Angiotensin II receptor binding in the rat nucleus tractus solitarii is reduced after unilateral nodose ganglionectomy or vagotomy.
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Angiotensin II↗
Biomedical subjects
B Jarrott
Publications and source records attributed to B Jarrott.
The effects of intracerebroventricular administration of compound 48/80 on behaviour and regional brain amine concentrations in the rat.
The intracerebroventricular injection of the mast cell degranulator, compound 48/80 (C48/80, 10 micrograms/kg), produced a marked behavioural syndrome in rats which included head and body shakes, paw tremor, excessive grooming, unusual posture and gait, mild diarrhoea, piloerection, extreme agitation and irritability to touch, sedation and catatonia. Fifteen minutes after C48/80, the histamine concentrations were decreased significantly in all brain regions examined, i.e. the cortex, cerebellum, midbrain, medulla oblongata-pons (MO-P) and hypothalamus. The noradrenaline (NA) concentrations were decreased in the cerebellum, hypothalamus and MO-P, whereas the dopamine (DA) content was decreased in the MO-P only. The concentrations of serotonin were not affected. As such, the behaviours following the acute degranulation of brain mast cells by C48/80 may result predominantly from the release of histamine and possibly NA and DA.
Animals↗
Distribution of neuropeptide Y immunoreactivity in the rat basal ganglia: effects of excitotoxin lesions to caudate-putamen.
The distribution of neuropeptide Y-like immunoreactivity (NPY-LI) within the rat basal ganglia was studied using microdissection with a sensitive radioimmunoassay, and excitotoxin lesions were made in an attempt to characterise the neurones containing NPY in this brain area. Immunoreactivity was unevenly distributed in the basal ganglia of control rats, with concentrations in the caudate-putamen (CP) and nucleus accumbens being appreciably higher than those found in the globus pallidus and substantia nigra (SN). Within the CP, immunoreactivity was concentrated in caudal and extreme rostral aspects. N-Methyl-D-aspartate lesions of the rostral CP significantly reduced immunoreactivity in this area, whilst levels in other regions of the basal ganglia were unaffected. Neurones containing NPY-LI are likely to be intrinsic to the CP and do not appear to project to the globus pallidus or SN.
Animals↗
Radioimmunoassay for the quantitation of lisinopril and enalaprilat.
A sensitive radioimmunoassay (RIA) capable of measuring either lisinopril (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl] -L-proline) or enalaprilat (1-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl] -L-proline), the active metabolite of enalapril has been developed. A suitable antiserum was raised against an immunogen prepared from conjugation of lisinopril, the lysyl analogue of enalapril, with succinoylated keyhole limpet hemocyanin. A novel radiotracer was also prepared for use in the assay by acylation of the epsilon amine group on the lysyl side chain of lisinopril with N-succinimidyl [2,3-3H]propionate. The antiserum was used at a final dilution of 1:44,500 and the sensitivity of the assay for enalaprilat was estimated at 2 pmol/mL plasma sample and 0.4 pmol/mL for lisinopril. Enalapril, the ethyl ester of enalaprilat, exhibited little cross-reactivity (0.005%), and several other compounds (captopril, proline, lysine, tyrosine, hippuric acid, and tryptophan) were found not to crossreact. In rabbits given a 2.03 mumol/kg iv dose of enalapril, plasma concentrations of enalaprilat were determined by the RIA technique and compared with an estimation of the enalaprilat concentrations derived from the extent of inhibition of plasma angiotensin converting enzyme (ACE). The plasma levels estimated by ACE inhibition were less than those obtained by the RIA in the first 45 min but were always greater in the samples taken after this time. Both assay methods showed that the conversion of enalapril to enalaprilat was rapid, and also indicated that there was initial rapid clearance of enalaprilat from the plasma.
Angiotensin-Converting Enzyme Inhibitors↗
Age-related changes in neuropeptide Y immunoreactivity (NPY-ir) in the cortex and spinal cord of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats.
The concentrations of neuropeptide Y immunoreactivity (NPY-ir) were measured in the cortex and cervical, thoracic and lumbar spinal cord of 8-, 18- and 31-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). This peptide was measured using a highly sensitive and specific radio-immunoassay (RIA) developed in our laboratory. The concentrations of NPY-ir in the cortex, cervical and thoracic spinal cord were significantly different between the two strains, with the levels being consistently lower in the SHR strain independent of age. While there was no obvious change in the levels of NPY-ir in the cortex with increasing age, there was a general trend for the levels to fall in all three spinal cord regions. The rate of decrease of NPY-ir in the thoracic spinal cord appeared greater in the SHR compared with the WKY rats. These biochemical differences observed in the cortex and thoracic spinal cord of SHR and WKY rats may be related to the behavioural and blood pressure differences observed in these strains.
Age Factors↗
Aromatic L-amino acid decarboxylase: histochemical localization in rat kidney and lack of effect of dietary potassium or sodium loading on enzyme distribution.
Utilizing a mono-specific antiserum produced in rabbits to hog kidney aromatic L-amino acid decarboxylase (AADC), the enzyme was localized in rat kidney by immunoperoxidase staining. AADC was located predominantly in the proximal convoluted tubules; there was also weak staining in the distal convoluted tubules and collecting ducts. An increase in dietary potassium or sodium intake produced no change in density or distribution of AADC staining in kidney. An assay of AADC enzyme activity showed no difference in cortex or medulla with chronic potassium loading. A change in distribution or activity of renal AADC does not explain the postulated dopaminergic modulation of renal function that occurs with potassium or sodium loading.
Animals↗
Theophylline pharmacokinetics in patients from a geriatric hospital: influence of cigarette smoking.
The influence of cigarette smoking on plasma theophylline elimination half-life was examined in a group of elderly in-patients, to determine whether the modifying effect of cigarette smoking is also present in this age-group. The plasma theophylline half-life was determined in five non-smokers and seven smokers aged 66-88 years after administration of 320 mg of theophylline syrup. A wide range of plasma theophylline half-lives was observed in each group. However, there was a significant difference (P less than 0.05) between the mean plasma theophylline half-life in smokers (5.41 h, SEM 0.69 h) and non-smokers (10.40 h, SEM 1.90 h). It was concluded that, although plasma theophylline half-life tends to be longer in this age-group, the modifying influence of cigarette smoking on plasma theophylline half-life can be demonstrated in the elderly, as well as in young adults.
Aged↗
Differences in regional brain concentrations of neuropeptide Y in spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats.
Regional brain concentrations of neuropeptide Y immunoreactivity (NPY) were measured in age-matched Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats using a sensitive and specific radioimmunoassay developed within our laboratory. In 5 of the 9 brain regions examined the SH rats had significantly lower NPY levels compared to the WKY strain. The largest differences occurred within the cortex (-43%), and cervical (-30%) and thoracic spinal cord (-30%), whilst smaller differences were observed in the midbrain (-11%) and medulla oblongata-pons (-18%). The concentrations of NPY in the hypothalamus and hippocampus did not vary between the strains. The SH rats contained significantly greater (+18%) NPY levels in the striatum compared to the WKY rats.
Animals↗
Effect of probenecid on the disposition of captopril and captopril dimer in the rat.
The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.
Animals↗
Thermodynamics of agonist and antagonist binding to the alpha 1-adrenoceptor studied using [125I]BE 2254.
The thermodynamics of binding of [125I]BE 2254 to the alpha 1-adrenoceptor in guinea pig brain membranes have been investigated at four different temperatures between 0 and 37 degrees C. The affinity and binding capacity of the radioligand did not vary with temperature. Thus, the change in enthalpy upon binding was close to zero whereas the change in entropy was large and positive (delta S degrees approximately 45 cal/mol-deg). In addition, [125I]BE 2254 has been used as a reporter ligand to probe the thermodynamics of the interaction of a variety of alpha-adrenoceptor agonists and antagonists with the alpha 1-adrenoceptor. Binding of all ligands was associated with large positive changes in entropy (delta S degrees between 18 and 48 cal/mol-deg) and little, or no, change in enthalpy, a finding that provides no convincing evidence for conformational rearrangement of alpha 1-adrenoceptors upon ligand binding.
Animals↗
Body temperature during and following 10-day subcutaneous infusion of clonidine in the rat.
Body temperature in the rat was measured during and after cessation of the continuous subcutaneous infusion of clonidine (10 micrograms/kg per hr) for 10 days. The body temperature of control animals displayed a distinct circadian rhythm. On each day the mean body temperature over the dark phase (2000-0800 hr) was consistently higher (0.6-0.9 degrees C) than the following light phase. The infusion of clonidine was essentially devoid of initial effects on body temperature. However, during the light phases of day 2 onwards the mean body temperature of the animals treated with clonidine was consistently higher (0.4-0.6 degrees C) than that of controls. No such differences were observed during the dark phases. It appeared that the infusion of clonidine limited the fall in body temperature which normally occurred at the onset of the light phases and this resulted in the treated rats displaying a relative hyperthermia. On cessation of the infusion of clonidine (at 2400 hr on day 11) a distinct hyperthermia was observed within 2 hr and was sustained for the remainder of the dark phase and subsequent light phase. This post-infusion hyperthermia was more pronounced than that observed during the period of infusion of clonidine. These results demonstrate that the circadian control of body temperature is disturbed both during and after continuous infusion of clonidine.
Adrenergic Fibers↗
Interaction of DNA-intercalating antitumor agents with adrenoceptors.
The interaction between some examples of mononuclear and binuclear DNA-intercalating antitumor agents and alpha- and beta-adrenoceptors has been studied using radioligand-binding assays. Competition for 125I-BE 2254, [3H]rauwolscine, and (-)-[3H]dihydroalprenolol binding was used to assess affinity for alpha 1-, alpha 2-, and beta-adrenoceptor-binding sites, respectively. Two homologous series of alkyl-linked diacridines and diquinolines were found to interact poorly with beta-adrenoceptors, with only the largest members having appreciable affinity. By contrast, these compounds bind strongly and in a complex manner to alpha 1- and alpha 2-adrenoceptors. The affinity of diacridines for both alpha-adrenoceptor classes has a parabolic dependence on alkyl chain length with the hexyl and pentyl derivatives being the most potent at the alpha 1- (Ki = 11.5 +/- 2.3 nM) and alpha 2- (Ki = 143 +/- 26 nM) binding sites, respectively. The dependence of inhibition constants on linker chain length for the diquinolines is more complicated, with the ethyl- and heptyl-linked dimers having the greatest affinity for each alpha subclass. There is a nadir in affinity for the pentyl and butyl ligands and an increase in dissociation constant for octyl and longer homologues. Thus, the ethyl diquinoline has Ki values of 6.6 +/- 1.2 and 110 +/- 14 nM for the alpha 1- and alpha 2- adrenoceptors, respectively, and, correspondingly, the heptyl derivative has values of 39 +/- 4 and 51 +/- 1 nM. These findings are discussed with respect to a model of the alpha-adrenoceptor in which the radioligand-binding site is situated in a trench or cleft, surrounded by a flat surface bounded by walls. Daunomycin was found to have no affinity for adrenoceptors of any type and mitoxantrone similarly fails to interact with alpha 2- and beta-adrenoceptors, but binds to the alpha 1 subclass with an inhibition constant (Ki) of 3930 +/- 420 nM. Bisantrene also has no affinity for beta-adrenoceptors but binds to alpha 1- and alpha 2- adrenoceptors with Ki values of 145 +/- 24 and 2310 +/- 430 nM, respectively. Among the mononuclear acridine drugs studied, only nitracrine shows detectable interaction with beta-adrenoceptors (Ki = 760 +/- 50 nM). This compound, like bisantrene, has high affinity for the alpha 1-adrenoceptor (Ki = 131 +/- 17 nM) and moderate affinity for the alpha 2 subclass (Ki = 2180 +/- 500 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
Acridines↗
Deafferentation of the rat hippocampus does not alter the affinity or binding capacity for the alpha 1-adrenoceptor radioligand [125I]BE 2254.
Sectioning the dorsal afferents to the rat hippocampus led to an 88% decrease in the level of noradrenaline in the dorsal third of the structure, a 62% reduction in the medial region and no significant change in the ventral third. The lesion did not produce a change in either the affinity or maximum binding capacity of the alpha 1-adrenoceptors in any of the three regions of the hippocampus, as assessed by the binding of the radioligand [125I]BE 2254. This result indicates that reported increases in the response to noradrenaline in hippocampal slices after denervation is most likely due to a loss of noradrenaline uptake mechanisms.
Afferent Pathways↗
Captopril disulfide conjugates may act as prodrugs: disposition of the disulfide dimer of captopril in the rat.
The absorption and metabolism of the disulfide dimer conjugate of captopril has been studied in the rat following both oral and intravenous dosing and compared with that of the active monomer, captopril. Metabolism of the dimer to captopril has been shown after both oral and intravenous administration of the dimer (10 mg/kg) with peak plasma levels of captopril (154 ng/ml) occurring at 1 hr post dose. By contrast the peak plasma level of captopril after oral administration of captopril (10 mg/kg) at the same dose was much higher at 678 ng/ml and also occurred at 1 hr post dose. Plasma captopril disulfide species were much higher than the plasma levels of captopril after the administration of either dimer or captopril and tended to persist for much longer than for monomeric captopril particularly after administration of the dimer. Both the dimer and its pharmacologically active product captopril were found in relatively large amounts in lung, kidney and liver following the oral administration of the dimer.
Administration, Oral↗
A non-alpha-adrenoceptor binding site for [125I]-BE 2254 in guinea pig brain membranes.
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Adrenergic alpha-Antagonists↗
Combined gas chromatographic-mass spectrometric procedure for the measurement of captopril and sulfur-conjugated metabolites of captopril in plasma and urine.
A gas chromatographic-mass spectrometric method is described for the simultaneous measurement of the novel anti-hypertensive drug captopril, and the following metabolites: captopril disulfide dimer, S-methyl captopril, and S-methyl captopril sulfone. With this method all derivatives can be chromatographed using conventional gas chromatography of hexafluoroisopropyl esters in one temperature-programmed run and these can then be quantitated using selected-ion monitoring techniques. Using urine or plasma, captopril, S-methyl captopril and the disulfide dimer of captopril in concentrations as low as 1 ng/ml, 10 ng/ml and 25 ng/ml, respectively can be detected. The reproducibility of the method is satisfactory both within-assay and inter-assay. This technique has demonstrated that the pattern of urinary excretion of these compounds in both man and rat was similar. Excretion of unchanged captopril, S-methyl captopril and the disulfide dimer over 6 h in man given captopril (50 or 100 mg) chronically was 18.3%, 0.97% and 3.06%, respectively. Corresponding excretion of these three compounds in the rat following a single 10 mg/kg dose was 18.3%, 2.69% and 1.8%, respectively. A possible sulfone oxidation product of S-methyl captopril was not detected in the urine of either man or rat.
Animals↗
Gastric and intestinal absorption of captopril in acutely and chronically treated rats: comparison with salicylic acid.
The gastric and intestinal absorption of captopril, an orally active angiotensin-converting enzyme inhibitor was determined using rat in situ gastric pouch and intestinal loop techniques and compared with the absorption of another acidic drug, salicylic acid, whose absorption has been well established from both gastric and intestinal sites. Captopril absorption was determined at two initial intraluminal concentrations in acute (untreated) rats and in rats that had been chronically treated with captopril. Salicylic acid absorption was determined at one concentration in acute rats. During the 40-min experimental period, captopril absorption at the 4.6 mM dose from the gastric pouch was 17.0 +/- 1.8% and 17.9 +/- 5.4% in acute and chronically treated rats, respectively, and 33.6 +/- 9.2% and 23.7 +/- 7.6%, respectively, from the intestinal loop. At the 11.5 mM dose the captopril absorption in 40 min was 13.7 +/- 2.7% and 17.3 +/- 4.2% from the gastric pouch of acutely and chronically treated rats, respectively, and 17.8 +/- 4.2% and 22.9 +/- 3.3%, respectively, from the intestinal loop. As similar fractions of the different administered doses were absorbed from the respective gastric and intestinal sites in both acutely and chronically treated rats, the absorption process of captopril appears to be principally by passive diffusion and unaffected by chronic administration of captopril. In comparison, salicylic acid was absorbed more rapidly and to a greater extent from both the gastric and intestinal preparations. The percent of salicylic acid absorbed into the plasma at the 11.5 mM dose was 44.8 +/- 4.4% and 65.3 +/- 5.3% from the gastric and intestinal preparations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The development of a relative hyperthermia during continuous clonidine infusion in the rat.
In rats the continuous infusion of clonidine (10 micrograms kg-1 h-1) produces a relative hyperthermia of approximately 0.6 degree C during the light phases but not the dark phases of a 10 day infusion period. It appears that the relative hyperthermia results from a clonidine infusion-induced attenuation of the fall in body temperature which normally occurs at the onset of the light phases.
Animals↗