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C Lillie

Publications and source records attributed to C Lillie.

At least 19 recordsLinked to original sources
PubMed1993

Assessment of a human recombinant manganese superoxide dismutase in models of inflammation.

We evaluated a novel human recombinant preparation of manganese superoxide dismutase (MnSOD) for anti-inflammatory and anti-oxidant activity compared with a copper zinc (CuZn) SOD preparation. The results showed that administration of MnSOD (50, 100 and 200 micrograms kg-1) in the Freund's Complete Adjuvant (FCA) mediated paw oedema model suppressed the inflammation at 4 hours by 43, 25 and 43% (P < 0.001, P < 0.01 and P < 0.001 at respective doses). However, 24 hours post-challenge, MnSOD (50 and 100 micrograms kg-1), suppressed the inflammation by 19% (P < 0.001). In contrast, Mn SOD at higher doses (400-800 micrograms kg-1; 2 mgkg-1) exacerbated the inflammatory response at 4 hours. This pro-inflammatory response declined progressively by 24 hours. Furthermore, CuZn SOD produced no significant effects on the inflammatory response. In the carrageenan-induced synovitis model, Mn SOD (25 and 50 micrograms; intra-articular administration) exacerbated the inflammation at 48 hours. In contrast, Mn SOD at 5 micrograms produced a significant suppression (44%, P < 0.05) in knee joint swelling at 24 hours. The CuZn SOD preparation produced marked pro-inflammatory effects in the joints whilst it lacked activity in the FCA-mediated paw oedema model. These findings support a therapeutic potential of MnSOD in inflammatory disorders, however the compound has a complex pharmaco-dynamic profile.

Animals↗
PubMed1991

Specific bradycardic agents. 2. Heteroaromatic modifications in the side chain of specific bradycardic benzazepinones: chemistry, pharmacology, and structure-activity relationships.

Compound 1 (UL-FS 49) has recently been described as the representative of a novel class of antiischemic compounds termed "specific bradycardic agents". In search of specific bradycardic agents with different pharmacokinetic profiles, heteroaromatic analogues of 1 have been synthesized and evaluated for their bradycardic activity, selectivity, and duration of action. The chain length n and the nature of the heteroaromatic system of compounds 2 strongly determine the biological activities. Unsubstituted benzothiophenes and benzofurans in combination with a chain length of n = 2 give the most active bradycardic compounds. Some of the new compounds combine high bradycardic potency and selectivity with a short duration of action and may thus be useful for the development of short-acting specific bradycardic drugs.

Animals↗
PubMed1990

Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a-new class of compounds exerting antiischemic properties.

Structural modification of the calcium-antagonist verapamil (1) by replacement of the lipophilic alpha-isopropylacetonitrile moiety by various heterocyclic ring systems has led to a new class of cardiovascular compounds which are characterized by a specific bradycardic activity. These agents reduce heart rate without binding to classical calcium channels or beta-adrenoceptors, interacting instead specifically with structures at the sino atrial node. Therefore they have also been termed sinus node inhibitors. The prototype falipamil (2) has been submitted to further optimization mainly by manipulation of the phthalmidine moiety. This has resulted in a second generation of specific bradycardic agents with increased potency and selectively and prolonged duration of action represented by the benzazepinone-derivative UL-FS 49 (4). Structure-activity relationships within this novel class of compounds have revealed a marked dependence of activity on the substitution pattern of the aromatic rings, the nature of the central nitrogen atom, and the length of the connecting alkyl chains. The crucial role of the benzazepinone ring for bradycardic activity can be best explained by its special impact on the overall molecular conformation.

Animals↗
PubMed1988

Effects of alinidine on survival and infarct size in rats with coronary artery occlusion.

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats. One group had coronary occlusion for 3 h while ligation lasted for 30 min in a second group and was followed by a 150-min reperfusion period. The area at risk and area of infarction were determined immediately after premature death or 3 h after the ligature was set, by means of Evans blue and triphenyltetrazoliumchloride staining and subsequent photometric quantification. Saline or alinidine (5 mg/kg i.v.) was administered 15 min prior to ligation. The alinidine groups received a further 0.5 mg/kg i.v. 1 and 2 h after ligation. A large number of animals in the control groups died during the first 30 min. The animals that survived 3 h had a smaller area at risk than those dying prematurely and about 100% of the area at risk became infarcted. All animals in the two alinidine groups survived the first 30 min. All these animals survived with a larger area at risk than the control groups. The area of infarction in relation to the area at risk was significantly smaller than in the control groups. The cardioprotective effects of alinidine may be explained by a reduction in heart rate and a slight reduction in blood pressure.

Animals↗
PubMed1987

Investigations differentiating the mechanism of specific bradycardic agents from that of calcium channel blockers.

The effects of two "specific bradycardic agents", falipamil (AQ-A 39) and the alinidine-congener STH 2148 (2-[N-(cyclopropylmethyl)-N-(2,6-dibromophenyl)amino]-2-imidazolin e), on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated in comparison to that of the "calcium channel blocker" verapamil. Addition of falipamil (10 micrograms/ml) to a maximally rate lowering concentration of STH 2148 (30 micrograms/ml) exerted no further bradycardic effect. In contrast, verapamil (0.1 microgram/ml) added to either STH 2148 (30 micrograms/ml) or a maximally effective concentration of falipamil (30 micrograms/ml) resulted in a further, significant reduction of sinus rate. The results are compatible with the idea of a common mechanism of the two specific bradycardic agents, different from that of calcium channel blockers.

Animals↗
PubMed1987

Specific bradycardic agents--a novel pharmacological class?

Data have been reviewed and presented which suggest that substances from two different chemical groups, congeners of alinidine and falipamil, respectively, can be described as representatives of a novel and distinct pharmacological class: specific bradycardic agents (SBAs). They are characterized by a slowing of the sinus rate within physiological limits as the prominent cardiovascular effect. Involvement of alpha-adrenoceptors, beta-adrenoceptors and cholinergic receptors as mediators of the bradycardic effects have been excluded. Experiments in isolated atrial preparations suggested that drugs of the same type as alinidine or as falipamil have a similar mode of rate lowering action which is different from that of Ca-channel blockers: low external Ca2+ increased and low Na+ as well as high K+ decreased the bradycardic effect of SBA; verapamil behaved in the opposite way. Combination of different SBAs did not result in excessive additive rate-lowering effects; in contrast, addition of verapamil to maximally acting concentrations of SBAs resulted in a further significant reduction in rate. SBAs were much more potent in reducing spontaneous sinus rate than in reducing BaCl2 induced automaticity, whereas Ca-channel blockers behaved in the opposite way. Differences in the cardiovascular profile against other drugs with rate lowering effects have been pointed out: beta-adrenoceptor blocking agents more markedly decrease contractility and Ca-channel blocking agents more markedly decrease contractility, slow down AV conduction and have vasorelaxing properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Antifibrillatory properties of alinidine after coronary artery occlusion in rats.

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats and mortality as well as changes in ECG were evaluated for 30 min thereafter. Saline or drugs were administered 15 min prior to ligation. In the control group, following a 4 min lag period ventricular arrhythmias as single ectopic beats, ventricular tachycardia and ventricular fibrillation (VF) appeared, reaching a maximum between 10 and 20 min and disappearing after 30 min. Mortality (40% in the control group) coincided with the period of maximal arrhythmias, with VF more common in animals that died than in those surviving. Alinidine, a drug which reduces sino-atrial rate specifically but has no conventional antiarrhythmic properties, reduced mortality and VF. By means of order statistics the quantity 'risk of death' was used for evaluation of drug effects, considering incidence of death and VF as well as duration of VF. This quantity was reduced in correlation with the dose of alinidine (1-6 mg/kg i.v.) and in correlation with the reduction of heart rate. Mexiletine, an antiarrhythmic drug with membrane-depressant properties, also reduced the 'risk of death' dose dependently (1-10 mg/kg i.v.), but there was no correlation with a decrease in heart rate. It is suggested that alinidine reduced 'risk of death' by means of a reduced oxygen demand due to a decrease in heart rate.

Animals↗
PubMed1985

Investigations into the bradycardic action of indoramin.

Indoramin is a selective alpha 1-antagonist which reduces blood pressure without reflex tachycardia and can cause a bradycardia. The direct bradycardic effect of indoramin was investigated in various isolated cardiac preparations as well as in the intact cat. In isolated guinea-pig atria indoramin reduced spontaneous atrial rate in concentrations similar to those that reduced maximal driving frequency but smaller than those reducing contractility (EC30 = 0.9, 1.3 and 5.2 micrograms/ml, respectively). In the isolated perfused electrically driven (2.5 Hz) guinea-pig heart, indoramin 1 microgram/ml mainly increased ST interval with no effect on QRS interval, higher concentrations (3 micrograms/ml) also increased the QRS interval. In anaesthetized cats indoramin 6 mg/kg i.v. reduced blood pressure and heart rate (increased cycle length), increased the ST interval and effective refractory period (measured by electrical stimuli from the right ventricle) but had little or no effect on the QRS interval and the diastolic stimulation threshold. With the 10 mg/kg dose the latter two parameters were increased. Analogous experiments with the antiarrhythmic drug mexiletine (class I) showed little changes in cycle length, effective refractory period and the ST interval, however, there was a marked increase in diastolic threshold. DL-sotalol, which as well as having a beta-adrenoceptor blocking action, also prolongs action potential duration (class III antiarrhythmic activity), had the same cardiac profile as indoramin. For both indoramin and sotalol a significant positive correlation was shown between increase in cycle length and increase in effective refractory period. It is suggested that indoramin exerts class III antiarrhythmic activity and that this property is responsible for the bradycardic action of the drug which is seen in doses that already markedly reduce blood pressure. In higher doses or concentrations indoramin also exerts class I antiarrhythmic activity which, however, does not contribute to the bradycardic effect.

Animals↗
PubMed1984

Cardiovascular characterization of UL-FS 49, 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-][2-(3,4-dimethoxyphenyl)ethyl] methylimino]propyl]-2H-3-benzazepin-2-on hydrochloride, a new "specific bradycardic agent".

UL-FS 49, a chemical congener of AQ-A 39 with structural similarities to verapamil, decreased the rate of spontaneously beating guinea-pig atria at much lower concentrations (effective concentration 30%, EC30 = 0.030 microgram/ml) than it decreased the contractility (2.5 Hz; EC30 = 108 micrograms/ml) and maximal driving frequency (EC30 = 11 micrograms/ml) in electrically driven atria. In comparable experiments AQ-A 39 was much less effective, the EC30 for the negative chronotropic effect being 0.61 microgram/ml. In rabbit aortic strips in the presence of 43 mM K+ and 1.8 mM Ca2+, UL-FS 49 relaxed contraction by 30% at 15 micrograms/ml. In contrast to UL-FS 49, several "Ca2+-antagonists" elicited aortic relaxation at lower concentrations than bradycardia. In anaesthetized cats (n = 6) 0.3 mg/kg i.v., UL-FS 49 increased the cardiac cycle length by 56 +/- 3.5% (S.E.), there were slight or no changes in blood pressure and ECG intervals PQ and QRS. ST and the effective refractory period (ERP), as determined by R-triggered extrastimuli in the right ventricle, were prolonged by 28 +/- 3.1% and 24 +/- 2.5% respectively. At comparable increases in cycle length AQ-A 39 prolonged ST and ERP significantly more than UL-FS 49. In isolated guinea-pig atria UL-FS 49 antagonized the carbachol-induced bradycardia; a 10-fold shift of the dose-response curve (CA10) was achieved with 11.3 micrograms/ml and the CA10 for AQ-A 39 was 1.7 micrograms/ml. In conscious dogs UL-FS 49, 1 mg/kg i.v., decreased the heart rate without changes in blood pressure. This was observed in dogs with both genuine sinus rate and heart rate elevated by either atropine or hydralazine. The bradycardic effect was positively correlated with the control heart rate. In conclusion, sinus bradycardia was the most prominent action of UL-FS 49 in isolated preparations as well as in intact animals. In comparison to its congener AQ-A 39, UL-FS 49 was more potent in lowering heart rate but less effective in prolonging repolarization time and in anticholinergic activity. It thus represents a new specific bradycardic agent.

Animals↗
PubMed1984

Effects of peripheral alpha 1- and alpha 2-adrenoceptor agonists on baroreceptor responsiveness in conscious dogs.

Baroreceptor responsiveness was investigated in conscious dogs following increasing doses (i.v.) of the selective alpha-adrenoceptor agonists methoxamine (alpha 1) and oxymetazoline (alpha 2), in the presence and absence of beta-adrenoceptor blockade. The study was repeated in another group of dogs with background afferent baroreceptor nerve activity reduced by continuous infusion of sodium nitroprusside. Both agonists dose dependently increased mean arterial pressure and reflexly decreased heart rate. In dogs pretreated with a beta-adrenoceptor antagonist a correlation between increase in mean arterial pressure (increase up to 70 mmHg) and increase in heart period (baroreceptor responsiveness) indicated no difference in the regression lines between methoxamine and oxymetazoline for both the normotensive and the sodium nitroprusside groups. However, in the dogs not pretreated with a beta-adrenoceptor antagonist the slope of the regression line for oxymetazoline was steeper than that for methoxamine (P less than 0.01) in the normotensive group. In the sodium nitroprusside group the regression line for oxymetazoline was situated significantly to the left of the methoxamine line (P less than 0.05). It is suggested that this greater bradycardic response to the alpha 2-adrenoceptor agonist oxymetazoline was caused by suppression of the cardiac sympathetic component (presynaptic modulation of noradrenaline release) in addition to the vagal activation and the sympathetic withdrawal component of the reflex. This indicates that drugs with alpha 2-adrenoceptor agonistic activity can influence a reflex physiological situation under conditions of low sympathetic nerve activity.

Adrenergic alpha-Agonists↗
PubMed1984

Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration.

The effects of the two "specific bradycardic agents" AQ-A 39 and alinidine on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated. At high external K+-concentrations (10.8 and 16.2 mmol/l) the bradycardic effect of the two drugs was diminished or abolished. In contrast, the negative chronotropic effect of the reference compound verapamil ("Ca2+-antagonist") was enhanced. These results show that the bradycardic effects of AQ-A 39 and alinidine are diminished in depolarized preparations, which makes it unlikely that in intact sinus node preparations the mechanism of action is the same as that of "Ca2+-antagonists".

Animals↗
PubMed1983

Comparison of the bradycardic effects of alinidine (St 567), AQ-A 39 and verapamil on guinea-pig sinoatrial node superfused with different Ca2+ and NaCl solutions.

Two new substances, alinidine (St 567) and AQ-A 39, previously described as 'specific bradycardic agents' were investigated with respect to their effects on the rate of electrical discharges from sinus nodes of isolated right guinea-pig atria. Both substances decreased the discharge rate concentration dependently within a wide range (3-100 micrograms/ml). Low external Ca2+ (0.18 mM) increased and low external NaCl (62 mM) decreased the rate lowering effect of alinidine as well as of AQ-A 39. In contrast, the reference compound verapamil (an inhibitor of slow inward current) was less effective in low Ca2+ and more effective in low NaCl. The similar reactions of alinidine and AQ-A 39 are discussed with respect to their different chemical structure and different electrophysiological action patterns as described so far.

Animals↗
PubMed1981

AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine), a specific bradycardic agent with direct action on the heart.

In isolated guinea-pig atria AQ-A 39 (5,6-dimethoxy-2[3[[alpha-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine) decreased the rate of spontaneously beating preparations, the contraction amplitude and maximal driving frequency of electrically driven preparations. However, the concentrations which reduced the parameters by 30% were different: 1.4 microgram/ml, 110 microgram/ml and 19 microgram/ml respectively. The bradycardic action was not affected by atropine (0.05 microgram/ml). In the ECG of anaesthetized cats (0.1-10 mg/kg i.v.) the prominent effect of AQ-A 39 was the increase in heart period (PP') and QT in contrast to the chemically related verapamil which mainly increased PQ. Blood pressure and ejection time were slightly affected whereas the diastolic period was markedly prolonged (5 mg/kg i.v.). The 'triple product' of heart rate X ejection time X blood pressure was decreased by AQ-A 39. In cats with acute occlusion of a coronary artery branch, AQ-A 39 diminished the elevation of the ST-segment of the epicardial electrogram. AQ-A 39 decreased the heart rate in conscious dogs (5 mg/kg i.v.), provided the initial heart rate was higher than approximately 130 beats/min, but increased the heart rate when the initial rates were lower. The drug revealed an anticholinergic effect by antagonising the bradycardic action of carbachol on isolated atria from guinea pigs. The prevalent effect on heart rate differentiated AQ-A 39 from other drugs with direct action on the heart such as antiarrhythmics, the so-called 'calcium antagonists' and cholinergic drugs. The profile resembled that of alinidine (St 567) and indicated a decrease in myocardial oxygen demand.

Animals↗
PubMed1980

Chemistry, pharmacology, and structure-activity relationships with a new type of imidazolines exerting a specific bradycardic action at a cardiac site.

The reaction of alkyl halides with 2-(arylimino)imidazolidines (I) leads to imidazoline derivatives II, in which the side chain is situated at the bridge nitrogen atom between the phenyl group and the imidazoline ring. The new imidazolines (II) exert a specific bradycardic action at a cardiac site. Syntheses and pharmacology are shown and structure-activity relationships discussed. The results reveal that the imidazoline derivatives (II) represent a class of compounds with a novel type of cardiac action.

Animals↗
PubMed1980

Central cardiovascular alpha-adrenoceptors. Relation to peripheral receptors.

Clonidine and related drugs cause a specific pattern of cardiovascular depression by an agonistic effect on alpha-adrenoceptors within the central nervous system (CNS). For further characterization of the central adrenoceptors, the actions of three substances of the "clonidine-type" derived from two different chemical groups were studied at peripheral vascular sites. Clonidine and two azepin derivatives had very weak vasoconstrictor activity in isolated perfused rat hindquarters. Signs of desensitization were observed when these drugs were administered repeatedly. However, these compounds exerted antagonism against the vasoconstricting effect of noradrenaline. The ranking order of these drugs in their antagonistic potency was the same as with their central cardiovascular depressor potency. In spinal rats, the three compounds raised blood pressure due to their alpha-adrenoceptor stimulation. The ranking order was the same for the pressor potency as for their central cardiovascular depressor potency. It is concluded that in isolated preparations the agonistic activity of clonidine-like substances on postsynaptic alpha-adrenoceptors might not be representative for their CNS effect.

Animals↗