Showing papers in "Clinical and Experimental Pharmacology and Physiology in 1978"

Further observations on the pathological responses of rat skeletal muscle to toxins isolated from the venom of the Australian tiger snake, Notechis scutatus scutatus.

Abstract: SUMMARY 1. Some aspects of the response of mammalian skeletal muscle following the injection of purified toxins from the venom of the Australian tiger snake, Notechis scutatus scutatus, are described. 2. The toxins used were notexin, notechis II-5, notechis II-1 and a modified form of notexin (PBP-notexin). They were injected into the dorso-lateral aspect of one hind limb so that the soleus muscle would be exposed to the toxins. 3. Within 1 h after the injection of notexin, the soleus muscles were oedematous and by 3–6 h, polymorphonuclear leucocytes had entered the interstitial spaces. The invasion of necrotic muscle fibres was extensive by this time. Muscle spindles appeared relatively unaffected by the toxin. 4. The muscle regenerated via myoblasts at 2–3 days to myotubes at 3–5 days, immature muscle fibres at 7–14 days and fully differentiated muscle fibres by 21–28 days. Even after 6 months, however, the nuclei of many muscle fibres remained in a central position. 5. A second component of Australian tiger snake venom was also found to be myotoxic. It was slightly less potent than notexin, but caused qualitatively similar damage to that caused by notexin. It was identified as notechis II-5. A third fraction, notechis II-l, was found to be inactive. 6. Notexin could be neutralized by incubation with tiger snake antivenene; the simultaneous injection of antivenene with notexin did not afford complete protection against muscle damage.

Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline.

Abstract: SUMMARY 1. To test the hypothesis that inhibition of cyclic nucleotide phosphodiesterase is the major mechanism of the bronchodilator action of theophylline in reversible airways disease, the effects of therapeutic plasma levels of the drug on human pulmonary phosphodiesterase activity were examined. 2. Therapeutic levels of theophylline inhibited the phosphodiesterase-catalysed hydrolysis of adenosine cyclic 3′,5′-monophosphate (cAMP) and guanosine cyclic 3′,5′-monophosphate (cGMP), but the percentage inhibition was relatively small. 3. The results, while supporting the assumed contribution of phosphodiesterase inhibition to the overall mechanism of theophylline action, suggest that other presently unknown factors must also be taken into consideration to fully explain the beneficial effects of theophylline in reversible airways disease.

The density of adrenergic nerves at various levels in the guinea‐pig lung

Abstract: 1. Guinea‐pig tracheal and lung segments were systematically examined for adrenergic nerves using the fluorescence histochemical technique. Fluorescence in nerves was enhanced with α‐methylnoradrenaline or by pretreating the animals with nialamide. 2. There was a progressive decrease in density of fluorescent fibres in airway smooth muscle from the laryngeal end of the trachea, which was densely innervated, to the bronchioles, which contained only occasional fibres. This was despite obvious fluorescence in blood vessels in the lung. 3. It is suggested that, if adrenergic nerves are involved in reflex bronchodilatation in this species, they directly control larger airways and other factors, e.g. non‐adrenergic inhibitory nerves, may be important in the control of smaller airways. Copyright

Effects of monosodium glutamate‐induced obesity in mice on carbohydrate metabolism in insulin secretion

Abstract: 1. The syndrome of obesity induced by neonatal injection of monosodium glutamate (MSG) has been further studied in mice. In confirmation of previous studies stunting and decreased pituitary and gonadal weights were observed. 2. After weaning food intake was consistently less in MSG-treated than control mice. Body lipid stores were significantly elevated in MSG-treated mice by 2 weeks of age and increased progressively up to 4 months. 3. Plasma glucose was comparable between MSG-treated and control mice in the fed state whereas after an overnight fast MSG-treated mice exhibited relative hypoglycaemia. 4. Obese MSG-treated mice did not exhibit resistance to exogenous insulin and disposed of an intravenous glucose load more rapidly than control mice. 5. Hyperinsulinaemia was present inconsistently in both fed and fasted mice and in response to administered glucose. 6. Neonatal administration of MSG provides a useful additional model for studying the role of the hypothalamus in obesity.

The influence of serotonin on the mitotic rate in the colonic crypt epithelium and in colonic adenocarcinoma in rats.

Abstract: 1. The mitotic rate in the crypts of Lieberkuhn of the descending colon and in dimethylhydrazine-induced adenocarcinomata of the descending colon of rat was measured using a stathmokinetic technique. 2. Intraperitoneal injection of a small dose (10 microgram/kg) of serotonin resulted in an increase in the tumour cell mitotic rate. 3. Blockade of serotonin receptors by 2-bromolysergic acid diethylamide and depletion of tissue serotonin levels following injection of DL-6-fluorotryptophan both result in a decrease in the tumour cell mitotic rate. 4. Treatment with serotonin, 2-bromolysergic acid diethylamide and DL-6-fluorotryptophan were all without effect on the colonic crypt cell mitotic rate.

Decreased cardiac beta-adrenoceptors in hypertensive rats.

Abstract: 1. beta-Adrenoceptors have been investigated in cardiac and renal cell membranes from hypertensive and normal rats. 2. The 125I-labelled beta-adrenoceptor antagonist 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol was used to measure directly the number and affinity of receptors. 3. Cardiac membranes from hypertensive rats had a lower concentration of beta-adrenoceptors than membranes from control normotensive animals, but the affinities of the receptors remained unchanged. Receptor concentration decreased by half and was similar in each of the three models of experimental hypertension investigated. 4. In contrast, kidney membranes from hypertensive animals had the same beta-adrenoceptor concentration and affinity as membranes from normotensive rats. 5. The decrease in cardiac beta-adrenoceptor concentration may reflect an increase in cardiac sympathetic drive in these experimental hypertensive models.

Some biochemical responses of rat skeletal muscle to a single subcutaneous injection of a toxin (notexin) isolated from the venom of the australian tiger snake notechis scuta tus scuta tus

Abstract: SUMMARY 1. Some biochemical responses of mammalian skeletal muscle to a single subcutaneous injection of a purified toxin from the venom of the Australian tiger snake, Notechis scutatus scutatus, have been investigated to determine the role of changes in peptide hydrolase enzymes in the muscle wasting caused by notexin administration. 2. Within 6 h of injection, serum creatine kinase activity was increased by five-to ten-fold, and remained elevated for at least 24 h. 3. There was an initial inflammatory response in the muscle adjacent to the site of injection; by 12 h after injection, muscle wet weight increased by 60%. 4. After the initial increase, wet weight fell to about 50% of normal at 7 days. Normal wet weight was achieved by 20 days after the injection. Over the period 1–20 days after the injection of the toxin, the changes in wet weight were mirrored by changes in non-collagen protein content. 5. The activities of cathepsin B and acid proteinase were increased following the injection of the toxin. By 2 days after injection, there was a ten-fold increase in the activity of cathepsin B, and a seven-fold increase in the activity of acid proteinase. The activity of both enzymes became normal by 20 days. 6. Experiments utilizing a variety of cytotoxic drugs suggested that the acid proteinase and cathepsin B are primarily located within invading phagocytic cells. 7. The results are discussed with reference to the previously described pathology of toxin-damaged skeletal muscle.

An in vivo investigation of the negative chronotropic effect of cholic acid in the rat

Abstract: SUMMARY 1. Experimental obstructive jaundice in the Wistar rat causes a significant decrease in heart rate. 2. Intravenous administration of cholic acid in vivo elicits a dose-dependent negative chronotropic effect. 3. Atropine or vagotomy significantly reduces, but does not abolish, the negative chronotropic effect of cholic acid. 4. Ganglion blockade and decerebration diminishes the negative chronotropic effect of cholic acid, but to a lesser extent than atropine or vagotomy. 5. Sympathetic depletion by reserpine slightly potentiates the response to cholic acid. 6. The effect of cholic acid injected cranially into the common carotid artery is less than when administered into the jugular vein. 7. The haemolysis caused by cholic acid does not appear to be involved in the negative chronotropic effect. 8. It is concluded that cholic acid causes both a direct as well as a vagally mediated negative chronotropic effect in the Wistar rat.

Cholic acid and the heart: in vitro studies of the effect on heart rate and myocardial contractility in the rat

Abstract: 1. Cholic acid has a dose-dependent negative chronotropic effect on isolated atria of Wistar rats. 2. The positive inotropic effect of cholic acid is the result of a negative chronotropic effect and can be eliminated by electrical pacing. 3. Cholic acid does not appear to exert its negative chronotropic effect through cholinoceptors and alterations in bath concentrations of calcium and potassium does not influence this effect significantly. 4. Cholic acid is a functional antagonist of isoprenaline. 5. It is suggested that cholic acid exerts its negative chronotropic effect by forming a monolayer on the surface of the cell membrane, thereby mechanically interfering with membrane function.

Free choline concentration and cephalin-N-methyltransferase activity in the maternal and foetal liver and placenta of pregnant rats.

Abstract: SUMMARY 1. The concentration of free choline and cephalin-N-methyltransferase activity of the maternal and foetal liver and placenta of rats in late pregnancy were determined. 2. The choline concentration of the liver fell from a mean of 130 nmol/g in adult non-pregnant rats to 38 nmol/g in late pregnancy. 3. The choline concentrations of the foetal liver and placenta had mean values of 135 and 442 nmol/g, respectively. 4. There was a significant 24% increase in the cephalin-N-methyltransferase activity of the liver during pregnancy. The enzyme activity in the foetal liver was 7% that of the maternal liver, and activity was undetectable in the placenta. 5. The results suggest that, during pregnancy, the maternal liver supplies choline to the placenta and foetal organs, like the liver, and that the demand for maternal liver choline far exceeds the supply available.

Gas chromatographic measurement of plasma levels of sodium valproate: tentative therapeutic range of a new anticonvulsant in the treatment of refractory epileptics

Abstract: 1. A precise and rapid gas chromatographic method for the measurement of plasma sodium valproate concentrations is presented. 2. The extraction is a single step procedure, and is reproducible and linear throughout the concentration range encountered. 3. Clinical evaluation of the drug is presented in eighteen epileptics on the basis of the percentage of days on which subjects had seizures before and after sodium valproate therapy. 4. A tentative therapeutic range for sodium valproate is presented on the basis of plasma levels and therapeutic effect.

The effect of corticotrophin (ACTH) administration on the pressor action of angiotensin II, noradrenaline and tyramine in sheep.

Abstract: SUMMARY 1. Pressor responses to angiotensin II, noradrenaline and tyramine were examined in sheep prior to and during the development of corticotrophin-induced hypertension. 2. Pressor responses to angiotensin II amide did not change with corticotrophin (ACTH) administration. Small significant increases in pressor responses to noradrenaline occurred at low doses only (0.27 and 1.06 /imol/h). Significant increases in response to tyramine occurred after 24 h of ACTH administration, but were not maintained after 6 days of ACTH. These changes are quantitatively small and do not suggest that changes in pressor sensitivity contribute significantly to the rise in blood pressure following ACTH administration. 3. Sodium depletion significantly reduced the pressor responses to angiotensin II amide at all doses and to tyramine in the middle range only, but did not affect the responses to noradrenaline.

Separation of two conjugates of clofjbric acid (cpib) found in the urine of subjects taking clofibrate

Abstract: SUMMARY 1. Two main conjugates of CPIB (2-[chlorophenoxy]-2-methylpropionic acid) are present in the urine of subjects taking clofibrate. The metabolites can be separated by thin-layer chromatography (TLC). 2. Both conjugates are hydrolysed by dilute alkali, but only one is hydrolysed by the enzyme β-glucuronidase. In eighty-five urine specimens this conjugate accounted for an average of 54.5% (range 25–70%) of the total CPIB, while 2.6–12.45% (mean 5.1%) was present as free CPIB.

Action of octopamine agonists and stereo isomers at a specific octopamine receptor

Abstract: SUMMARY 1. (±)-Octopamine, (±)-N-methyl octopamine and (-)-α-methyl octopamine increase the amplitude of contraction of the spontaneously beating ventricle of the mollusc Tapes watlingi through action on a specific octopamine receptor. 2. Unlike the excitatory responses to dopamine, noradrenaline or serotonin, the excitatory response of the ventricle to agonists at the octopamine receptor is attenuated by metoclopramide. 3. Compounds with potent agonist activity at the octopamine receptor all have a single phenolic hydroxyl in the para position of the benzene ring and a β-hydroxyl group in the phenethylamine side chain. O-Methylation of the para phenolic group or removal of the /3-hydroxyl group results in complete loss of agonist activity. Bulky substituents but not a single methyl group on the amino groups impair agonist activity. 4. The octopamine receptor is stereo-selective, (-)-octopamine is more than twenty times more active than (+)-octopamine. 5. The weak octopamine-like activity of (-)-N-methyl and a-methyl meta octopamine indicates that the stereo-selective receptor has a relative rather than an absolute requirement for a single phenolic hydroxyl in the para position of the benzene ring. 6. These data indicate the presence of a specific, stereo-selective receptor for octopamine in the ventricle of the mollusc Tapes watlingi. 7. The stereo-selectivity and structural specificity of the octopamine receptor differentiates it from receptors for dopamine and serotonin also present in the ventricle.

CARDIAC AND BRONCHIAL β‐ADRENOCEPTOR ANTAGONISTIC POTENCIES OF ATENOLOL, METOPROLOL, ACEBUTOLOL, PRACTOLOL, PROPRANOLOL AND PINDOLOL IN THE ANAESTHETIZED DOG

Abstract: SUMMARY 1. The β-adrenoceptor antagonists atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol have been tested for their ability to reduce isoprenaline-induced bronchodilation and tachycardia in the anaesthetized dog. 2. Atenolol, metoprolol, acebutolol and practolol all possessed a similar degree of cardioselectivity in this animal model.

Differential blockade of octopamine and dopamine receptors by analogues of clozapine and metoclopramide.

Abstract: SUMMARY 1. Sulpiride, but not procainamide, antagonizes the excitatory effects of (±)-octopamine receptors in the Tapes ventricle. Neither compound attenuates dopamine excitation. 2. Clozapine will attenuate the effects of (±)-octopamine and (-)-α-methyl octopamine at the octopamine receptor but not the excitatory effects of dopamine at dopamine receptors. 3. Clozapine is more potent than its 2-positional isomer HF 2046 in attenuating octopamine excitation. However, HF 2046, unlike clozapine, will attenuate the excitatory effects of dopamine. 4. These data indicate that replacement of the 8-chloro substituent in the clozapine nucleus with a 2-chloro substituent decreases the ability of the compound to blockade octopamine receptors. However, the 2-chloro-substituted compound (HF 2046) now has the added ability to blockade excitatory dopamine receptors. 5. The greater potency of clozapine than HF 2046 as an octopamine antagonist suggests that it is the 8-chloro-substituted aromatic ring of clozapine which overlaps the aromatic site usually occupied by the octopamine aromatic ring.

Cardiovascular and respiratory effects of carotid body stimulation in the monkey.

Abstract: SUMMARY 1. The carotid bodies were stimulated in the anaesthetized pig-tailed macaque monkey (M. nemestrina) using (i) brief injections of cyanide or CO2-equilibrated bicarbonate solution into a common carotid artery, and (ii) longer perfusion with hypoxic hypercapnic blood in vascularly isolated chemoreceptor preparations. 2. In spontaneously breathing animals brief stimuli (thirty-one tests, seven monkeys) consistently increased pulmonary ventilation (by 97 ± 10% of control), slowed the heart rate (the pulse interval increasing by 36 ± 7.5%), and increased femoral vascular resistance (by 44 ± 7%). 3. More sustained chemoreceptor stimulation with asphyxial blood (nineteen tests, five monkeys) increased ventilation by 187 ± 23%, but transient bradycardia occurred in only eight of nineteen tests and was followed by tachycardia; in the remaining tests, only tachycardia occurred. After 20–40 s, the pulse interval was 5.8 ± 0.9% below the control level. Femoral vascular resistance either increased (five tests, two animals) or decreased (six tests, two animals). 4. Evidence is presented that in the monkey the autonomic effects of chemoreceptor stimulation are influenced by the level of respiratory activity with bradycardia and vasoconstriction occurring when the level is low, and tachycardia and vasodilatation when it is high. 5. The interaction of autonomic responses resulting from carotid body stimulation and from mechanisms initiated by the concomitant hyperventilation are qualitatively similar in the monkey and in subprimate species, although there may be quantitative differences such as would account for the species differences to disturbances produced, for instance, by arterial hypoxia.

A sequential study of adrenocorticosteroid level in human pregnancy

Abstract: 1. Peripheral plasma levels of aldosterone, corticosterone, cortisol, 11-deoxycorticosterone (DOC) and 11-deoxycortisol were measured sequentially throughout pregnancy in eleven women. 2. Mean plasma concentrations were significantly increased above non-pregnant values at 8 weeks for DOC, at 12 weeks for corticosterone, cortisol and 11-deoxycortisol, but not until 24 weeks for aldosterone. 3. It is suggested that during human pregnancy, the maternal adrenal is responding differently to corticotrophin, pituitary or placental, and that other factors, for example prolactin, may be stimulating the adrenal directly or modifying the action of corticotrophin.

Warfarin sodium: steady-state plasma levels and patient age.

Abstract: SUMMARY 1. Steady-state plasma levels of warfarin were measured in thirty-nine ambulatory patients attending a haematology clinic. 2. Plasma concentrations, plasma clearance, and prothrombin ratio showed no significant differences when patients below 65 years of age were compared with those above 65 years. The mean daily maintenance dose of warfarin required was marginally greater for the younger patients but the difference was not statistically significant (P= 0.10). 3. A significant relationship was found between the daily maintenance dose of warfarin required by all patients and their mean steady-state plasma level (r = 0.5667, P< 0.001). 4. For one elderly hospitalized patient it was apparent that there was a marked depression of the vitamin K-dependent clotting factor synthesis by warfarin which was associated with a hypoprothrombinaemic response.

The measurement of glomerular blood flow in the rat kidney: influence of microsphere size

Abstract: 1. Radioactively labelled microspheres were used to determine glomerular blood flow in glomerular populations with distinct vascular characteristics. Two batches of microspheres (15 +/- 5.0 micrometer diameter and 7.0--10 micrometer diameter) were utilized. 2. The results show that the larger microspheres overestimate the superficial glomerular blood flow (414 +/- 61 nl/min, mean +/- s.e.m.) and underestimate the deep glomerular blood flow (98 +/- 10 nl/min), when compared with the data obtained with 7.0--10 micrometer diameter microspheres (317 +/- 30 nl/min and 209 +/- 23 nl/min, respectively). 3. The rheological artefact associated with the use of larger microspheres is confirmed by finding an uneven size distribution of microspheres lodged in the glomeruli. In each of three experiments, the mean diameter of 200 microspheres lodged in the superficial glomeruli (16.43 +/- 0.27 micrometer, 15.87 +/- 0.23 micrometer and 16.58 +/- 0.27 micrometer) was significantly greater than that found in the deep glomeruli (15.36 +/- 0.15 micrometer, 15.25 +/- 0.21 micrometer and 15.73 +/- 0.24 micrometer; P less than 0.01, less than 0.05 and less than 0.01, respectively). No such difference was detected when the 7.0--10 micrometer spheres were used. 4. Glomerular blood flow can be measured at all depths of the rat's cortex and the demonstrated rheological artefact associated with use of the larger spheres is circumvented with the use of 7.0--10 micrometer microspheres.

The effect of heart rate on myocardial ouabain uptake and on the susceptibility to ouabain cardiotoxicity in the dog

Abstract: SUMMARY 1. Tissue ouabain concentrations were estimated 30 min after intravenous 3H-ouabain administration to sedated dogs, the heart rates of which were adjusted to range between 50 and 200 beats/min. Significant correlations were present between heart rate and ouabain content in left ventricle (r=0.93, P< 0.001), in right ventricle and left atrium. In contrast, no significant correlations were present between heart rate and ouabain content in liver, in renal cortex, skeletal muscle or plasma. 2. To determine the functional effect of the greater myocardial ouabain uptake associated with higher heart rate, anaesthetized open-chest dogs were studied. The heart rates of two groups were controlled at 199 ± 9 (s.d.) beats/min and 90 ± 14 beats/min during ouabain administration, and 30 min later, at a common heart rate, acetyl strophanthidin tolerance tests were performed. 3. Acetyl strophanthidin infusion induced ventricular tachycardia significantly earlier, after a correspondingly lower dose in the fast heart rate group (P<0.01). Significant inverse correlations were present between the concentrations of ouabain in both left and right ventricular muscle and the duration of acetyl strophanthidin infusion. 4. The results indicate that higher heart rate is associated with greater myocardial ouabain uptake and that this ouabain is functionally active.

Thromboxane b2 inhibits prostaglandin e2 inactivation by the rat isolated perfused lung

Abstract: SUMMARY 1. The effect of thromboxane B2 (T×B2) on inactivation of prostaglandin E2 (PGE2) by the rat isolated perfused lung has been studied. 2. TxB2 when infused in low concentrations (100 ng/ml) into the pulmonary artery reduced PGE2 inactivation approximately two-fold. 3. The rat isolated fundus strip was contracted by higher concentrations of TxB2 (1.0 Mg/ml) in the presence of hyoscine, mepyramine, methysergide, phenoxy-benzamine and propranolol. The size of contraction was reduced by indomethacin in concentrations known to inhibit prostaglandin synthetase. 4. Thus, in circumstances in which T×B2 and PGE2 are released concomitantly by the lung, low concentrations of TxB2 may augment PGE2 release by reducing its inactivation.

Blood flow and relative tissue oxygenation of normal and partially ischaemic myocardium: effect of co2

Abstract: 1. Ischaemia of a portion of the myocardium in the dog heart was produced by tying off a small branch of a coronary artery: flow in the occluded region was reduced from 5 to 82% of the initial value. 2. The effect of inhalation of 5% CO2 in air on relative tissue PO2 and perfusion in normal and partially ischaemic myocardium was determined. 3. After 10 min inhalation of 5% CO2, there was an increase in tissue perfusion as measured by hydrogen desaturation; the increase was inversely proportional to the degree of flow reduction. 4. Relative intramyocardial PO2 measured polarographically, decreased with occlusion and increased after CO2 inhalation; the changes were inversely proportional to the degree of reduction in PO2. 5. The increase in flow after CO2 inhalation suggests that partially ischaemic myocardial tissue is capable of further vasodilation.

The effects of sympatholytic drugs on the cardiovascular response to tilting in anaesthetized cats.

Abstract: 1. Using cats anaesthetized with chloralose and urethane, comparison was made of the abilities of several antihypertensive and sympatholytic drugs to lower systemic blood pressure, and to depress the compensatory cardiovascular responses to bilateral carotid occlusion and to 45 degrees head-up tilting. Similar comparisons were also made of the effects of these drugs on the perfusion pressure of the vascularly isolated autoperfused hindquarters, and the response of this to carotid occlusion and tilting. The effects of bilateral vagotomy and haemorrhage on these responses were also studied. 2. It was found that hypotensive doses of both bretylium and guanethidine (3.0 mg/kg, i.v.) markedly depressed the ability of cats to restore their systemic blood pressure and to constrict their hindquarters vasculature during tilting. Both drugs depressed the carotid occlusion reflex in the systemic, but not in the hindquarters, circulation. Neither propranolol, 2.0 mg/kg, i.v., nor bilaterial vagotomy had any effect on these parameters and haemorrhage sufficient to cause marked hypotension was without effect on the systemic responses to carotid occlusion or tilting. 3. Clonidine (1.0, 5.0 and 25 microgram/kg, i.v.), xylazine (62.5, 125 and 250 microgram/kg, i.v.) and reserpine (0.5 and 2.0 mg/kg, i.v.) all caused considerable hypotension but had no effect on the response to tilting of the systemic circulation, apart from somewhat prolonging recovering time. The highest dose of clonidine moderately depressed the hindquarters perfusion pressure, and the response of this to tilting. 4. Clonidine (5.0 and 25 microgram/kg, i.v.) and xylazine (125 and 250 microgram/kg, i.v.) depressed the systemic pressor responses elicited by the ganglion stimulants DMPP and McN-A-343. This may indicate that the ability of clonidine to prolong the pressure recovery during tilt may be due to impaired peripheral sympathetic transmission. 5. It is concluded that drugs which significantly reduce the compensatory pressure reponses to tilting in anaesthetized cats may also cause postural disturbances in man, whilst drugs which merely prolong the period required for pressure compensation seem much less likely to cause serious clinical impairment of orthostatic reflexes. It appears that the cardiovascular response to bilateral carotid occlusion may not provide a good index of the integrity of orthostatic reflexes.

The antagonism by propranolol and alpha-methylpropranolol (ICI 77602) of vascular and cardiac responses to isoprenaline in anaesthetized dogs.

Abstract: 1. In anaesthetized dogs, alpha-methylpropranolol was less potent than propranolol in antagonizing both vascular (hind limb perfusion pressure) and cardiac heart rate) responses to isoprenaline. 2. alpha-Methylpropranolol was more potent in antagonizing vascular than cardiac responses to isoprenaline, but this selectivity was no greater than that seen also with propranolol. 3. Isoprenaline sensitivity was greater in the hind limb than the heart and vascular-selective antagonism was more pronounced in those dogs in which this differential sensitivity was the greatest. 4. Introduction of an alpha-methyl group into propranolol decreases its beta-adrenoceptor antagonist potency but does not enhance vascular selectivity.

THE EFFECT OF PRAZOSIN ON PRE‐ AND POSTSYNAPTIC α‐RECEPTORS IN THE PITHED RAT

Abstract: SUMMARY 1. Prazosin had a marked inhibitory effect on post-synaptic a-receptors in the pithed rat, as measured by the blood pressure response to the cumulative administration of clonidine. 2. Prazosin had no inhibitory effect, however, on the pre-synaptic a-receptor, as measured by the clonidine-induced reduction in the tachycardia produced by stimulation of the cardiac nerves. 3. These results suggest that prazosin has a selective antagonistic affinity for post-synaptic a-receptors.

Intrarenal action of angiotensin II in restoring renal artery pressure after acute renal artery stenosis.

Abstract: SUMMARY 1. The renal artery of conscious dogs was acutely narrowed over 30 s to reduce renal artery pressure distal to the stenosis to 40 mmHg and the stenosis was maintained for 1 h. The distal renal artery pressure was rapidly restored to a plateau slightly below pre-stenosis values within 10–15 min. Rises in systemic blood pressure and plasma renin activity were small and transient. 2. This restoration was an active process, mediated by the intrarenal effects of angiotensin II (AH), since it was greatly diminished or abolished when the renal artery was narrowed in the presence of angiotensin I-converting enzyme inhibitor or angiotensin receptor antagonist (l-Sar-8-Ue All). However, it was not diminished by ‘total’ autonomic effector blockade. 3. This angiotensin II-mediated restoration of renal artery pressure may be of homeostatic significance for the maintenance of glomerular filtration rate.

The effect of some centrally active drugs on corticosterone secretion and metabolism in rats

Abstract: SUMMARY 1. Male rats were treated with morphine sulphate (10 mg/kg), methadone (10 mg/kg) and chlorpromazine (8.0 mg/kg) respectively, for 2 weeks. 2. At the end of this period, the adrenal glands of treated rats had increased in weight. 3. The concentration of corticosterone in the peripheral plasma was significantly lowered in the chlorpromazine-treated rats, increased in the methadone-treated rats and was unchanged in the morphine-treated rats. 4. The metabolic clearance rate of [1,2-3H]corticosterone decreased in the chlorpromazine-treated rats, while only a slight reduction was observed with methadone treatment. 5. These results showed that chronic treatment with either morphine or methadone did not suppress the adrenal function. The possible site of action of chlorpromazine in suppressing corticosterone secretion is discussed.

Peripheral muscle effects of levodopa in the anaesthetized cat

Abstract: SUMMARY 1. Levodopa, dopamine, noradrenaline and adrenaline (in increasing order of potency) depressed the tension and degree of fusion of incomplete tetanic contractions of the slow-contracting soleus muscle in chloralose-anaesthetized cats. 2. The effects of all compounds were antagonized by propranolol (50-20 μg/kg), but not practolol (1.0-5.0 mg/kg). This indicates that effects are mediated by β2-adrenoceptor stimulation. 3. The effect of levodopa, but not of the catecholamines, was antagonized by prior administration of the dopa decarboxylase inhibitor benserazide. This indicates that levodopa itself is inactive, whereas its decarboxylated metabolites are active. 4. The depressant action of β-adrenoceptor agonists on incomplete tetanic contractions of the cat soleus muscle, which are exerted directly on the muscle fibres, is a model for effects exerted on slow-contracting units of human muscles; the latter effects probably underlie the tremor observed after β-adrenoceptor agonist administration. 5. These results therefore suggest that levodopa, via its decarboxylated metabolites, dopamine, noradrenaline and adrenaline, may produce or exacerbate tremor in man. Thus in Parkinsonian patients, any centrally induced relief of tremor that levodopa may produce may be masked by tremorogenic effects of such metabolites exerted in the periphery.

Comparison of the anorectic and motor activity effects of some aminoindanes, 2-aminotetralin and amphetamine in the rat

Abstract: 1. The anorectic and motor activity effects of 1-aminoindane, 2-aminoindane, some N-substituted 2-aminoindanes, 2-aminotetralin, amphetamine and fenfluramine were determined in rats. 2. The two compounds with structures most like the extended conformation of amphetamine, 2-aminotetralin and 2-aminoindane, were potent anorectics. At dosages which halved the intake of food over 1 h, amphetamine increased motor activity, 2-aminotetralin had no effect, and 2-aminoindane reduced motor activity. 3. Both the anorectic and central stimulant actions of 2-aminoindane were absent in N-ethyl- and N-isopropyl-2-aminoindane. 4. 1-Aminoindane, whose structure is like the folded conformation of amphetamine, produced a small anorectic effect and depressed motor activity.