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Biomedical subjects

H M Snow

Publications and source records attributed to H M Snow.

At least 37 records · Page 2Linked to original sources
PubMed1991

Comparative effects of beta-adrenoceptor partial agonists on isolated rat atrium.

The chronotropic effect of three beta-1-adrenoceptor partial agonists prenalterol, xamoterol and epanolol has been compared on the right atria of the rat in order to evaluate their intrinsic activity and to place them in rank order of effectiveness. The results show that prenalterol, xamoterol and epanolol are all partial agonists. The intrinsic activities relative to that of isoprenaline are 0.84 for prenalterol, 0.59 for xamoterol and 0.29 for epanolol. This rank order of intrinsic activities should remain the same in different species and in man. Both atenolol and propranolol reversed the chronotropic effects of the three agonists. The KB of the two blockers was similar against prenalterol and xamoterol, which indicates that the two partial agonists are probably competing for the same population of receptors. The EC50 is twice as large than KB for xamoterol, which is consistent with isoprenaline working through both beta-1- and beta-2- receptors and xamoterol finds it more difficult to block the beta-2-receptors.

Adrenergic beta-Agonists↗
PubMed1990

Changes in exercise tolerance and resting haemodynamics during long-term treatment of heart failure with xamoterol.

The long-term efficacy of xamoterol in improving effort capacity and haemodynamics was investigated in a study lasting 1 year in heart failure patients. Following a 3 month, double-blind period of treatment with xamoterol, patients continued therapy for a further 9 months. Exercise duration rose by 27% at 3 months and this improvement was maintained at 12 months. Similarly, the statistically significant increase in cardiac index and reduction in pulmonary wedge pressure and exercise heart rate persisted for 12 months.

Aged↗
PubMed1990

Relationship between positive inotropic responses and plasma concentrations of xamoterol in middle-aged and elderly patients.

1. We examined the relationship between the contractile state of the left ventricle and the plasma concentration of xamoterol in patients with ischaemic heart failure. 2. Identical studies were conducted in 14 middle-aged (all male; mean age 51.3 years, range 42-61) and 10 elderly patients (six male, four female; mean age 67.7 years, range 64-72). 3. Patients received seven cumulative doses (0.0005-0.2 mg kg-1) of xamoterol. After each dose the rate of change of pressure in the left ventricle at a developed pressure of 40 mm Hg and normalised for this pressure, (dP/dt)/DP40, and plasma concentrations of xamoterol were measured. 4. There were dose-related increases in (dP/dt)/DP40. Curves relating changes in (dP/dt)/DP40, expressed as a percent of the maximum observed response, to changes in xamoterol plasma concentrations were constructed for the middle-aged and elderly patients. From these curves the mean effective concentration (EC) value to produce a particular response could be calculated. In the sample sizes studied, the difference between the EC values over a range of responses for the middle-aged and elderly patients did not reach statistical significance, indicating that cardiac responsiveness to xamoterol was similar in the two groups of patients. 5. Plasma concentrations of xamoterol over the range of 39 to 150 ng ml-1 produced positive inotropic responses which varied between 70% and 90% of the maximum observed effect of xamoterol.

Adult↗
PubMed1989

Modulation of the autonomic control of the failing heart.

The failing heart operates with an abnormal combination of heart rate, stroke volume, and enddiastolic volume. This mismatch becomes more evident during exercise of patients with heart failure, when an increase in cardiac output is achieved with higher heart rate, a lower stroke volume and a higher enddiastolic volume. Using the beta 1-adrenoceptor partial agonist xamoterol which lacks beta 2-adrenoceptor agonism the response of the heart to sympathetic stimulation can be modulated. At rest and low levels of exercise xamoterol provides an inotropic support of the heart, whereas it reduces inappropriate tachycardia at higher levels. Thereby, xamoterol tends to normalize the balance of the inotropic and chronotropic control of the failing heart, because cardiac output is increased with a more normal combination of heart rate, stroke volume, and filling pressure. The beneficial effects of xamoterol are discussed as being especially important for failing ischemic hearts, because the balance between energy supply and energy demand may be improved by xamoterol.

Adrenergic beta-Agonists↗
PubMed1989

The pharmacology of xamoterol: a basis for modulation of the autonomic control of the heart.

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta-adrenoceptor partial agonist which is of benefit in the chronic treatment of heart failure (e.g. The German and Austrian Xamoterol Study Group, 1988). These results contrast with those obtained with other beta-adrenoceptor drugs, prenalterol and pirbuterol which were unsuccessful on chronic dosing (Currie et al., 1984; Glover et al., 1985). 2. Unlike prenalterol and pirbuterol, xamoterol has no significant agonist activity at the beta 2-adrenoceptor and has shown no tachyphylaxis in animals or man. 3. The overall action of xamoterol is to modulate sympathetic control of the heart such that at rest and at low levels of exercise the heart receives inotropic support whilst during more severe exercise, heart rate is reduced. In patients with left ventricular dysfunction these effects lead to an improvement in the relation between filling pressure and cardiac output at all levels of activity such that a given cardiac output is achieved with a lower filling pressure. It is suggested that this alteration in the pattern of cardiac activity over a long period of time results in a beneficial adaptation of the myocardium and is a possible explanation of the observed clinical improvement.

Adrenergic beta-Agonists↗
PubMed1989

The effects of age, sex and treatment with xamoterol on exercise capacity in patients with heart failure.

The influence of age, sex and xamoterol treatment on exercise capacity has been investigated in 705 heart failure patients who took part in a multicentre, placebo-controlled study. Regression analysis suggests that although less than 20% of the total variation in exercise capacity between patients is explained by these factors, useful information may be gained by taking them into account. Exercise capacity declines with age, more rapidly in males than in females; the benefits of xamoterol are independent of age and sex. This approach demonstrates that exercise testing is a sensitive indicator of physical performance and allows the effects of treatment to be seen in context.

Adrenergic beta-Agonists↗
PubMed1989

The cardiovascular pharmacology of xamoterol, cicloprolol, prenalterol and pindolol in the anaesthetised dog.

An anaesthetised dog preparation was used to examine the pharmacological profiles of xamoterol, cicloprolol, prenalterol and pindolol. The effects of these agents on heart rate and hind limb perfusion pressure revealed that xamoterol is highly cardioselective and has no significant agonist activity at beta 2-receptors and no membrane stabilising effect. These pharmacological properties are not complicated by the formation of active metabolites and may explain the clinical benefits in the long-term treatment of heart failure.

Adrenergic beta-Agonists↗
PubMed1989

Long-term efficacy of xamoterol (a beta 1-adrenoceptor partial agonist) in patients with mild to moderate heart failure.

This study was designed to assess the efficacy of xamoterol in 14 patients with mild to moderate heart failure over a period of 18 months. A beneficial effect on exercise capacity and a lowering of heart rate on exercise was sustained, and ejection fraction did not change, although some deterioration may be expected over this length of time in patients with heart failure. Xamoterol is safe and effective, and its benefits are maintained over at least 18 months.

Adrenergic beta-Agonists↗
PubMed1989

Effects of xamoterol on sodium excretion in volunteers.

Xamoterol has been shown to reduce the frequency of oedema and lung crepitations in heart failure. We examined its effects on blood pressure and renal function in healthy volunteers. Systolic blood pressure rose, sodium and chloride excretion increased and there was a strong correlation in individual subjects between rises in systolic blood pressure and in sodium excretion. Although no changes in glomerular filtration rates were seen, changes sufficient to explain the observed rise in sodium excretion are well within the experimental error of this study. Xamoterol may increase sodium excretion by an action on renal haemodynamics.

Adrenergic beta-Agonists↗
PubMed1989

Effects of xamoterol, a beta 1 adrenoceptor partial agonist, in patients with ischaemic dysfunction of the left ventricle.

The effects of xamoterol (200 mg twice a day) in 21 patients with left ventricular dysfunction were studied in a double blind, randomised, crossover, placebo controlled trial with treatment periods of four weeks. Most patients had moderate heart failure (New York Heart Association class II), all had ischaemic heart disease, a history of a myocardial infarction, and symptoms of dyspnoea on exertion. Patients were assessed in terms of exercise duration (bicycle ergometer), clinical signs of heart failure, symptoms and activities, and ejection fraction. Xamoterol increased exercise duration (mean (SD] (from 445 (8) seconds to 484 (8) seconds) and ejection fraction (from 41.9 (1.3)% to 46.6 (1.3)%) and reduced the signs and symptoms of heart failure. The results of this study show that xamoterol is a safe and effective treatment for left ventricular dysfunction resulting from ischaemic heart disease.

Adrenergic beta-Agonists↗
PubMed1987

The effects and dose-response relationship of xamoterol in patients with ischaemic heart disease.

1. In a double-blind placebo controlled four-way crossover study the effects and dose response relationships of xamoterol were studied in nine patients with angina and dyspnoea secondary to chronic left ventricular dysfunction. The duration of exercise on a treadmill and heart rate were measured at the end of each phase of the study at 2 h and 24 h after dosing. 2. Xamoterol at 200 mg and 400 mg orally once daily had no effect on the mean resting heart rate but there was a small (5.7 beats min-1) but significant reduction in resting heart rate on 600 mg at 2-2.5 h after dosing. All three doses of xamoterol significantly reduced the maximum exercise heart rate at 2-2.5 h after dosing. 3. Xamoterol at all three doses significantly increased exercise duration at 2-2.5 h after dosing but not at 24 h. 4. Mean plasma xamoterol concentration at both 2-2.5 h and 24 h after dosing were dose related. The EC50 for xamoterol is 33.5 ng ml-1, where EC50 is the effective plasma concentration required to produce 50% of the maximum effect on exercise heart rate.

Adrenergic beta-Agonists↗
PubMed1984

Facilitation of calcium blocking and membrane effects by intrinsic sympathomimetic activity.

The interactions between ICI 118, 587 (Corwin) a beta 1-selective partial adrenergic agonist, and atenolol (Tenormin), propranolol (Inderal) and verapamil were examined first in anaesthetised dogs pretreated with syrosingopine and vagotomised. ICI 118, 587 was administered iv in cumulative doses of 0.1 to 1000 micrograms X kg-1. In four animals, heart rate increased from 102 +/- 4 to 188 +/- 12 beats X min-1 with a KA of 2.5 +/- 0.9 micrograms X kg-1. ICI 118, 587 was then administered to five groups each of four animals pretreated with atenolol (250 micrograms X kg-1 and 500 micrograms X kg-1iv), propranolol (250 micrograms X kg-1 and 500 micrograms X kg-1) or verapamil (200 micrograms X kg-1 plus 5 micrograms X kg-1 X min-1 iv). Both atenolol and propranolol shifted the dose response curve to the right but verapamil did not. Atenolol did not lower the maximal heart rate response to ICI 118,587. Both propranolol and verapamil slowed heart rate significantly (P less than 0.05) after, but not before, ICI 118,587. Further studies were then carried out in vitro. Cat papillary muscles were superfused with physiological saline at pH 7.4 and with either atenolol or ICI 118,587 at 5 X 10(-5) mol X litre-1. Tension was recorded at Lmax over a [Ca2+] range of 0.5 to 8 X 10(-3)mol X litre-1. The pA2 for verapamil against Ca2+ in the presence of atenolol and ICI 118,587 was 5.25 +/- 0.10 and 6.57 +/- 0.22 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1982

The cardiovascular effects of ICI 118,587: A beta 1-adrenoceptor partial agonist.

1 In a preparation in which cardiovascular reflexes were prevented from occurring, ICI 118,587 (1-(p-hydroxyphenoxy)-3-beta-(morpholinocarbonamido) ethylamino-2-propranol fumarate) caused dose-dependent positive chronotropic and inotropic effects upon the dog heart. 2 The increase in heart rate brought about by ICI 118,587 was about 43% of the maximum increase produced by isoprenaline. 3 For a given chronotropic effect produced by either ICI 118,587 or isoprenaline, each compound produced a similar inotropic effect as indicated by an increase in LV dp/dtmax. 4 In contrast to the direct stimulant action of ICI 118,587 on the heart no direct effects on vascular smooth muscle were observed. 5 ICI 118,587 was shown to be a competitive antagonist of the chronotropic and vasodilator effects of isoprenaline on the heart and blood vessels and of the chronotropic effects of noradrenaline on the heart. 6 It is concluded that ICI 118,587 is a selective beta 1-adrenoceptor partial agonist.

Adrenergic beta-Agonists↗
PubMed1981

Beta-adrenoceptor stimulant properties of amidoalkylamino-substituted 1-aryl-2-ethanols and 1-(aryloxy)-2-propanols.

Parallel series of 2-[(2-amidoethyl)amino]-1-arylethanols and 1-[(2-amidoethyl)amino]-3-(aryloxy)-2-propanols have been prepared, and the compounds were tested as beta-adrenoceptor stimulants on the heart and circulation of the dog. The corresponding 2-(alkylamino)-1-arylethanols and 3-(alkylamino)-2-propanols have been tested for comparison and the structure-activity relationships (SAR) examined. The arylethanols are potent full agonists, showing selectivity for the heart relative to blood vessels, while the (aryloxy)propanols are even more cardioselective and are partial agonists. Within a narrow series of 1-[(amidoethyl)amino]-3-(4-hydroxyphenoxy)-2-propanols, careful examination of the SAR of the amide group showed that great variation in cardioselectivity and degree of agonism may be produce. From this study ICI 118587, N-[20[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-4-morpholinecarboxamide, was selected for its high cardioselectivity and 50% agonist properties. This compound in under clinical evaluation as a cardiac stimulant.

Adrenergic beta-Agonists↗
PubMed1975

The assessment of acid-base disturbance in man by the use of carbon dioxide titration curves.

1. Carbon dioxide titration curves were determined in vivo in dog and man at various degrees of acute non-respiratory acidaemia and alkalaemia. 2. The slope of the CO2 titration curve (delta log Pco2/delta pH) was found to increase with the severity of the acute non-respiratory alkalaemia the slope (delta log Pco2/delta pH) tended towards unity. 3. A simple scheme based on the CO2 titration curves determined in vivo has been proposed for the assessment of acute acid-base disturbances in man. 4. Carbon dioxide titration curves were also determined in vivo in patients with chronic respiratory and non-respiratory acidaemia and it was found that these curves were not significantly different from those obtained in states of acute acid-base disturbances. It is therefore suggested that the scheme described in this paper is applicable to all acid-base disturbances.

Acid-Base Equilibrium↗
PubMed1975

Effect of destruction of the posterior pituitary on the diuresis from left atrial receptors.

1. In anaesthetized dogs, stimulation of atrial receptors after destruction of the pituitary gland results in a diuresis. This response was not abolished by the administration of bretylium tosylate and was also observed in a surgically denervated kidney. 2. The diuresis is qualitatively similar to that observed in anaesthetized dogs with intact pituitary glands. 3. It is concluded that the diuresis which results from stimulation of the left atrial receptors is mediated by a blood-borne agent which is not the antidiuretic hormone.

Animals↗
PubMed1975

Atrial receptors and heart rate: the efferent pathway.

1. Stimulation of left atrial receptors by distension of the junctions between the pulmonary veins and the left atrium is known to cause a reflex increase in heart rate. It was suggested that the efferent path of this reflex was solely in the sympathetic nerves to the heart but more recently the existence of a vagal efferent component has been postulated by Albrook, Bennion & Ledsome (1972). 3. The junctions between the pulmonary veins and the levt atrium were distended before and after the administration of I.C.I. 66082 and bretylium tosylate. The response of an increase in heart rate was significantly decreased after the administration of I.C.I. 66082 (5 mg/kg) and abolished after the administration of bretylium tosylate (10 mg/kg). 3. It is concluded that the efferent pathway of the reflex is solely in the sympathetic nerves to the heart.

Animals↗