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M G Collis

Publications and source records attributed to M G Collis.

At least 19 recordsLinked to original sources
PubMed1998

The effect of alpha 1 adrenoceptor antagonist prazosin on capillary supply, blood flow and performance in a rat model of chronic muscle ischaemia.

OBJECTIVE: This study explores whether the a1 blocker prazosin improves capillarisation, blood flow and muscle performance in chronically ischaemic muscles. DESIGN: Rat skeletal muscles were made ischaemic by unilateral ligation of the common iliac artery. The animals received prazosin and muscle blood flow, performance and capillary supply were studied 2 or 5 weeks later. MATERIALS AND METHODS: Prazosin (50 mg/l) was given in drinking water to animals with limited or intact blood supply. Muscle isometric twitch tension and fatigue index and blood flow at rest and during contractions (estimated by radio labelled microspheres) were measured in tibialis anterior, TA, and extensor digitorum longus, EDL. Capillary supply (capillary/fibre ratio, C/F) was estimated in frozen muscle sections stained for alkaline phosphatase in TA, EDL and soleus, S. RESULTS: Prazosin increased significantly capillary supply in ischaemic muscles after 2 and 5 weeks and blood flow during contractions (control muscles 163 +/- 6 ml. 100 g-1 min-1; ligated 2 weeks 25 +/- 7, ligated +prazosin 116 +/- 38 ; ligated 5 weeks 27 +/- 7, +prazosin 137 +/- 29, p < 0.05 vs. ligated). Fatigue index (final/peak tension over 5 min contractions at 4 Hz in %) was significantly improved by prazosin after 2 weeks (FI = 69 +/- 3% controls, 35 +/- 4% ligation, 60 +/- 3% ligation +prazosin) and less after 5 weeks (52 +/- 12% ligation, 61 +/- 3% ligation +prazosin). In contrast, prazosin had no effect on muscle performance in normal muscles in spite of it increased C/F and blood flow. CONCLUSIONS: Alpha1 adrenoceptor blockade is an effective way for improvement of capillary supply, blood flow and muscle performance in ischaemic muscles; the effect on muscle performance is most pronounced 2 weeks after induction of ischaemia.

Adrenergic alpha-Antagonists↗
PubMed1996

In vivo characterisation of ZM 241385, a selective adenosine A2A receptor antagonist.

The in vivo characterisation of ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-+ ++ylamino] ethyl)phenol), a novel, non-xanthine, selective adenosine A2A antagonist is described. In anaesthetised dogs ZM 241385 (i.v.) was 140-fold more potent in attenuating vasodilator responses to exogenous adenosine in the constant flow perfused hind limb than the bradycardic effects. In pithed rats in which blood pressure was supported by angiotensin II infusion, ZM 241385 (10 mg kg-1, i.v.) did not inhibit the hypotensive or bradycardic effects of the A3/A1 receptor agonist N(6)-2-(4-amino-3-iodophenyl)ethyladenosine (APNEA). In conscious spontaneously hypertensive rats, ZM 241385 (3-10 mg kg-1, p.o.) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine. No inhibition of the bradycardic effects of adenosine was observed following these doses of ZM 241385. The results indicate that ZM 241385 can be used to evaluate the role of adenosine A2A receptors in the action of adenosine in vivo.

Adenosine↗
PubMed1994

Myocardial infarction and purine transport inhibition in anaesthetised ferrets.

The potential cytoprotective effect of the purine transport inhibitor S-(p-nitrobenzyl)-6-thioinosine (NBTI) in a model of myocardial ischaemia and reperfusion was investigated in the anaesthetised ferret. The left anterior descending coronary artery (LAD) was occluded for 90 min, producing ischaemia in 53 +/- 3% of the left ventricular free wall, followed by 240 min reperfusion. NBTI (0.5 mg kg-1, i.v.) was given prior to ischaemia or prior to reperfusion. In addition the effect of purine transport inhibition was investigated in animals subjected to ischaemia without reperfusion. NBTI reduced infarct size from 84.0 +/- 1.7 to 71.4 +/- 3.7% of the area at risk (P < 0.05) when given prior to occlusion of the LAD. NBTI was ineffective however when given 15 min prior to reperfusion. NBTI had no effect upon infarct size produced by ischaemia without reperfusion. The effect of NBTI was independent of significant changes in myocardial blood flow during ischaemia and reperfusion or upon neutrophil infiltration.

Adenosine↗
PubMed1994

Characterization of adenosine receptors in the rat isolated aorta.

1. Adenosine and its analogues relaxed the isolated rat aorta by an endothelium-dependent mechanism with an order of potency of 5'-N-ethylcarboxamidoadenosine (NECA) > 2-(p-(2-carboxy-ethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > adenosine = N6-(2-(4-amino-phenyl)ethyl)adenosine (APNEA) = N6-cyclopentyladenosine (CPA) > 5'-methylthioadenosine (MTA), although the maximal response achieved by CGS 21680 was less than that achieved by NECA. 2. Both 8-sulphophenyltheophylline (8-SPT) and MTA antagonized responses to the adenosine analogues, but there were some anomolous features of this antagonism and NECA was inhibited more powerfully than the other agonists. This suggests that as well as A2a receptors mediating relaxation, the rat aorta may relax to adenosine analogues by other mechanisms.

Adenosine↗
PubMed1993

Adenosine receptor subtypes.

The numerous and widespread effects of adenosine provide both an opportunity for the development of novel therapeutic agents acting via adenosine receptors and the challenge of achieving selectivity of action. The feasibility of achieving selectivity is enhanced if receptor subtypes can be identified. Biochemical, functional and receptor-cloning studies are beginning to provide convergent data supporting the existence of A1, A2A, A2B and A3 receptors. However, studies of the functional significance of these receptors in intact tissues both in vitro and in vivo have lagged behind the biochemical studies. In this article, Michael Collis and Susanna Hourani review the current status of adenosine receptor classification and propose that ligands with greater selectivity need to be evaluated in a wide range of functional preparations if the therapeutic potential of this area is to be realized.

Adenosine↗
PubMed1992

Further characterization of the protective effect of 8-cyclopentyl-1,3-dipropylxanthine on glycerol-induced acute renal failure in the rat.

In the rat, treatment with the alkylxanthine 8-cyclopentyl-1,3-dipropylxanthine (CPX) at a dose of 0.1 mg kg-1 antagonizes adenosine-induced falls in renal blood flow and reduces the severity of glycerol-induced acute renal failure. Treatment of glycerol-injected rats with 0.03 mg kg-1 of CPX resulted in no significant improvements in a range of indices of renal function. However, treatment with 0.1 or 0.3 mg kg-1 doses of CPX did significantly ameliorate acute renal failure although there were no significant differences in the degree of protection of renal function afforded by these two doses. In glycerol-injected rats, 0.1 or 0.3 mg kg-1 CPX administered either as a single dose or repeated doses every 12 h for two days did not inhibit renal phosphodiesterase. Thus the beneficial effects of CPX can be produced by doses that have no effect on renal phosphodiesterase activity whereas 0.1 mg kg-1 of CPX has been shown previously to antagonize the actions of adenosine. The findings provide further evidence that the beneficial effect of CPX in glycerol-induced acute renal failure is a consequence of adenosine antagonism and not phosphodiesterase inhibition.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.

1. The effect of the selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of cisplatin-induced acute renal failure was investigated in the rat. 2. CPX at doses of 0.03, 0.1 and 0.3 mg kg-1, i.v. caused increasing degrees of antagonism of adenosine-induced bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or cisplatin. CPX at a dose of 0.03 mg kg-1 significantly antagonized adenosine-induced bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg-1 produced significant blockade for periods longer than 5 h. 3. Administration of cisplatin (6 mg kg-1, i.v.) caused acute renal failure characterized by decreased inulin and p-aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl- ions and by increased plasma levels of urea and creatinine. Kidney weight was increased in cisplatin-treated rats and renal tubule necrosis occurred. 4. Administration of CPX (0.03 mg kg-1, i.v.; twice daily for two days) to rats given cisplatin did not reduce the severity of the resultant renal failure. However, treatment with 0.1 mg kg-1 CPX attenuated the increases in plasma creatinine/urea levels observed in rats on days 3 and 7 after induction of renal failure. In addition, this dose significantly reduced renal tubule damage and increased inulin and p-aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg-1 although the increase in inulin clearance was not statistically significant. However, this higher dose of CPX significantly increased Na+ and K+ excretion compared to vehicle-treated rats. 5 CPX at doses of 0.03, 0.1 and 0.3 mgkg- produced blockade of an A1-receptor mediated response i.e. adenosine-induced bradycardia, but only treatment with the higher doses of CPX (0.1 and 0.3mgkg-1) ameliorated nephrotoxicity produced by cisplatin. The lack of any protective effect afforded by the lowest dose of CPX could be a result of its shorter duration of action.6. This study indicates that adenosine plays a significant role in the pathophysiology of cisplatin-induced acute renal failure.

Acute Kidney Injury↗
PubMed1991

The effect of 8-cyclopentyl-1,3-dipropylxanthine on the development of cyclosporin-induced acute renal failure.

The effect of the selective A1-adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 0.1 mg kg-1 i.v.) administered twice daily to rats has been assessed on the development of renal dysfunction induced by four daily injections of cyclosporin (60 mg kg-1 i.p.). The series of cyclosporin injections resulted in a polyuria accompanied by a 64-70% increase in plasma urea and creatinine concentrations and a 50% reduction in inulin clearance. However, cyclosporin administration resulted in no change in p-aminohippurate clearance nor was there any evidence of tubular necrosis or vascular damage. CPX treatment did not improve any index of renal function perturbed by cyclosporin. The findings provide evidence that adenosine does not play a role in the pathophysiology of cyclosporin nephrotoxicity.

Acute Kidney Injury↗
PubMed1991

Diuretic and saliuretic effects of 1,3-dipropyl-8-cyclopentylxanthine, a selective A1-adenosine receptor antagonist.

We have previously shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, has a diuretic effect. In this study, the diuretic and adenosine antagonist effects of the A1-receptor selective compound 1,3-dipropyl-8-cyclopentylxanthine (CPX) have been examined in the conscious rat. CPX (0.1 and 0.3 mg kg-1 i.v.) significantly attenuated bradycardic but not hypotensive responses evoked by adenosine. In contrast, 8-PT (3 mg kg-1 i.v.) significantly antagonized both adenosine-induced bradycardia and hypotension. CPX (0.1 and 0.3 mg kg-1 i.v.) evoked a dose-related diuretic and saliuretic response in the conscious rat. These results indicate that the diuretic effects of adenosine antagonists are associated with blockade of the A1-receptor sub-type.

Adenosine↗
PubMed1990

The role of adenosine in exercise hyperaemia of the gracilis muscle in anaesthetized cats.

1. A number of metabolites have been proposed to control the vascular tone of skeletal muscle during exercise. The present study was designed to investigate the role of adenosine in this response by determining the effect of the adenosine receptor antagonist 8-phenyltheophylline. 2. The gracilis muscle of anaesthetized cats was exposed and made to contract by stimulating the obturator nerve (at 1 Hz, 5 V, 0.1 ms) for 20 min. Gracilis muscle blood flow and tension were measured during exercise and for 20 min following exercise. Initially this was performed in each animal during the infusion of a vehicle solution (50% polyethylene glycol 400, 50% 0.1 M-NaOH, 0.1 ml min-1 I.V.). Exercise was then repeated during infusion of either further vehicle (group I), 8-phenyltheophylline (group II) or 3-propylxanthine (group III), both at 2.7 x 10(7) mol min-1 kg-1. 3. In group 1 (n = 4) gracilis muscle blood flow during the first exercise period increased by 47.5 +/- 11.3 ml min-1 (110 g)-1 and gracilis muscle tension by 8.6 +/- 1.3 kg (100 g muscle mass)-1 at 20 min of exercise. These responses were not significantly different when repeated. 4. In group II (n = 5), blood flow increased by 46.9 +/- 9.9 ml min-1 (100 g)-1 and tension by 6.5 +/- 0.7 kg (100 g muscle mass)-1 during vehicle infusion. Infusion of 8-phenyltheophylline at a rate which abolished the vasodilatation response to 2-chloroadenosine, significantly reduced the muscle blood flow increase to 19.8 +/- 2.7 ml min-1 (100 g muscle mass)-1 (P less than 0.05) but the tension response was unaffected (increased by 7.0 +/- 0.8 kg (100 g muscle mass)-1). 8-Phenyltheophylline did not affect gracilis muscle blood flow or tension at rest. 5. Administration of 3-propylxanthine, which did not modify the vasodilatation response to 2-chloroadenosine, failed to alter the vascular responses to muscle contraction. 6. These results suggest that activation of adenosine receptors can contribute to up to 40% of the vasodilatation observed during isometric twitch contraction of the gracilis muscle of cats.

Adenosine↗
PubMed1989

The cardiovascular pharmacology of ICI 170777 ((6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4- thiadiazin-2-one) a novel compound with positive inotropic and vasodilator effects.

1. This paper describes the cardiovascular effects of ICI 170777, a novel compound which enhances cardiac contractility and causes arterial and venous dilatation. 2. The positive inotropic effects of ICI 170777 on the heart were demonstrated by an increase in left ventricular dP/dtmax in the anaesthetized and conscious dog, and by an increase in tension development in isolated papillary muscles from the cat. 3. In the anaesthetized dog, the positive inotropic effects of ICI 170777 and of isoprenaline were attenuated by atenolol (5 mg kg-1, i.v.). Atenolol displaced the dose-response curve to ICI 170777 to the right by 4 fold but displaced the isoprenaline dose-response curve to the right by 247 fold. In vitro, however, atenolol (10 microM) had no significant effect on the positive inotropic response to ICI 170777. In the ganglion-blocked anaesthetized dog, infusion of a low dose of ICI 170777 which had no effect on the basal left ventricular dP/dtmax, selectively potentiated the positive inotropic effects of isoprenaline. These results indicate that ICI 170777 has both a non-adrenoceptor-mediated positive inotropic effect on the heart and also facilitates the beta-adrenoceptor-mediated control of contractility. 4. In the denervated and perfused hind-limb of the dog, ICI 170777 reduced arterial perfusion pressure and increased limb circumference at a constant arterial flow and venous pressure. This indicates that ICI 170777 has direct dilator actions on both arterial and venous vessels. In this preparation, diazoxide exerted an arterial selective vasodilator effect and sodium nitroprusside was a relatively selective venous dilator. ICI 170777 exhibited a balanced arterial and venous dilator effect which was intermediate in profile between that of diazoxide and that of sodium nitroprusside. 5. In the conscious dog, low doses (2-5 mgkg -, orally) of ICI 170777 evoked an increase in left ventricular dP/dt,,, with no significant effect on heart rate or blood pressure. At a higher dose (10mg kg 1, orally) it also reduced blood pressure and caused a significant increase in heart rate. The duration of the positive inotropic effect of 5mg kg- (orally) of ICI 170777 was 10-12 hours. This response did not diminish following repeated administration of the compound. 6. The positive inotropic action and balanced arterial and venous dilator effect of ICI 170777 indicate that the compound may be useful in the treatment of congestive heart failure, a disorder that is characterized by decreased cardiac contractility and enhanced arterial and venous constrictor tone.

Anesthesia↗
PubMed1989

Apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine for adenosine A1 and A2 receptors in isolated tissues from guinea-pigs.

1. The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3-dipropyl-8-cyclopentylxanthine (CPX), an antagonist which has been reported to be A1 selective, and the non-selective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea-pig. 2. The isolated tissues used were atria (bradycardic response, proposed A1 sub-type), aorta and trachea (relaxant response, proposed A2 sub-type). 3. Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea). 4. pA2 values for 8PT were similar on the three tissues (6.3-6.7), however, the pA2 value for CPX on the atria (7.9-8.4) was greater than that on the aorta (6.6) or trachea (6.6). 5. These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub-type and that those which mediate relaxation in the aorta and trachea are of the A2 type.

Adenosine↗
PubMed1989

Amelioration of glycerol-induced acute renal failure in the rat with 8-cyclopentyl-1,3-dipropylxanthine.

1. Previous studies have shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, can ameliorate the severity of glycerol-induced acute renal failure (ARF) in the rat. In the present study we have examined the effects of an antagonist with selectivity for adenosine A1-receptors (8-cyclopentyl-1,3-dipropylxanthine, CPX) on the development of ARF. 2. In the anaesthetised rat 8-PT (4 mg kg-1, i.v.) and CPX (0.1 mg kg-1, i.v.) antagonised adenosine-evoked responses which are thought to be mediated via A1-receptors (bradycardia and decrease in renal blood flow). The agonist dose-ratio produced by CPX was equal to or greater than that found with 8-PT (heart rate and renal blood flow respectively). The hypotensive response to adenosine which is predominantly due to A2-receptor activation was also antagonised by 8-PT, whereas CPX was a much less effective antagonist of this response. 3. Administration of CPX (0.1 mg kg-1, i.v.; twice daily for two days) significantly attenuated the increase in plasma levels of urea and creatinine, the increased kidney weight and the renal tubule damage observed in rats 2 days following induction of ARF with intramuscular glycerol injection. In addition treatment with CPX significantly enhanced the clearances of inulin and p-aminohippurate. 4. After glycerol injection, the mortality rate over 7 days in untreated and vehicle-treated rats was 43% and 21% respectively. In contrast, all animals treated with CPX survived over the 7 day observation period. 5. These results support the suggestion that adenosine is an important factor in the development of ARF and indicate that this effect of the purine is likely to be mediated via an adenosine A1-receptor.

Acute Kidney Injury↗
PubMed1989

Pharmacokinetics of 8-phenyltheophylline in the rat.

The pharmacokinetics of the adenosine antagonist 8-phenyltheophylline (8-PT) have been investigated in the rat. After intravenous administration to male rats with normal renal function, 8-PT was rapidly cleared from plasma with a t1/2 of about 14 min. Its apparent volume of distribution was some 76 mL/100 g and plasma clearance was 3.5 mL min-1/100 g. Injection via the carotid artery did not alter the kinetics of 8-PT, but when given through the portal vein a first-pass effect was observed. Moreover, 8-PT could not be detected in plasma following intraperitoneal injection. The kinetics of 8-PT were not altered in male rats with acute renal failure and no difference was noted between male and female animals with respect to the kinetics of 8-PT following intravenous injection. It is concluded that the pharmacokinetic properties of 8-PT are likely to complicate its use in-vivo.

Acute Kidney Injury↗
PubMed1988

Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat.

Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF.

Acetylglucosaminidase↗
PubMed1988

Amelioration of glycerol-induced acute renal failure in the rat with 8-phenyltheophylline: timing of intervention.

The importance of timing and duration of 8-phenyltheophylline (8-PT) administration in determining its beneficial action in glycerol-induced acute renal failure (ARF) was investigated by examining the effects of a single dose of 8-PT given immediately following (0 h) glycerol injection and at 1 and 3 h after glycerol injection. 8-PT when given at 0 h significantly lowered plasma urea and creatinine concentrations and significantly increased inulin clearance when compared both to untreated animals and those that received the vehicle for the drug. By contrast, 8-PT when administered at 1 h afforded no protective effect on renal function and, when injected at 3 h, the only significant effect was lowered plasma creatinine levels when compared to untreated rats; at this latter time it did not lower plasma urea levels or improve inulin clearance. None of the 8-PT injections attenuated the increase in kidney weight associated with ARF or reduced the kidney damage as assessed by histological examination. The results show that a single administration of 8-PT made immediately following glycerol injection can ameliorate the biochemical and functional indices of impaired renal function, but does not produce an improvement in kidney morphology.

Acute Kidney Injury↗
PubMed1987

Apparent affinity of some 8-phenyl-substituted xanthines at adenosine receptors in guinea-pig aorta and atria.

1 Some 8-phenyl-substituted, 1,3 dipropyl xanthines have previously been demonstrated to have a 20-400 fold greater affinity for A1 binding sites in rat CNS membranes than for A2 adenosine receptors in intact CNS cells from guinea-pigs. In the present study these compounds (1,3, dipropyl-8-phenylxanthine: DPPX; 1,3 dipropyl-8-(2 amino-4-chlorophenyl) xanthine: PACPX; 8-(4-(2-amino-ethyl)amino) carbonyl methyl oxyphenyl)-1,3-dipropylxanthine: XAC; and D-Lys-XAC) together with two that have not been reported to exhibit A1-receptor selectively (8-(p-sulphophenyl)theophylline: 8-PST; 8-(4-carboxy methyl oxyphenyl)-1,3-dipropylxanthine: XCC) have been evaluated as antagonists of the effects of 2-chloroadenosine in two isolated cardiovascular tissues. 2 The isolated tissues used were guinea-pig atria (bradycardic response) and aorta (relaxation), which are thought to possess A1 and A2 adenosine receptors, respectively. 3 All the xanthines antagonized responses evoked by 2-chloroadenosine in both tissues but did not affect responses evoked by acetylcholine (atria) or sodium nitrite (aorta). 4 The xanthines, 8-PST, XAC, D-Lys XAC, XCC and DPPX appeared to be competitive antagonists of the effects of 2-chloroadenosine, as Schild plot slopes did not differ significantly from unity. The 1,3-dipropyl substituted compounds had pA2 values from 6.5 to 7.4 and were more potent than the 1,3 dimethyl substituted 8-PST (pA2 4.9 to 5). 5 For individual xanthines, there was no difference between pA2 values obtained in the atria and in the aorta. 6 Responses evoked by 2-chloroadenosine in atria and aorta were antagonized to a similar degree by PACPX (1 microM). The agonist dose-ratio evoked by 10 microM PACPX was no greater than that evoked by 1 microM of the xanthine in both tissues. This was probably a consequence of the limited aqueous solubility of PACPX. 7. These results fail to demonstrate A, receptor selectivity for DPPX, XAC, D-Lys XAC or PACPX in tissues from the guinea-pig. The A, selectivity previously found for these compounds may therefore be due to their high affinity for binding sites in rat CNS cell membranes.

2-Chloroadenosine↗