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Biomedical subjects

G Allan

Publications and source records attributed to G Allan.

At least 109 records · Page 6Linked to original sources
PubMed1987

BW A575C: pharmacological profile in vivo of a novel angiotensin converting enzyme inhibitor and beta-blocker.

The novel compound BW A575C, N-(1-(S)-carboxy-5-[4-(3-isopropylamino-2-(R,S)-hydroxypropoxy)-indole-2 - carboxamido]pentyl)-(R,S)-alanyl-(S)-proline, is a potent angiotensin converting enzyme (ACE) inhibitor and beta-blocker in vitro. It was therefore of considerable interest to establish whether this novel pharmacological profile was maintained in vivo. In conscious instrumented normotensive rats and dogs, intravenous and oral administration of BW A575C causes a dose-dependent rightward displacement of the pressor dose-response curve to angiotensin I (dose ratio of 29.5 and 16.1 in rats and dogs, respectively, at 1.0 mg/kg i.v.) and the tachycardia dose-response curve to isoprenaline (dose ratio of 3.1 and 8.0 in rats and dogs, respectively, at 1.0 mg/kg i.v.). In these experiments BW A575C is approximately 2-10 times more active as an ACE inhibitor than as a beta-blocker. In conscious instrumented acute renovascular hypertensive dogs, where plasma renin activity is elevated 10-fold, BW A575C (1.0 mg/kg i.v.) causes a reduction in blood pressure of 35% within 10 min of injection, which is sustained for up to 4 h. This reduction in blood pressure is accompanied by a consistent, but nonsignificant, reduction in heart rate. These results confirm the novel pharmacological profile of BW A575C in vivo and demonstrate that this compound is an effective antihypertensive agent in a renin-dependent model of hypertension.

Adrenergic beta-Antagonists↗
PubMed1987

BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and beta-adrenoceptor-blocking properties.

BW A575C (N-(1-(S)-carboxy-5-[4(3-isopropylamino-2-(R, S)-hydroxypropoxy)indole-2- carboxamido]pentyl)-(R, S)-alanyl-(S)-proline) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and beta-adrenoceptor-blocking properties. BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea-pig right atrial preparation (pKB 7.18 +/- 0.05, cf. pindolol 8.9 +/- 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 +/- 2.1 nM, cf. enalaprilat, 4.4 +/- 0.8 nM). Intravenous administration of BW A575C (1-100 micrograms kg-1 min-1) to the pithed rat inhibited in a dose-dependent fashion both angiotensin I-induced pressor responses and isoprenaline-induced tachycardia. Dose-ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a beta-adrenoceptor blocking agent. Intravenous administration of BW A575C (1 mg kg-1) to the conscious rat inhibited angiotensin I-induced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril. Intravenous administration of BW A575C (1 mg kg-1) to either conscious dogs or rats inhibited both angiotensin I-induced pressor responses and isoprenaline-induced heart rate responses. Dose-ratios obtained from such studies demonstrated that in these species, BW A575C was 2-10 times more active as an ACE inhibitor than as a beta-adrenoceptor blocking agent.

Adrenergic beta-Antagonists↗
PubMed1987

Effects of BW A256C, a novel class 1 antiarrhythmic agent, on maximum rate of depolarisation of cardiac action potentials in vitro: frequency, use, and voltage dependence.

The frequency, use, and voltage-dependence of the effects of a novel antiarrhythmic agent, BW A256C, on the maximum rate of depolarization (Vmax) of action potentials in guinea-pig right ventricle were studied using standard microelectrode recording techniques in vitro. BW A256C (10(-6) M) reduced Vmax in a frequency-dependent way in the range 0.33-3.3 Hz; the maximum reduction was at the highest frequency. BW A256C did not cause resting block of Vmax. The onset of use-dependent Vmax reduction at 3.3 Hz followed a monoexponential function with a very slow rate constant, 0.019 +/- 0.003 AP-1. The recovery from use-dependent reduction, studied by applying single extra stimuli at various times after trains of stimuli at 3.3 Hz, was also very slow; half-life (t 1/2) for recovery was 119.0 +/- 19.2 s, and the time constant tre was 171.7 +/- 27.7 s. For comparison, the values for Flecainide (10(-5) M), obtained under identical conditions, were: rateon, 0.106 +/- 0.010 AP-1; t 1/2, 7.68 +/- 0.20 s; tre 11.07 +/- 0.29 s (means +/- SEM). In the presence of BW A256C (10(-6) M), the normalised diastolic membrane potential-Vmax curve was significantly shifted in the hyperpolarizing direction. The mean shift was 5.5 +/- 1.1 mV, measured at the 50% reduction of Vmax level. BW A256C is therefore classified as a novel "slow" class 1C antiarrhythmic agent.

Action Potentials↗
PubMed1986

BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents.

BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2 -isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 X 10(-6) M and 1.8 X 10(-6) M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-1) caused a dose-dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. In conscious dogs, intravenous infusion (total dose, 1.5 mg kg-1) or oral administration of BW A256C (1.25-5 mg kg-1) caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity.

Aconitine↗
PubMed1986

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion.

Haemorrhagic shock was induced in anaesthetized, open-chest dogs by controlled arterial bleeding, sufficient to reduce and maintain mean arterial blood pressure at 40 mmHg for 30 min. The blood volume was then restored to the pre-shock level by rapid, intravenous reinfusion of the blood shed during the shock period. Haemorrhagic shock produced significant haemodynamic changes, characterized by a marked depression of myocardial function. Cardiac output (1226 +/- 57 ml min-1), peak aortic blood flow (6030 +/- 383 ml min-1) and maximum rate of rise of left ventricular pressure (2708 +/- 264 mmHg s-1) were all reduced by more than 50%. The haemodynamic profile was markedly improved by reinfusion of shed blood but this improvement was not sustained. There was a gradual decline such that 50% of the untreated animals suffered complete circulatory collapse and death between 60 and 120 min following reinfusion. Neither haemorrhagic shock, nor reinfusion of shed blood produced any consistent or significant changes in the myocardial adenine nucleotide pool. The ATP, ADP and AMP levels were, respectively, 25.9 +/- 4.2; 15.6 +/- 1.0; 4.3 +/- 1.9 nmol g-1 protein, before haemorrhagic shock; 21.6 +/- 3.4; 21.5 +/- 2.5; 10.2 +/- 2.7 nmol g-1 protein, after 30 min haemorrhagic shock; and 29.9 +/- 3.9; 16.5 +/- 1.2; 4.2 +/- 1.1 nmol g-1 protein, 60 min following reinfusion of shed blood. Pretreatment with allopurinol (50.0 mg kg-1 i.v.), 60 min before inducing haemorrhagic shock, had no significant effect upon the haemodynamic response to shock, but did prevent the gradual decline seen following reinfusion in the untreated animals. All of the allopurinol-treated animals displayed significantly better haemodynamic profiles than the untreated animals, furthermore, there was a 100% survival rate in this group. 5 Allopurinol had no significant effect upon the myocardial adenine nucleotide pool either during haemorrhagic shock or following reinfusion of shed blood.

Adenine Nucleotides↗
PubMed1986

Effects of an increase in haemoglobin O2 affinity produced by BW12C on myocardial function in the erythrocyte-perfused rabbit heart in vitro and myocardial infarct size in the dog.

The effects of BW12C on myocardial function in the erythrocyte-perfused rabbit heart and on myocardial infarct size in the anaesthetized dog have been evaluated. Perfusion of rabbit hearts with erythrocytes pretreated with BW12C (10(-3) M-4 X 10(-3) M) produced concentration-dependent decreases in left ventricular pressure (LVP), LVP dP/dt and coronary perfusion pressure. A concomitant decrease in PO2 and an increase in lactate production by the myocardium was also observed. Perfusion of rabbit hearts with Krebs Henseleit buffer containing BW12C (10(-5)-10(-4) M) caused no change in measured variables. Although BW12C (10(-3) M) caused a small decrease in LVP, coronary perfusion pressure and heart rate, these changes were not significant. In anaesthetized dogs, an infusion of BW12C (total dose 50 mg kg-1, i.v.) caused small, but significant, changes in haemodynamic status. The oxygen saturation curve was shifted to the left and relative % oxygenation (P20) was shifted to the left throughout the course of the experiment. (P20, control 16.3 +/- 0.4 mmHg; after BW12C 7.9 +/- 1.4 mmHg). Pretreatment with BW12C (total dose 50 mg kg-1) caused no change in area at risk but significantly increased the myocardial infarct size by 410%. These studies with BW12C demonstrate that alteration in haemoglobin-oxygen affinity can induce adaptive physiological changes in tissue function and metabolism and can assume a critical role when oxygen supply may be impaired due to a flow-limiting stenosis.

Aldehydes↗
PubMed1985

Naturally cytotoxic tonsillar leukocytes: phenotypic characterization of the effector population.

Human palatine tonsil sections were examined to investigate the distribution of cells bearing the cell surface markers of peripheral blood natural killer (PB-NK) cells. Leu-7+ (HNK-1+) cells were localized predominantly in lymphoid follicles, whereas OKM1-, Mac-1-, and Mo2-labelled cells were found in the epithelial and subepithelial regions and epithelial crypts. OKT10+ cells showed a variable distribution, being found in follicles and interfollicular or subepithelial regions. No. B73.1+ cells could be identified in tonsil sections. Leu-7+ cells appeared not to be responsible for tonsillar natural cytotoxicity, since Leu-7 (HNK-1) antibody- and complement-mediated lysis under conditions that markedly reduced PB-NK activity failed to abolish cytotoxicity, and positive selection by means of the FACS IV gave no enrichment of activity. Similarly, cells labelled with the antibodies B73.1, Leu-11b, OKT8, OKT10, and TDR 31.1 (anti-major histocompatibility complex class II framework determinant) were not enriched with regard to NK activity either. However, positive selection with OKM1, Mac-1, or Mo2 showed that cells bearing these markers were responsible for essentially all tonsillar NK activity. No large granular lymphocytes were identified in such populations enriched for NK activity. The observation that PB-NK cells labelled faintly with Mo2 weakens the argument that a non-adherent mononuclear phagocyte population was responsible for the activity. These data therefore support the existence of heterogeneity within naturally cytotoxic cell populations.

Antibodies, Monoclonal↗
PubMed1985

The cardiovascular and platelet actions of 9 beta-methyl carbacyclin (ciprostene), a chemically stable analogue of prostacyclin, in the dog and monkey.

9 beta-Methyl carbacyclin (9 beta Me; ciprostene) is a synthetic, chemically stable analogue of prostacyclin (PGI2; epoprostenol). The platelet anti-aggregating and cardiovascular effects of 9 beta Me have been compared to PGI2 in anaesthetized monkeys and dogs. In addition, their haemodynamic effects have been compared in open-chest anaesthetized dogs and conscious dogs. Intravenous infusion of 9 beta Me and PGI2 to the anaesthetized monkey resulted in a dose-dependent hypotension, tachycardia and inhibition of ex vivo ADP-induced platelet aggregation. 9 beta Me was 72 times less active than PGI2 both as a hypotensive and anti-aggregating agent. Intravenous infusion of 9 beta Me and PGI2 to the anaesthetized beagle dog resulted in a qualitatively similar haemodynamic profile. Thus both substances induced a dose-dependent hypotension accompanied initially by a slightly increased heart rate, a dose-dependent increase in cardiac output, stroke volume and an increased peak LV dP/dt. At the higher doses studied, the initial increases in the parameters measured were succeeded by dose-dependent falls. 9 beta Me was 76 times less active than PGI2 as a hypotensive agent. In the anaesthetized greyhound, a dose-dependent anti-aggregating and hypotensive effect was seen with either drug, with 9 beta Me being 23 and 40 times less active than PGI2, respectively. Intravenous infusion of 9 beta Me and PGI2 to the conscious beagle dog induced a dose-dependent hypotension and a variable effect on heart rate. 9 beta Me was 33 times less active than PGI2 as an hypotensive agent. The duration of the hypotensive response induced by 9PMe was not significantly different from that induced by PGI2 in either monkey or beagle dog.

Adenosine Diphosphate↗
PubMed1984

A double-blind randomized trial of cimetidine in acute upper gastrointestinal bleeding.

Two hundred and thirteen patients were studied in a double-blind trial of cimetidine versus placebo in the treatment of acute upper gastrointestinal haemorrhage. One hundred and six patients were randomly allocated to receive cimetidine and 107 to receive placebo. There was no significant reduction in transfusion requirements, incidence of further haemorrhage, length of stay in hospital, or mortality in the treated group. There was no subgroup of patients with acute upper gastrointestinal bleeding which appeared to benefit from treatment with cimetidine.

Adolescent↗
PubMed1983

Aberrant replication of chromosomal DNA segments in CHO cells as a manifestation of a DNA repair system.

We have previously demonstrated that transient blocking of DNA synthesis with drugs such as 1-beta-D-arabinofuranosylcytosine results in some segments of the chromosomal DNA being replicated more than once in a single cell cycle. One explanation for this phenomenon might be that it is due to a perturbation of the cellular mechanism which normally controls the process of initiating replication of the chromosomal DNA and which ensures that each DNA segment is normally replicated once only in each cell cycle. To examine an alternative explanation, we have used the Chinese hamster ovary CHO-K1 cell line to test whether UV irradiation induces aberrant double replication of chromosomal DNA segments. We present data which show that UV irradiation induces a linear increase (regression coefficient, 0.996) in aberrant reinitiation of DNA replication in DNA segments replicated earlier in the same cell cycle. This was shown by DNA strands labelled with bromodeoxyuridine (BrdU) being synthesized off 3H-labelled template strands which were themselves synthesized during a [3H]thymidine pulse shortly before the UV irradiation. We suggest that blocked replication forks trigger an emergency response to unreplicated DNA segments in which abnormal origins of replication are used to circumvent this damage. This results in abnormal patterns of DNA replication, and it occurs whether DNA replication forks are blocked metabolically (such as with an inhibitor of DNA polymerase) or physically (as in the case of pyrimidine dimers).

Animals↗