.2 to 8.2 +/- 3.0 mumol min-1 100 g-1. Increasing carotid sinus pressure back to 188 +/- 11 mmHg resulted in increases in all the variables to values not significantly different from their initial values. Tying renal sympathetic nerves at low carotid sinus pressure (73 +/- 11 mmHg) caused an increase in all of the variables. After denervation there was no response to changes in carotid sinus pressure. These results show that changes in carotid sinus pressure can result in significant reflex effects on renal function and that these effects are mediated by renal sympathetic nerves.

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Normal conscious dogs were given a meal of meat or doses of individual amino acids by stomach tube. The concentration of amino nitrogen in systemic arterial plasma and the rate of urea production both increased; the magnitude and time course of these increases varied with the individual amino acid administered. There was a relationship between the plasma amino nitrogen concentration and urea production following L-serine, L-alanine, L-proline. dicarboxylic acids and L-cystine similar to that obtained after meat ingestion. It is suggested that these amino acids were transaminated as rapidly as they were absorbed to produce an increase in a general pool of amino acids. Following L-threonine, L-valine, D-serine and immediately after glycine, a small increase in urea production was accompanied by a larger increase in plasma amino nitrogen concentration. It is suggested that these amino acids 'escaped' transamination in the gut wall and liver and that the increase in plasma amino nitrogen was due to a high concentration of the individual amino acid administered.

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Normal conscious dogs were given 100 mmol glycine, L-serine, L-alanine, L-threonine, L-proline, L-glutamic acid (50 mmol), L-aspartic acid and L-valine by stomach tube. All these amino acids increased glomerular filtration rate (G.F.R.). There was no increase in G.F.R. following L-cystine or D-serine. The intravenous infusion of L-proline, but not glycine, caused increase in G.F.R. The results suggest that the increase in G.F.R. was not due to a high plasma concentration of the individual amino acids but was related to the metabolism of amino acids with production of urea. It is postulated that after meat and during the metabolism of amino acids a factor is released which reaches and acts on the kidney to cause the increase in G.F.R.

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Bitches maintained on a low Na intake, were given doses of saline (0.125 mol.litre(-1) NaCl, 0.025 mol.litre(-1) NaHCO3, 0.004 mol.litre(-1) KCl) by stomach tube. Doses of 100 and 200 cm3 produced only minor increases in Na excretion; after 300 cm3, Na excretion rose from about 2 to about 60 micromol.min(-1). Plasma protein fell by 1.8 litre(-1) for each 100 cm3 of saline retained. Within normal ranges of Na excretion there is a threshold of plasma protein concentration above which Na is retained and below which Na is excreted. Changes in exogenous creatinine clearance were measured allowing calculation of the filtered load of Na, which shows that the absolute tubular reabsorption of Na and water is increased in volume expansion by isotonic saline. Meat produced large increase in glomerular filtration rate without much increase in Na excretion and mechanisms are discussed by which Na reabsorptin is more effective after meat than after doses of saline. Creatinine cleaerance increased by 0.67 cm3.min(-1) for each fall of 1 g.litre(-1) in plasma protein; this is predicted by a theory that the glomerular capillary blood pressure is 9.3 kPa (70 mmHg) rather than 6.7 kPa (50 mmHg).

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1. When normal conscious dogs were given small doses of (NH4)2SO4 by stomach tube, the rate of excretion of SO4 increased due to increase in plasma SO4 without change in creatinine clearance. After eating meat, increased SO4 excretion was due to increase in glomerular filtration rate without change in plasma SO4. 2. The calculated rate of tubular reabsorption of SO4 did not change significantly either after (NH4)2SO4 or after meat. 3. The rate of production of SO4 after meat was estimated. In 4 hr approximately one fifth of the S in meat was converted to inorganic SO4; in the same time approximately one third of the N in the meat was converted into urea. 4. Half of the SO4 in the doses of (NH4)2SO4 was absorbed from the gut; all of the NH was converted into urea. (NH4)2SO4 thus produced acidosis. 5. After (NH4)2SO4, increased excretion of NH4+ accompanied the increased excretion of SO4-but Na+, K+ in urine also increased.

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1. The exogenous creatinine clearance of conscious dogs has been measured by a method in which no loading doses of water or saline were given. The urine volume was thus in the normal range, 0-1-0-3ml./min. 2. Under these conditions, the exogenous creatine clearance of fourteen dogs, measured 17 hr after a meal, was 2-74 ml./min kg-1+/-0-54 (s.d.). This is about 40% lower than values usually regarded as "normal." 3. A meal of meat, 10g/kg, increased exogenous creatinine clearance reflects an increase in glomerular filtration rate. Since this occurs with small doses of meat, increase in glomerular filtration may be important in normal renal function of dogs.

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1. After a meal of meat (10g/kg), urea excretion in dogs increased by about 200%, plasma urea by 60% and exogenous creatinine clearance by 40% in comparison with control experiments. 2. Urea, given by stomach tube in doses producing the same increase in plasma urea, caused urea excretion to increase by only 90%, with no increase in creatinine clearance. With the increased glomerular filtration rate after meat there was added excretion of urea. 3. In control experiments and after urea, the rate of excretion of urea was directly proportional to plasma urea. The ratio urea clearance/creatinine clearance, was 0-45. 4. After meat, urea clearance increased more than creatinine clearance, the ratio increasing to 0-55, i.e. a smaller fraction of the filtered urea was re-absorbed after meat. 5. After meat, 10g/kg, the rate of urea production rose to 230-600 mumole/min for 4-6 hr.

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