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Biomedical subjects

A S Manning

Publications and source records attributed to A S Manning.

At least 37 records · Page 2Linked to original sources
PubMed1985

Reperfusion-induced ventricular fibrillation. Modification by pharmacological agents.

We have assessed the ability of several of the main groups of antiarrhythmic agents to modify the incidence of reperfusion-induced ventricular fibrillation in the isolated working rat heart preparation with transient coronary artery occlusion. Hearts were perfused with Krebs-Henseleit medium containing 5 microM epinephrine to provide some level of exogenous catecholamine support. Compounds selected were: the fast sodium channel inhibitors lignocaine (1 and 10 microM) and prenylamine (4 microM) (the latter also possessing slow calcium channel antagonistic actions); the beta-adrenergic blocking agents oxprenolol (1.2 microM), timolol (0.13 microM), metoprolol (1.0 microM), and acebutolol (5.6 microM); and the slow calcium channel antagonist nifedipine (0.05 and 0.5 microM). After 15 min of coronary artery occlusion, over 90% of control hearts fibrillated 30-60 sec after the onset of reperfusion. Drugs reduced this to the following: prenylamine, 0% (p less than 0.001); 1 microM lignocaine, 83%; 10 microM lignocaine, 33% (p less than 0.01); oxprenolol, 92% (NS); timolol, 92% (NS); metoprolol, 42% (p less than 0.01); acebutolol, 67% (p less than 0.05); 0.05 microM nifedipine, 83% (NS); and 0.5 microM nifedipine, 67% (NS). Thus, inhibition of the fast inward sodium channel with agents such as prenylamine and lignocaine, (when begun before coronary-artery occlusion) offers maximal protection against reperfusion-induced ventricular fibrillation, while beta-blockade with timolol and oxprenolol and slow calcium channel inhibition with nifedipine do not offer any significant protection. The beta-blocking agents metoprolol and acebutolol produce a partial reduction that may be due to a membrane-stabilizing action, rather than to beta-blockade.

Adrenergic beta-Antagonists↗
PubMed1985

Calcium antagonists and myocardial protection during cardioplegic arrest.

The ability of nifedipine, verapamil, and diltiazem to enhance cardioplegic protection has been assessed using an isolated rat heart preparation as a model of cardiopulmonary bypass and ischemic arrest. With normothermic ischemia (30 or 35 min at 37 degrees C), the addition of these compounds enhanced the protective properties of the St. Thomas' cardioplegic solution. All these compounds showed bell-shaped dose-response characteristics, with the optimal concentrations in terms of functional recovery and enzyme leakage of verapamil being 1.0 mumole/liter; nifedipine, 0.075 mumole/liter; and diltiazem, 0.5 mumole/liter. However, under conditions of hypothermia (150 or 180 min at 20 degrees C), none of these compounds improved postischemic functional recovery, although there was some reduction in enzyme leakage. From these results, further experiments were undertaken to investigate the relationship between calcium antagonists and temperature. Verapamil improved functional recovery at 34, 31 and 29 degrees C, but not at 27, 25, and 20 degrees C. These results suggest a common site of action between hypothermia and calcium antagonists in promoting functional recovery after ischemia.

Animals↗
PubMed1984

Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol.

We have investigated the possibility that xanthine oxidase-linked free radical production has a role in the genesis of arrhythmias during ischemia and reperfusion. In this study, rats were treated with allopurinol (20 mg/kg, orally, 24 hours before study, plus 20 mg/kg, iv, 15 minutes prior to study). Using an anesthetized open-chest preparation with either coronary artery occlusion for 30 minutes, or 5 minutes followed by 10 minutes reperfusion, we monitored and compared the rhythm disturbances in experimental vs. placebo-treated rats (n = 18 in each group). Allopurinol treatment reduced the incidence of ventricular tachycardia during ischemia from 88% to 50% (P less than 0.05) and the number of premature ventricular complexes from 471 +/- 120 to 116 +/- 46 (P less than 0.02), but the treatment had no effect upon the incidence or duration of ventricular fibrillation or upon mortality. In contrast, far more dramatic protection was observed during reperfusion after 5 minutes of ischemia. Allopurinol treatment reduced the incidence of ventricular fibrillation from 67% to 11% (P less than 0.01), reduced the mean duration of fibrillation from 230 +/- 70 to 14 +/- 1 seconds (P less than 0.05), and reduced mortality by half (10/18 to 4/18), although this did not reach a level of statistical significance. In addition, the mean duration of tachycardia was reduced from 83 +/- 26 to 38 +/- 8 seconds (P less than 0.05). Allopurinol pretreatment thus affords some protection against ischemia-induced arrhythmias, but a higher degree of protection against reperfusion-induced arrhythmias. Allopurinol inhibits xanthine oxidase activity, and, in turn, this inhibits superoxide radical production.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗
PubMed1983

The effect of beta blockade and partial agonist activity during myocardial ischemia.

In this study, we have investigated the importance of partial agonist activity during myocardial ischemia by comparing the effects of equiblocking doses of oxprenolol, which possesses partial agonist activity, to propranolol which does not. In the isolated, globally ischemic (low-flow) rat heart, when propranolol or oxprenolol was added alone during the ischemic period, only propranolol reduced enzyme leakage relative to control. However, when the hearts were perfused (10 min) prior to ischemia with these drugs, both beta blockers caused a significant reduction in enzyme leakage. Under conditions of enhanced sympathetic drive (in the presence of 0.01 microM isoproterenol), both beta blockers reduced enzyme leakage to differing extents. In hearts with low sympathetic drive (reserpine pretreatment), enzyme leakage was unaffected by propranolol and exacerbated by oxprenolol. The results of this study suggest that oxprenolol and propranolol influence ischemic damage to differing extents and that this difference is due to partial agonist activity. Also, the protective action of all beta-blocking compounds depends greatly on the background level of sympathetic drive.

Animals↗
PubMed1983

Calcium antagonists and myocardial protection: diltiazem during cardioplegic arrest.

Using an isolated rat heart preparation as a model of cardiopulmonary bypass and ischemic arrest, the effects of the addition of the calcium antagonist, diltiazem, to St. Thomas' cardioplegic solution were investigated. Under conditions of normothermic ischemic arrest (37 degrees C, 35 min), the addition of diltiazem improved the protective properties of the St. Thomas' cardioplegic solution. Moreover, studies with varying concentrations produced a bell-shaped dose-response curve for diltiazem with its optimal concentration at 0.5 mumoles/liter (0.21 mg/liter) when postischemic recovery of aortic flow was improved from 53.2 +/- 4.3% to 79.2 +/- 4.4% (p less than 0.01) and postischemic creatine kinase leakage was reduced by approximately 40%. Despite this marked additional protection when ischemic arrest was normothermic, diltiazem afforded no improvement in protection under conditions of hypothermic (20 degrees C, 180 min) ischemic arrest.

Animals↗
PubMed1983

Nifedipine and cardioplegia: rat heart studies with the St Thomas' cardioplegic solution.

The ability of nifedipine to enhance myocardial protection was assessed using an isolated rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest. With normothermic ischaemic arrest (35 min, 37 degrees C), nifedipine addition improved the protective properties of the St Thomas' cardioplegic solution. Optimal protection was observed with 0.075 mumol nifedipine X litre-1, where post-ischaemic recovery of aortic flow was improved from 47.9 +/- 5.2% to 76.7 +/- 2.9% (P less than 0.001) and creatine kinase leakage was reduced by approximately 50%. Despite the marked additional protection under normothermic conditions the drug was unable to improve contractile recovery after a period of hypothermic ischaemic arrest (150 min, 20 degrees C) although it did allow a significant reduction (22%) in creatine kinase leakage. In other studies, the ability of nifedipine to replace the cardioplegic solution was examined. Under normothermic conditions, it showed a good ability to protect against ischaemia, but this protection did not match that afforded by the St Thomas' cardioplegic solution. Under hypothermic conditions the drug failed to substitute for the cardioplegic solution, suggesting that a common modality between hypothermia and nifedipine-induced protection.

Animals↗
PubMed1983

Cardioplegia and slow calcium-channel blockers. Studies with verapamil.

The ability of dl-verapamil to enhance myocardial protection when given before, during, or after myocardial ischemia was assessed with the use of an isolated working rat heart model of cardiopulmonary bypass and ischemic cardiac arrest. Under conditions of normothermic ischemic arrest (30 minutes at 37 degrees C), the addition of verapamil enhanced the protective properties of the St. Thomas' Hospital cardioplegic solution. Optimal protection was observed with verapamil concentrations of 0.5 mg/L (1.09 mumol/L) of cardioplegic solution. Under these conditions, postischemic enzyme leakage was reduced by 32.2% and the postischemic recovery of aortic flow was improved by 18.7%. Despite the additional protection at normothermia, the drug at several concentrations appeared unable to improve functional recovery after an extended period of hypothermic arrest (150 minutes at 20 degrees C), although under these conditions its inclusion in the cardioplegic solution could substantially reduce enzyme leakage. In other studies, the ability of various doses of verapamil alone as a substitute for the cardioplegic solution was examined. At the optimal dose (again 0.5 mg/L), and under normothermic conditions, verapamil alone was a good protection against ischemic injury, although this protection did not match that afforded by the St. Thomas' Hospital cardioplegic solution. In similar studies under hypothermic conditions, the drug failed to afford tissue protection, perhaps indicating some common modality between hypothermia and verapamil-induced protection. Pretreatment with verapamil (0.1 mg/L) prior to ischemia offered moderate additional protection, but its use during reperfusion failed to enhance overall recovery.

Animals↗
PubMed1982

Long-term prenylamine therapy: effects on responses to myocardial ischaemia in the isolated rat heart.

The effects of long-term administration of prenylamine gluconate were studied to define changes induced by chronic treatment that may alter the responses of the myocardium to ischaemic stress. Prenylamine gluconate was administered orally to rats (10 mg or 100 mg/kg per day) for 2 weeks. At the end of this period, hearts were excised for perfusion studies. In comparison with gluconate-treated controls, hearts from the group treated with the lower dose of prenylamine showed a significant reduction in basal cardiac function that was not apparent in the group treated with the higher dose of prenylamine. After a period (35 min) of ischaemia stress (reduced flow), a reduction in enzyme leakage and an increase in post-ischaemic functional recovery were observed in hearts from animals treated with the lower dose of prenylamine. In contrast, hearts from the group treated with the higher dose showed no significant improvement. However, chronic prenylamine therapy was shown to reduce in a dose-dependent manner the incidence of post-ischaemic arrhythmias. Thus, although the antiarrhythmic efficacy of long-term treatment with this agent appears to be proportional to the dosage, the ability of prenylamine to reduce ischaemic damage and promote functional recovery does not show a linear relationship with the drug dose.

Adenosine Triphosphate↗
PubMed1982

Prenylamine and the myocardial response to ischaemia and reperfusion: effects of acute and chronic treatment.

The ability of prenylamine gluconate (Segontin) to influence the extent of myocardial ischaemic injury was investigated in the isolated 'working' rat heart preparation. The drug was administered either acutely alone (4 microM litre-1 in the perfusion medium) or chronically plus acutely in which case animals were pre-treated (10 mg kg-1 day-1 orally) for 10 days and the drug was then also added (4 microM litre-1) to the perfusate. Acute administration alone resulted in a small reduction in spontaneous functional performance in the aerobic isolated heart in comparison with gluconate treated controls. It also increased the percentage of hearts able to recover functional activity after a period of severe ischaemia and decreased ischaemia induced injury as assessed by enzyme leakage. In contrast to the acute results the combination of chronic and acute administration of prenylamine did not significantly alter spontaneous cardiac function. Although a small increase in the number of hearts that recovered function was apparent, there was a concomitant decrease in post-ischaemic functional performance with no reduction of ischaemia induced enzyme leakage.

Animals↗
PubMed1982

Effects of hydrogen peroxide on cardiac function and post-ischaemic functional recovery in the isolated 'working' rat heart.

The effects of hydrogen peroxide on the normal and ischaemic myocardium were investigated using the isolated 'working' rat heart preparation. In the range 0-3 microM no changes in heart rate, aortic flow, coronary flow, or aortic pressure were observed. Between 3 and 30 microM, however, there was a dose-dependent fall in aortic flow and an accompanying increase in coronary flow, the total cardiac output remaining unchanged. At concentrations about 30 microM functional failure occurred. Following a 24-min ischaemic period during which time 6 microM hydrogen peroxide was infused via the aorta at a constant rate to remove any vasodilatory effect, all hearts failed to recover. In contrast, 50% of control hearts recovered pump function. In conclusion, therefore, hydrogen peroxide can reduce function in the aerobic working rat heart and may exert a vasodilatory effect. When this effect is eliminated hydrogen peroxide affords no protection during ischaemia and appears to exacerbate tissue injury.

Animals↗
PubMed1981

Long-term beta-blockade: prolonged protective action on the ischaemic myocardium.

In this study we have assessed the possibility that long-term beta-blockade may offer additional protection against myocardial ischaemia that is separate from that afforded by acute beta-blockade. In addition, the effect of intrinsic sympathomimetic activity (ISA) on this additional protection was also investigated. Equipotent doses (4 mg . kg-1 body wt . day-1) of oxprenolol (possessing ISA) or propranolol (without ISA) were administered orally to rats for 3 weeks. Hearts were excised an perfused as isolated "working" heart preparations at variable times after the last dose. Hearts excised on the final day of drug administration showed significantly higher basal functional performance compared with untreated hearts. After 30 min reduced flow ischaemia (in the presence of exogenous catecholamine drive) hearts were aerobically reperfused and functional recovery measured. In both chronically beta-blocked groups, at times when plasma drug levels were undetectable, the number of hearts that recovered function and the cellular levels of creatine phosphate and glycogen were significantly increased. In addition, hearts from the oxprenolol-treated group perfused on the final day of drug administration, exhibited a greater recovery of heart rate compared with both propranolol treated and untreated groups. These results indicate that secondary consequences of long-term beta-blockade are beneficial to the ischaemic myocardium in the presence of high catecholamine drive. In addition, the possession of ISA by oxprenolol offered some advantages in terms of post-ischaemic functional recovery.

Adenosine Triphosphate↗
PubMed1980

Myocardial electrical instability after abrupt withdrawal of long-term administration of propranolol to guinea pigs.

1. Abrupt termination of chronic propranolol therapy has baeen suggested to cause a 'rebound' phenomenon. To investigate this possibility guinea pigs were given propranolol orally for 21 days. 2. At various times over a 10 day period after the last dose hearts were removed and subjected to aerobic perfusion, ischaemia and reperfusion. Rhythm disturbances were measured and compared with corresponding values in control hearts from the control untreated animals. 3. Three to 6 days after termination of drug administration a pronounced increase in myocardial electrical instability was observed. During pre-ischaemic aerobic perfusion the incidence of arrhythmias was increased and during reperfusion the incidence of ventricular fibrillation rose dramatically.

Animals↗
PubMed1980

Protection of the myocardium during ischemic arrest: possible toxicity of carnitine in cardioplegic solutions.

Carnitine has been suggested as an agent for the protection of the myocardium during regional ischemia and it might therefore be able to reduce tissue injury during surgically induced global ischemia. Using an isolated working rat heart model we have assessed the way in which various concentrations of carnitine infuence the efficacy of the St. Thomas' Hospital Cardioplegic Solution. Carnitine was found to exert a dose-dependent detrimental effect upon the ischemic myocardium, with high concentrations abolishing all the protective properties of the cardioplegic solution. Furthermore, this compound appeared to promote the occurrence of reperfusion dysrhythmias.

Animals↗
PubMed1980

Beta-blockade and ischaemic injury: effects of partial agonist activity.

In this study we have attempted: firstly to assess the extent to which the presence of partial agonist activity in a beta-blocking compound and/or sympathetic drive, influence ischaemic injury, and secondly to determine if any of the observed differences are due to changes in contractile activity. In the isolated, globally ischaemic (low flow) rat heart, oxprenolol (which possesses partial agonist activity) did not reduce creatine kinase leakage to the same extent as propranolol (no partial agonist activity) regardless of the background level of catecholamine drive. However, increasing background catecholamine drive increased the relative protection against enzyme leakage, of both beta-blockers. Under conditions of zero contractile activity (high K+ - medium) neither beta-blocker reduced enzyme leakage. Thus at equi-blocking doses oxprenolol and propranolol reduce enzyme leakage to different extents and the lesser protection afforded by oxprenolol is likely to be attributed to the presence of partial agonist activity. In addition, the reduction in enzyme leakage caused by both these compounds is due to reductions in contractile activity.

Animals↗
PubMed1980

Myocardial ischaemia: an isolated, globally perfused rat heart model for metabolic and pharmacological studies.

A model of myocardial ischaemia is described and has been characterized in terms of functional, ultrastructural, electrophysiological and metabolic changes. The model fulfills a number of criteria considered to be of importance in any model of myocardial ischaemia namely (1) the myocardium is ischaemic as opposed to hypoxic, (2) the coronary flow is reduced but not totally abolished, (3) that flow reaching the ischaemic myocardium is fully oxygenated and contains a mixture of substrates. It is proposed that this model is of value for the investigation and assessment of pharmacological interventions during myocardial infarction.

Animals↗