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Biomedical subjects

B Jarrott

Publications and source records attributed to B Jarrott.

At least 145 records · Page 8Linked to original sources
PubMed1984

The involvement of central alpha adrenoceptors in the antihypertensive actions of methyldopa and clonidine in the rat.

The antihypertensive effects of methyldopa and clonidine result from agonist activity at alpha adrenoceptor sites within the brain. Methyldopa is converted enzymatically to alpha-methylnoradrenaline in noradrenergic neurones in rat brain and replaces the natural transmitter, noradrenaline. Radioligand receptor studies show that alpha-methylnoradrenaline differs from noradrenaline in being much more selective (70 times) for the alpha 2 subclass of adrenoceptors than noradrenaline and it is likely that the antihypertensive action of methyldopa results from selective activation of alpha 2 adrenoceptors by alpha-methylnoradrenaline in the nucleus tractus solitarius and the anterior hypothalamus. Radioligand studies also show that clonidine is a selective alpha 2 adrenoceptor agonist although it probably interacts with alpha 1 adrenoceptors at higher concentrations. With regard to a withdrawal syndrome after cessation of clonidine treatment, the cardiovascular and behavioural components can now be characterised in a rat model. The components include increases in basal blood pressure and heart rate, as well as increases in cardiovascular reactivity and also increases in rapid eye movement (REM) sleep, body shakes and tremor which is reminiscent of an opiate withdrawal syndrome. Increased central noradrenergic activity is involved in this syndrome and alpha 1 and alpha 2 adrenoceptors mediate opposing effects on the REM sleep rebound component.

Animals↗
PubMed1984

Rapid eye movement (REM)-sleep during and after continuous infusion of the oxazoline derivate S3341: a comparison with clonidine.

The frequency and duration of rapid eye movement (REM)-sleep episodes were examined in normotensive rats during and after cessation of continuous infusion of either clonidine (10 micrograms/kg/h) or the oxazoline derivative S3341 (50 micrograms/kg/h) for 10 days. Both compounds abolished REM-sleep during the infusion. On cessation of the clonidine infusion there was a rebound increase in the frequency and duration of REM-sleep episodes. These episodes were associated with markedly exaggerated blood pressure fluctuations. On cessation of the S3341 infusion, the frequency and duration of REM-sleep episodes returned to control levels. Blood pressure responses were not different from controls. These post-infusion differences may be related to the greater degree of selectivity of S3341 for the alpha 2-adrenoceptor rather than the alpha 1-adrenoceptor subtype.

Animals↗
PubMed1983

Beta-adrenoceptor-blocking drugs: current status and the significance of partial agonist activity.

There is some evidence that partial agonism is an important property of beta-blocking drugs, and this property may be exploited to produce a new range of positive inotropic drugs. With the established beta-adrenoceptor-blocking drugs, the level of partial agonist activity is weak and the dose-response curve for this property is shallow. However, its absence appears to increase the likelihood of inducing bronchospasm and bradycardia, and drugs that lack intrinsic sympathomimetic activity appear more likely to be associated with rebound cardiac arrhythmias on cessation of treatment. The idea of a small level of hormone activity--in this case, catecholamine activity--being necessary to maintain normal cardiac and perhaps bronchial function is not new. Minimal doses of steroids are essential to maintaining the inotropic action of cardiac muscle. There is now enough accumulated evidence to suggest that a minimal degree of beta-adrenoceptor stimulation is also important for normal bronchial and cardiac function, and its absence increases the incidence of bradycardia and the risks of bronchospasm and rebound arrhythmias.

Adrenergic beta-Agonists↗
PubMed1983

S-methylation of captopril. Demonstration of captopril thiol methyltransferase activity in human erythrocytes and enzyme distribution in rat tissues.

The presence of a methyltransferase enzyme in human red blood cells (RBCs) capable of S-methylation of captopril is described. The apparent Michaelis-Menten (Km) constant for captopril was 0.5 mM and the maximum velocity (Vmax) was 0.391 pmoles S-methylcaptopril (mg protein)-1 min-1. There is some evidence presented to show that S-methylcaptopril inhibited its own formation with a ki value of 5.81 mM. Captopril thiol methyltransferase activity was also examined in rat tissues and was found to be present in all tissue studied. Subcellular localisation studies in rat liver suggest that the enzyme was microsomal in origin. The order of activity was liver greater than heart greater than spleen greater than lung greater than kidney much greater than RBC (rat). This tissue distribution was quite different from previous studies using other thiol substrates and is consistent with more than one form of thiol methyltransferase enzyme in tissues.

Animals↗
PubMed1983

Tissue distribution of captopril, reducible captopril conjugates and S-methylcaptopril in the rat.

The tissue distribution of captopril, an antihypertensive drug possessing a free sulfhydryl group, and its sulfur-conjugated metabolites was studied in rats by gas chromatography-mass spectrometry at 15, 30 and 60 min following a single 10 mg/kg oral dose of captopril. It was found that tissue accumulation of captopril was rapid with both free and oxidized-forms already present at 15 min post-dose. A maximum concentration of captopril was achieved at 30 min in tissues studied, being substantially higher in kidney (14.2 micrograms/g), with lesser amounts occurring in liver, lung, heart, blood cells, spleen and plasma in that order. Oxidized disulfide forms of captopril were usually present in the same or slightly higher proportion than free captopril except for liver which only contained detectable disulfides at 15 min after oral dosing. S-methylcaptopril was also present at 30 min in all tissues examined with highest levels occurring in liver and kidney (1.05 micrograms/g) followed by plasma, lung, heart, spleen and blood cells.

Animals↗
PubMed1983

An in situ gastric pouch technique for direct measurement of the gastric absorption of drugs in the rat.

The preparation of an in situ gastric pouch technique that will allow a direct measurement of drug absorption is described. This technique has been developed in rats, but could be easily utilized in different laboratory animals. This technique has the major advantages of providing a direct measurement of the quantity of drug crossing the gastric mucosa into the bloodstream and enabling a direct comparison with results obtained using in situ intestinal loop preparations.

Absorption↗
PubMed1983

Characterization of central alpha-adrenoceptors using 3H-clonidine and its derivatives.

alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Our studies have shown that 3H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, 3H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but 3H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.

Adrenergic alpha-Agonists↗
PubMed1982

Lack of alpha-adrenoreceptor binding of [125I]BE2254 to rat basilar artery membranes.

Rat basilar arteries do not contain classical alpha- or beta-adrenoreceptors as assessed by electrophysiological techniques even though these arteries are innervated by catecholamine-containing perivascular nerves. These arteries were therefore examined for their ability to selectively bind an alpha-adrenoceptor radioligand, [125I]BE2254 (2/beta/4-hydroxyphenyl)-ethylaminomethyl)-tetralone). For comparison, rat tail arteries were also studied as these are known to contain functional alpha-adrenoreceptors. It was found that basilar artery membranes had only one-third of the specific binding of tail artery membranes and this finding collaborates the electrophysiological data.

Animals↗
PubMed1982

Pharmacokinetic properties of captopril after acute and chronic administration to hypertensive subjects.

The pharmacokinetic properties of captopril were studied in two groups of hypertensive patients; (1) those who had never taken captopril (acute group), and (2) those who had been taking captopril for at least 6 months (chronic group). It was found that after 100 mg of captopril orally, the mean peak plasma level in the chronic group was three times higher than that in the acute group while the area under the curve was twice as high in the chronic group. These data suggest that bioavailability increases with chronic administration, and thus it may be possible to reduce the dosage of captopril and still maintain blood pressure control while reducing side effects.

Captopril↗
PubMed1982

Development of a radioiodinated ligand for characterising alpha 1-adrenoceptors.

Two alpha-adrenoceptor antagonists, phentolamine and 2-(beta-(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE 2254) which are phenolic derivatives were radioiodinated after chloramine-T oxidation of Na125I and the labelled material isolated by chromatography. 125I-phentolamine does not bind selectively to alpha-adrenoceptors in guinea pig brain whereas the 125I-BE 2254 derivative binds rapidly, reversibly and with high affinity to these receptors with a Kd of 230 pM. At low concentrations of 125I-BE 2254 (less than 100 pM) approx. 90% of the bound radioligand is specifically bound and under these conditions drug displacement studies show that the ligand binds predominantly to the alpha 1 subclass of adrenoceptors. Binding measurements to kidney and smooth muscle membrane preparations indicate that 125I-BE 2254 may also be a useful tool in the study of alpha-adrenoceptors in peripheral tissues. The high specific activity of 125I-BE 2254 permits the use of minimal quantities of membrane material for receptor assay and ligand displacement measurements, e.g. 250 micrograms per assay tube, and this provides a significant advantage over the use of existing radioligands such as 3H-prazosin which requires approx. 40 times as much tissue.

Animals↗
PubMed1982

Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects.

The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 micrograms, 150 micrograms and 250 micrograms in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19-22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 micrograms) also produced significant reductions in plasma catecholamine levels.

Adult↗
PubMed1982

Tissue pharmacokinetics of clonidine in rats.

The antihypertensive drug clonidine exhibits nonlinear pharmacokinetics in man and rats after intravenous injection. In order to define the basis of this nonlinearity, tissue kinetics of clonidine in rats were determined at three dose levels. It was found that tissue concentrations of clonidine were linearly related to dose increases in most organs with the exception of the heart, suggesting that there was a limited binding capacity in this organ. The rate of disappearance of clonidine from most tissues was best described by a monoexponential curve with half-lives of 30 to 120 min. An exception was the stomach, and clonidine accumulated in this organ, probably due to a pH partitioning effect of this weak base. Renal clearance of clonidine in rats was also examined and found to decrease by approximately 40% when the dose was increased from 50 microgram/kg to 250 microgram/kg. It was concluded that renal clearance and and possibly fecal clearance could explain the nonlinear pharmacokinetics of clonidine.

Animals↗
PubMed1982

Clinical pharmacology of adrenergic-adrenoreceptor-blocking drugs.

The development of beta-adrenoreceptor-blocking drugs provided an important group of agents to treat the cardiovascular disorders hypertension, angina pectoris, and cardiac arrhythmias and to manage patients with thyrotoxicosis. For clinical purposes, these drugs can be divided into two groups, that is, those with intrinsic sympathomimetic activity (ISA) and those without (non-ISA). The non-ISA drugs include propranolol, which is noncardiac selective: labetalol, which is noncardiac selective with alpha blockade: and and metoprolol and atenolol, which are cardiac selective. The drugs with ISA include pindolol, oxprenolol, and alprenolol which are noncardiac selective, and practolol which is cardiac selective. These drugs resemble isoprenaline in chemical structure, but their interaction with the beta-adrenoreceptors causes no response or only a slight response if the drug has ISA. By occupying the receptors, they block excitation by noradrenaline released from the sympathetic nerves and by adrenaline from the adrenal medulla. Drugs with ISA appear to depress cardiac activity and to interfere with bronchodilator drive less than do non-ISA drugs. Beta-blocking drugs differ considerably in their bioavailability because of differences in the rate and extent of metabolism in the first past through the liver after absorption from the gut. The therapeutic dose range varies widely for those with low bioavailability but is more predictable for those with high bioavailability. The drugs also differ in plasma protein binding and in their receptor affinities. In addition to their usual adverse effects, which include exacerbation of cardiac failure, bronchospasm, sleep disturbances, and Raynaud's phenomenon, concern has arisen about possible ocular and mucocutaneous side effects with beta-blocking drugs. This is a recognized problem with practolol, and it is not certain whether it occurs with other beta-blocking drugs. A double-blind study reported here of 110 matched patients, 36 of whom were on pindolol for more than 2 years, did not reveal any evidence of oculomucocutaneous problems related to drug treatment.

Adrenergic beta-Antagonists↗
PubMed1982

New developments in alpha-adrenoreceptor drugs for the treatment of hypertension.

The alpha 1- and alpha 2-adrenoreceptor types are defined in terms of the selective binding of radioligands and their displacement from membrane preparations by a range of agonists and antagonists. Their distribution is described in brain, kidney, heart, and peripheral blood vessels. A group of centrally acting clonidine-like drugs are classified in terms of their selectivity for the alpha 2-adrenoreceptors, and it is suggested that differences between alpha-adrenoreceptors in various tissues may allow development of highly selective alpha 2-adrenoreceptor agonists for specific tissue sites such as the juxtaglomerular cells and brainstem nuclei controlling blood pressure. It is further suggested that the aim of treatment with such compounds is to modulate adrenergic activity while retaining normal homeostatic mechanisms. For this purpose, competitive agonists and antagonists are preferable to compounds which bind irreversibly to the receptor.

Adrenergic alpha-Antagonists↗
PubMed1982

[3H]-guanfacine: a radioligand that selectively labels high affinity alpha2-adrenoceptor sites in homogenates of rat brain.

[3H]-guanfacine (N-amidino-2-(2,6-dichloro 3[3H] phenyl) acetamide hydrochloride; 24.2 Ci/mmol) has been used as a radioligand in homogenates of rat cerebral cortex. Specific binding of [3H]-guanfacine was linear with respect to tissue concentration (2.5-15 mg/ml), saturable and not markedly affected in the pH range 6.5-8.0. Analysis of the saturation of [3H]-guanfacine binding using an iterative least squares fitting procedure gave best fits to a single site model. [3H]-guanfacine binding was of high affinity (Kd 1.77 +/- 0.24 nM; n = 8) to a population of non interacting sites (nH 0.99 +/- 0.02; n = 8) with a density of 118.2 +/- 8.4 fmol/mg protein (n = 8). Highest levels of binding were achieved in cerebral cortex followed by thalamus greater than hypothalamus greater than medulla/pons greater than spinal cord greater than striatum greater than cerebellum. Binding was stereoselective with regard to the (-)-isomer of noradrenaline and the order of potency for displacement of [3H]-guanfacine by agonists was naphazoline greater than clonidine greater than (-)-adrenaline greater than (-)-alpha methylnoradrenaline greater than (-)-noradrenaline greater than (+/-)-alpha-methylnoradrenaline greater than (+)-noradrenaline greater than methoxamine greater than (+)-adrenaline greater than phenylephrine and by antagonists was phentolamine greater than dihydroergocryptine greater than piperoxane greater than yohimbine greater than prazosin greater than labetalol greater than indoramin suggested binding to alpha 2-adrenoceptors. The monovalent cations Na+ and K+ and also guanosine 5'-triphosphate (GTP) produced concentration-dependent inhibition whereas the divalent cations Ca2+, Mg2+, and Mn2+ first enhanced, then inhibited [3H]-guanfacine binding. Na+ (150 mM) or GTP (100 microM) produced marked reductions and Mn2+ (5 mM) marked increases in the number of receptor sites labelled by [3H]-guanfacine. 9 It is concluded that [3H]-guanfacine preferentially labels a high affinity state of the alpha 2- adrenoceptor in homogenates of rat cerebral cortex.

Adrenergic alpha-Agonists↗
PubMed1982

Effects of clonidine infusion and withdrawal on blood pressure and behaviour in the rat. A preliminary study.

Clonidine (10 micrograms/kg/hr) was administered continuously to normotensive rats for 5 days using osmotic minipumps. This treatment attenuated the episodic fluctuations in blood pressure normally observed during rapid eye movement (REM) sleep. However, 18-24 hr after withdrawal of clonidine, pronounced fluctuations in blood pressure superimposed upon tonic increases in pressure as well as muscular twitching and irregular respiration were seen during sleep. These responses were abolished by an injection of clonidine or phentolamine. The results demonstrate that after withdrawal of clonidine administration, an increased lability of blood pressure occurs during sleep and probably results from an increased frequency and duration of REM sleep.

Animals↗