PubMed Health⌕ Search

Biomedical subjects

D T Burden

Publications and source records attributed to D T Burden.

12 recordsLinked to original sources
PubMed1991

Inhibition by Ro 31-6930 of agonist and allergen induced bronchoconstriction in anaesthetised guinea-pigs and cats.

Ro 31-6930, a potent smooth muscle relaxant from the novel class of potassium channel openers, has been compared with BRL 38227, salmeterol and theophylline in a range of models of airway function. Ro 31-6930 relaxed isolated tracheal muscle from sensitised guinea-pigs which had been contracted by ovalbumin and was equipotent with salmeterol in inhibiting antigen-induced bronchospasm in anaesthetised, sensitised guinea-pigs. In both anaesthetised guinea-pig and cat, Ro 31-6930, BRL 38227 and theophylline were more potent against 5-HT evoked increases in lung resistance than they were on falls in dynamic compliance. Although salmeterol had equivalent activity on both parameters it is unlikely that the small difference seen with the other compounds reflect a preferential effect on large airways. In addition, Ro 31-6930 was an effective bronchodilator when given by inhalation to the anaesthetised guinea-pig. In view of the protective activity of Ro 31-6930 against antigen challenge in the sensitised guinea-pig and its potency in relation to other bronchodilators, it is considered that compounds which relax airway smooth muscle by the opening of plasmalemmal potassium channels may have a role in the treatment of asthma.

Aerosols↗
PubMed1990

Preclinical pharmacology of Ro 31-6930, a new potassium channel opener.

The present study compares the effects of Ro 31-6930, a novel potassium channel opener, with those of cromakalim and nitrendipine on blood pressure and other haemodynamic parameters. In conscious, spontaneously hypertensive rats (SHR) the oral dose of Ro 31-6930 for lowering blood pressure was 10 times lower than that of cromakalim and some 100 times lower than that of nitrendipine. In addition, the duration of antihypertensive activity of Ro 31-6930 was longer than that of cromakalim or nitrendipine. The tachycardia evoked by Ro 31-6930 and cromakalim was of shorter duration than the antihypertensive effect of either agent. In a repeat, once daily dosing experiment no tolerance was observed to the antihypertensive effect of Ro 31-6930 over a 22-day period. In conscious normotensive cats Ro 31-6930 was 10 times more potent than cromakalim and 1,000 times more potent than nitrendipine in reducing blood pressure. The duration of hypotensive activity was in excess of 5 h for each agent. In anaesthetised dogs all three agents reduced mean arterial pressure (MAP) and total peripheral resistance (TPR), while increasing cardiac output (CO) via a rise in stroke volume (SV). Both Ro 31-6930 and cromakalim significantly reduced femoral (FVR) and mesenteric vascular resistances (MVR), while only cromakalim reduced renal vascular resistance (RVR). Ro 31-6930 is a potent new antihypertensive agent that compares favourably with cromakalim and nitrendipine.

Anesthesia↗
PubMed1984

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1. Structure-activity relationships are discussed, and the optimum position of the heteroatom in the 4-substituent is defined.

Adrenergic beta-Antagonists↗
PubMed1983

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1976

Hypotensive responses following oral adminstration of beta-adrenoceptor blocking drugs to the conscious cat.

On oral administration, the non-selective beta-adrenoceptor blocking drugs (+/-)-bufuralol, (-)-bufuralol, propanolol, oxprenolol, pindolol and alprenolol produced hypotensive responses in the conscious cat; (+)-bufuralol was without effect. The selective beta-adrenoceptor blocking drugs practolol and atenolol had no effect on blood pressure but tolamolol elicited a hypotensive response. All the drugs tested reduced the tachycardia due to intravenous isoprenaline in the conscious cat; however, not all doses of these drugs reduced blood pressure. (+)-Bufuralol was devoid to beta-adrenoceptive blocking activity. Only tolamolol reduced the pressor response to i.v. phenylephrine in the conscious cat, indicating that alpha-adrenoceptive blocking activity may contribute to its hypotensive action. The results suggest that beta-adrenoceptive blocking activity is necessary for the hypotensive responses of these drugs. However, for the different drugs, there was no correlation between peripheral beta-adrenoceptive blocking activity and hypotensive response.

Adrenergic alpha-Antagonists↗
PubMed1975

An investigation of the tachycardia produced by intracerebro-ventricular injections of isoprenaline in mice.

1. Isoprenaline, 3.5-20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose-dependent tachycardia. 2. Pretreatment with either reserpine or pempidine blocked nervously-mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated. 3. Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline. 4. When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose-dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation. 5. This was confirmed by the appearance of a late-developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice. 6. It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.

Adrenal Glands↗
PubMed1972

Assessment of the effectiveness of -adrenoceptor blocking agents towards cardiac and bronchiolar responses of the pithed guinea-pig to electrical stimulation of the spinal outflow.

1. The responses of heart rate and resistance to lung inflation of the pithed guinea-pig on electrical stimulation of the thoracic spinal roots could be related to similar responses to injected catecholamines, such that dose-stimulus frequency relations could be plotted.2. The range of frequency of stimulation that was equi-effective with a dose range of injected catecholamines was higher for effects on air overflow than for heart rate. The slope of the relations for heart rate also differed from that for air overflow. These features may reflect a difference in effectiveness of the sympathetic innervation of heart and bronchial tree.3. Propranolol was equally effective in reducing the responses of heart rate and air overflow to injected noradrenaline. Practolol was somewhat more active against the effects of noradrenaline on air overflow than on heart rate, though equally active against the effects of isoprenaline.4. For the assessment of equivalent blockade of the effects of cord stimulation on heart rate and air overflow, frequency-ratios corresponding to a noradrenaline dose-ratio of 2 were derived from the slopes of the dose-frequency relations; for air overflow this value was approximately 2 and for heart rate approximately 1.4.5. When the doses required to produce these degrees of blockade were computed from the dose-response relations for blockade of the effects of cord stimulation by propranolol, they were found to be similar for effects on heart rate and air overflow. For practolol, the effective dose for block of heart rate increase was found to be lower than that for air overflow.

Acetanilides↗
PubMed1971

Effect of beta-adrenoceptive blocking agents on the response to bronchoconstrictor drugs in the guinea-pig air overflow preparation. Appendix describing a new modification of the air overflow method.

1. Propranolol augmented the bronchoconstrictor response to methacholine or histamine, recorded by air overflow in the anaesthetized, vagotomized guinea-pig.2. After adrenalectomy, propranolol was still active, though less so than before.3. In the pithed guinea-pig, there was no augmentation of the effect of bronchoconstrictors on air overflow. The action of propranolol could thus be due to the beta-adrenoceptor blockade of compensatory sympathetic bronchodilator activity, as concluded by McCulloch, Proctor & Rand (1967).4. Electrical stimulation of the thoracic region of the spinal cord of the pithed guinea-pig reduced the effect of bronchoconstrictors on air overflow. This reduction could be blocked by propranolol; practolol was much less effective.

Acetanilides↗
PubMedDate not supplied

The in vivo examination of the irreversible beta-adrenoceptor antagonist Ro 03-7894 on cardiac rate and contractility.

1. Two benzofuran-2-ethanolamines Ro 03-5255 (1-(5-acetylamino-benzofuran-2-yl)-1-hydroxy-2-isopropylaminoethane) and Ro 03-7894 (1-(5-chloracetyl aminobenzofuran-2-yl)-1-hydroxy-2-isopropylaminoethane) which had previously been shown to exhibit respectively competitive and irreversible beta-adrenoceptor antagonism in guinea-pig isolated atria, were compared in vivo using isoprenaline-induced tachycardia of anaesthetized guinea-pigs and heart rate and contractility (dp/dtmax) of open-chest anaesthetized guinea-pigs and of conscious cats. 2. In urethane-anaesthetized guinea-pigs doses of 3 mg/kg, s.c. of both antagonists produced significant blockade of the rate response to an 80% of maximum dose of isoprenaline after 4 h. In other experiments, guinea-pigs were pretreated with the antagonists and the responses to isoprenaline were then monitored. The slopes of the dose-response curves to isoprenaline were depressed for up to 24 h by Ro 03-7894 but this was not so with Ro 03-5255. 3. In conscious cats the course of blockade by Ro 03-7894 was followed in the same animals and was still evident after 48 h. In contrast, the beta-adrenoceptor blockage produced by Ro 03-5255 was not evident 24 h after administration. 4. The persistence of blockade by Ro 03-7894 was consistent with the irreversible mode of action demonstrated in vitro.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

The effects of bufuralol, a beta-adrenoceptor antagonist with predominant beta 2-adrenoceptor agonistic activity, in the cat and the dog.

The effects of bufuralol and its carbinol metabolite have been compared with those of propranolol in the anaesthetised and conscious cat and dog. Bufuralol and its carbinol metabolite are nonselective beta-adrenoceptor antagonists; the former has equivalent potency to propranolol, whereas the latter is six times more potent. In anaesthetised animals both bufuralol and its metabolite exhibited partial agonistic activity, resulting in tachycardia and vasodilation. In conscious cats there was no change in heart rate or slight bradycardia, whereas in dogs both compounds again produced tachycardia. In anaesthetised and conscious cats and conscious dogs, both bufuralol and the metabolite increased abdominal aortic blood flow. There was a reduction in blood pressure in the conscious dog. It is concluded that the partial agonistic activity of bufuralol and its carbinol metabolite is exerted mainly at the beta 2-adrenoceptor, producing vasodilation and reducing peripheral resistance, resulting in a reduction in blood pressure with a long duration of action.

Adrenergic beta-Agonists↗