Biomedical subjects

J R Parratt

Publications and source records attributed to J R Parratt.

At least 109 records · Page 6Linked to original sources

PubMed1988

The effects of PAF antagonists on ischaemia and reperfusion arrhythmias and ischaemia-induced platelet aggregation.

These studies were performed to investigate a role of PAF in the genesis of life-threatening arrhythmias and platelet aggregation accompanying myocardial ischaemia and reperfusion. Pretreatment with the PAF antagonists SRI 63-441 (10 mgkg-1 iv) and BN 52021 (5 mgkg-1 iv) significantly reduced the number of arrhythmias during a thirty minute coronary artery occlusion period in open-chest anaesthetised greyhounds, particularly ventricular tachycardia. Both drugs also reduce the incidence of ventricular fibrillation resulting from reperfusion of the myocardium. Myocardial ischaemia in control animals resulted in a marked fall in platelet count in blood draining the ischaemic area, which was abolished by both SRI 63-441 and BN 52021. These results suggest a role for PAF in the genesis of ischaemia and reperfusion-induced arrhythmias, possibly by inducing platelet aggregation.

Animals↗

PubMed1987

Antiarrhythmic effects of the thromboxane antagonist BM 13.177.

The effects of the thromboxane antagonist BM 13.177 (5 mg kg-1 + 0.15 mg kg-1 min-1) was investigated on the ventricular arrhythmias that result from coronary artery occlusion and reperfusion in anaesthetised open-chest greyhounds. BM 13.177 markedly reduced the severity and incidence of arrhythmias resulting from ischaemia; the number of ventricular ectopic beats was reduced from 1,084 +/- 159 (in controls) to 544 +/- 179 (in dogs given BM 13.177) and the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) were reduced from 86 to 22% and from 30 to 10% respectively. Following reperfusion the incidence of VF was 86% in controls and 44% in dogs given BM 13.177. Thus the total incidence of VF during the combined ischaemia-reperfusion insult was significantly reduced by treatment with BM 13.177 from 90% (in control dogs) to 50%. These results lend further support to the hypothesis that thromboxane is involved in the genesis of arrhythmias and that blockade of thromboxane receptors may be a suitable approach to antiarrhythmic therapy under conditions of ischaemia and reperfusion.

Animals↗

PubMed1987

The effects of chronic lead treatment and hypertension on the severity of cardiac arrhythmias induced by coronary artery occlusion or by noradrenaline in anaesthetised rats.

The aim of this study was to investigate whether chronic (3 months) lead (250 or 1000 ppm), administered as lead acetate in the drinking water, commencing either after weaning (in normotensive or spontaneously hypertensive male rats) or from conception (normotensive rats only) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or by noradrenaline. Treatment with lead alone had no marked effect on the arrhythmias elicited by either method. Spontaneously hypertensive rats treated with either dose of lead exhibited more ectopic beats following coronary artery occlusion than normotensive rats but not more than those observed in control spontaneously hypertensive rats. An enhanced arrhythmogenic effect of noradrenaline was observed only in hypertensive rats administered 250 ppm lead. Both doses of lead accelerated the development of high blood pressure and in normotensive rats the higher dose also resulted in an elevated pressure. Following administration of lead, blood lead concentrations were elevated to 0.96 and 2.11 mumol l-1 after 250 and 1000 ppm, respectively. Accumulation of lead in heart and bone was also observed. We conclude that chronic exposure to these concentrations of lead, when combined with high blood pressure, slightly enhances the susceptibility of the heart to arrhythmias induced by myocardial ischaemia.

Anesthesia↗

PubMed1987

Eicosanoids and susceptibility to ventricular arrhythmias during myocardial ischaemia and reperfusion.

Increased levels of the major metabolites of thromboxane (TxA2) and prostacyclin (PGI2) are found in venous blood draining the ischaemic region of the myocardium of dogs subjected to acute coronary artery occlusion. This suggests that these arachidonic acid derivatives are released under conditions of myocardial ischaemia and may be considered as mediators of some of the consequences of coronary blood flow reduction, including arrhythmogenesis. The present experimental evidence suggests that thromboxane release is detrimental both in the early stages of ischaemia and in reperfusion since the severity of both ischaemia and reperfusion-induced arrhythmias is reduced by selective inhibition of thromboxane synthesis or by thromboxane receptor blockade. Since the local administration of prostacyclin (or iloprost) or the promotion of local prostacyclin production (with nafazatrom) reduces the severity of ischaemia and reperfusion-induced arrhythmias, it is suggested that prostacyclin may act as a local, endogenous antiarrhythmic agent. The conclusion thus far from these experimental studies suggests that the prostacyclin-thromboxane balance is one important factor involved in determining the severity of ischaemia and reperfusion-induced arrhythmias but that the mechanisms have not as yet been clearly defined.

Animals↗

PubMed1987

Effects of alterations in sympathetic nervous activity on the severity of reperfusion-induced arrhythmias in anaesthetised rats.

The effects of a number of interventions influencing sympathetic nervous activity on the severity of coronary artery reperfusion-induced arrhythmias in anaesthetised rats have been examined. Noradrenaline (0.1 microgram kg-1 min-1) reduced the mortality that usually occurred as a consequence of ventricular fibrillation. Isoprenaline (5 micrograms kg-1) did not significantly affect the severity of reperfusion-induced arrhythmias, although arrhythmias occurring during the 5-min period of ischaemia were exacerbated. The alpha-adrenoceptor antagonist nicergoline (0.25 and 0.5 mg kg-1 min-1) markedly suppressed both the ventricular tachycardia and fibrillation occurring upon release of the occlusion, whereas prazosin (1.0 mg kg-1) only slightly reduced the incidence of ventricular tachycardia. The beta-adrenoceptor antagonists atenolol and timolol did not significantly modify the severity of these reperfusion-induced arrhythmias. Pretreatment with reserpine (0.1 mg kg-1) or 6-hydroxydopamine (20 mg kg-1), which depleted myocardial catecholamine concentrations by 90%, had no effect on the indices of arrhythmic activity. Similarly, administration of L-thyroxine (1 mg kg-1) or propylthiouracil (50 mg kg-1) on 7 consecutive days prior to coronary artery occlusion did not alter the incidence of arrhythmias occurring upon reperfusion. Taken as a whole, these results do not suggest an important role for sympathetic nervous activity in the genesis of reperfusion-induced arrhythmias in anaesthetised rats.

Adrenergic alpha-Antagonists↗

PubMed1987

Failure of allopurinol and a spin trapping agent N-t-butyl-alpha-phenyl nitrone to modify significantly ischaemia and reperfusion-induced arrhythmias.

The possible role of free radicals in the genesis of occlusion and reperfusion-induced arrhythmias was studied by determining the effects of the xanthine oxidase inhibitor allopurinol (400 mg p.o. 24 h before experimentation +25 mg kg-1 i.v.) and the free radical scavenger N-t-butyl-alpha-phenyl nitrone (PBN; 50 mg kg-1 i.v.) on these arrhythmias in chloralose anaesthetized greyhounds. Neither of the drugs had any major effects on haemodynamic variables, although allopurinol caused a significant increase in heart rate. The mean number of extrasystoles observed during ischaemia in dogs given allopurinol or PBN was not significantly different from those seen in controls. Further, the incidence of ventricular fibrillation during either occlusion or reperfusion was unchanged by either drug and there was thus no improvement in survival. These results suggest that, in this model of myocardial ischaemia and reperfusion, free radicals may not play a major role in the genesis of life-threatening arrhythmias.

Allopurinol↗

PubMed1987

Leukotriene antagonist FPL 57231 prevents the acute pulmonary effects of Escherichia coli endotoxin in cats.

We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1986

The effects of ICS 205-930, a 5-HT antagonist, on arrhythmias and catecholamine release during canine myocardial ischaemia and reperfusion.

The effects of ICS 205-930 [3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester), an antagonist of 5-HT at neuronal M receptors, were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. Intravenous administration of 0.3 or 2.0 mg kg-1 of ICS 205-930 did not significantly alter haemodynamics or blood gases. The higher dose had marked antiarrhythmic activity. The total number of ischaemia-induced extrasystoles was reduced to 167 +/- 64 compared with 467 +/- 99 in controls. Ventricular fibrillation induced by reperfusion after 40 min of ischaemia was also significantly reduced from 80 to 33%. Immediately following release of the coronary artery occlusion significant increases in plasma noradrenaline and dopamine concentrations were detected in local coronary venous blood draining from the ischaemic area in control dogs. This catecholamine release was also evident in the dogs which received 2 mg kg-1 ICS 205-930 but was less marked. Thus the antiarrhythmic activity of ICS 205-930 may be related to antagonism of detrimental effects of 5-HT, such as the ability to facilitate the release of noradrenaline from sympathetic nerve terminals in the heart, although other mechanisms may be involved.

Animals↗

PubMed1986

The effects of ethanol and lead, alone and in combination, on the severity of arrhythmias induced by coronary artery occlusion, and by noradrenaline, in anaesthetised rats.

The aim of this study was to investigate whether chronic (3 or 10 months) administration, via the drinking water, of lead (25 ppm) and/or ethanol (25% v/v) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or noradrenaline infusion in pentobarbitone-anaesthetised male Sprague-Dawley rats. The cardiac effects of acute intravenous infusions of ethanol (17, 33 and 66 mg kg-1 min-1) were also measured. Chronic exposure to ethanol and/or lead in the drinking water had no marked effect on the severity of arrhythmias occurring within the initial 30 min of coronary artery occlusion. In control rats and in those administered ethanol and/or lead for 10 months, noradrenaline (16 micrograms kg-1 min-1 given IV 1 h post-occlusion for a 15-min period) induced a similar number of ectopic beats during the infusion period, although these arrhythmias persisted beyond the infusion period in treated animals only. There was a significant accumulation of lead in the bone but not in the blood of lead-treated rats. Blood ethanol concentrations varied considerably between animals, ranging from 0 to 319 mg %. Ethanol (66 mg kg-1 min-1) given acutely and yielding a blood concentration of 174 mg % had a slight antiarrhythmic effect in this model.

Anesthesia↗

PubMed1986

Critical appraisal of secondary prevention after myocardial infarction. What have beta-blockers to offer in the experimental situation?

This contribution reviews the beneficial effects of beta-adrenoceptor blocking drugs in experimental myocardial ischaemia (infarction). These effects include the ability to reduce early, life-threatening ventricular arrhythmias, improvement in ultimate long-term survival from an ischaemic insult with or without subsequent reperfusion and a reduction in the extent and degree of myocardial (and microvascular) ischaemic damage. Most of the evidence for protection, however, comes from studies in which drugs have been administered before the onset of ischaemia. Much less is known about the effects of intervening with beta-blocking drugs after the commencement of the ongoing infarction process. Although beta-blockers have a great deal to offer in the experimental situation there remains the strong possibility that other approaches might be able to offer even more. One promising approach is the combination of a beta-blocking drug with a specific inhibitor of thromboxane synthesis.

Adrenergic beta-Antagonists↗

PubMed1986

The haemodynamic and metabolic effects of tolmesoxide with special reference to impaired myocardial function.

The haemodynamic, metabolic and regional blood flow effects of the vasodilator, tolmesoxide (1 mg kg-1 min-1 for 20 min by intravenous infusion) were examined in two groups of greyhound dogs anaesthetized with alpha-chloralose and mechanically ventilated. One group of dogs was thoracotomized and subjected to acute coronary artery occlusion. In these dogs tolmesoxide was infused 2.5 h after occlusion when there was evidence of impaired myocardial function. Tolmesoxide administration resulted in marked systemic hypotension which was associated with myocardial stimulation (increase in heart rate and LVdP/dtmax). These effects were less marked in thoracotomized dogs subjected to coronary artery occlusion. Cardiac stimulation was attenuated by pretreatment with the beta-adrenoceptor antagonist, atenolol. Peripheral resistance and left ventricular end-diastolic pressure (LVEDP) were reduced by tolmesoxide. In spite of the systemic hypotension, the marked reduction in LVEDP resulted in an enhanced subendocardial driving pressure and an increased blood flow to ischaemic regions of the left ventricular wall as measured with Xe133 clearance. Blood flow to normal regions of the left ventricular wall was also increased by tolmesoxide. A metabolic and respiratory acidosis may have contributed to the haemodynamic effects of tolmesoxide. Plasma renin levels were significantly elevated by the drug. Tolmesoxide administration thus resulted in cardiac stimulation, reduced both pre-load and after-load, yet maintained coronary and pulmonary perfusion. This haemodynamic profile of tolmesoxide would explain the beneficial effects obtained with this drug in the treatment of cardiac failure.

Animals↗

PubMed1986

Feline endotoxin shock: effects on tissue histamine and histidine decarboxylase activity.

Tissue histamine levels as well as specific and non-specific histidine decarboxylase were examined before and at various times (5 and 10 min) after the intravenous injection of a lethal dose (2 mg kg-1) of E. coli endotoxin in anaesthetized cats. Histamine levels were increased 5 min after endotoxin, especially in the skin, liver, lung and stomach. There was evidence, in most of the cats, for a rapid and substantial activation of specific histidine decarboxylase especially in the lungs, liver, heart and gastrointestinal tract 5-10 min after endotoxin administration. It is suggested that endotoxin induces the local formation of histamine and that this formation and local release may contribute to the pathophysiology of endotoxin shock in this species.

Animals↗

PubMed1986

Stereospecific antiarrhythmic effect of opioid receptor antagonists in myocardial ischaemia.

The effects of the stereoisomers of two different antagonists at opioid receptors were examined on the ventricular arrhythmias that result from acute coronary artery ligation in anaesthetized male rats. (-)-Mr 1452(but not the (+)-isomer, Mr 1453) reduced, in a dose-dependent manner, the number of ventricular ectopic beats and the incidence or duration of both ventricular tachycardia and fibrillation. (-)-WIN 44,441-3 (but not its (+)-isomer, WIN 44,441-2) had a similar protective effect in ischaemia. These results suggest that antagonism of the effects of endogenous opioid peptides at specific receptors results in reduced severity of arrhythmias in myocardial ischaemia.

Animals↗

PubMed1986

Modification by oxygen free radical scavengers of the metabolic and cardiovascular effects of endotoxin infusion in conscious rats.

Since oxygen free radicals may have a role in the pathophysiology of endotoxin shock, we have studied the effects of a wide range of compounds (alpha-tocopherol, reduced glutathione, allopurinol, superoxide dismutase (alone or in combination with catalase) and phenyl butylnitrone) that can act either to remove free radicals as they are generated or to prevent their generation. The effects of these substances on the metabolic and cardiovascular responses to endotoxin were examined in conscious rats. The intravenous infusion of endotoxin (10 mg/kg i.v. given over 4 h) resulted in systemic hypotension, transient tachycardia, an increase in plasma lactate, and an initial hyperglycemia followed, in those rats that died before 24 h, by hypoglycemia. The hypotension and tachycardia produced by endotoxin were not significantly modified by alpha-tocopherol, allopurinol, or superoxide dismutase, alone or in combination with catalase. The tachycardia was attenuated by reduced glutathione and phenyl butylnitrone. alpha-Tocopherol attenuated the initial hyperglycemia produced by endotoxin whilst alpha-tocopherol, allopurinol, and phenyl butylnitrone all significantly attenuated the endotoxin-induced increase in plasma lactate. Among the free radical scavenging systems studied, only alpha-tocopherol and phenyl butylnitrone improved survival. These results suggest a contribution from oxygen-free radicals to the pathophysiology of endotoxemia.

Allopurinol↗

PubMed1985

The effects of chronic low lead treatment and hypertension on the severity of cardiac arrhythmias induced by coronary artery ligation in anesthetized rats.

The aim of this study was to investigate whether chronic (1, 3, 6, 12, or 16 months) low lead (5 or 25 ppm), administered as lead acetate in the drinking water, commencing either after weaning or from conception, altered the susceptibility of the heart to arrhythmias induced by coronary artery ligation in pentobarbitone anesthetized male Sprague-Dawley rats. The cardiac effects of chronic (3 or 12 months) administration of lead (25 ppm) were also examined in spontaneously hypertensive rats. Treatment from weaning of normotensive rats with 5 or 25 ppm lead for periods of 1, 3, or 6 months had no statistically significant effect on the severity of ischemia-induced arrhythmias. Each of the groups treated from conception with 5 or 25 ppm lead for periods of 1, 12, or 16 months exhibited a higher incidence of ventricular tachycardia than the appropriate control group, but the difference was statistically significant only in the case of animals treated with 25 ppm lead for 12 months. The incidence of ventricular fibrillation was significantly higher in rats treated from conception for 16 months with 5, but not with 25 ppm lead. Spontaneously hypertensive rats treated with 25 ppm lead for 3 but not for 12 months had significantly more ectopic beats than control Sprague-Dawley rats. Lead treatment for the longer exposure periods only caused significant accumulation of lead in the blood whereas all lead treatments resulted in a marked accumulation in the bone. We conclude that chronic exposure to low concentrations of lead does not consistently alter susceptibility of the heart to ischemia-induced arrhythmias in anesthetized rats

Administration, Oral↗

PubMed1985

Arachidonic acid cascade and the generation of ischemia- and reperfusion-induced ventricular arrhythmias.

This article reviews the evidence we found in our study that the local generation of thromboxane and prostacyclin is one important factor involved in determining the severity of the ventricular arrhythmias that result from acute myocardial ischaemia and subsequent reperfusion. The hypothesis examined is that thromboxane release, presumably from platelets, is harmful in the early stages of ischaemia (perhaps because this induces further platelet aggregation and/or a reduction in blood flow as a result of both active vasoconstriction and of mechanical obstruction) and that prostacyclin generation (presumably mainly from endothelial cells) is beneficial at this time. The evidence is that in anaesthetised greyhound dogs, blockade of the thromboxane receptor (AH 23848) or inhibition of thromboxane synthesis (with a variety of "specific" inhibitors of thromboxane synthetase such as dazoxiben, dazmegrel, and "low-dose" aspirin) slightly reduces the severity of ischaemia-induced arrhythmias and markedly increases survival after myocardial reperfusion by reducing reperfusion-induced ventricular fibrillation (e.g., from 80% in control dogs to less than 20% in treated dogs). The evidence that prostacyclin generation is helpful in this situation comes from studies with locally infused prostacyclin or iloprost and with nafazatrom, a drug that increases the amount of prostacyclin released into local coronary venous blood soon after the onset of myocardial ischaemia; these procedures also reduce the number of ventricular extrasystoles occurring during ischaemia and the incidence of reperfusion-induced ventricular fibrillation. These findings do not imply that arachidonic acid derivatives are the only, or even the main, biochemical factor involved in the generation of these arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The effects of the protease inhibitor, aprotinin, on the course of shock induced by endotoxin in cats.

The administration of endotoxin derived from Escherichia coli to anaesthetized cats resulted, within the first 5 min, in an initial increase in right atrial pressure and a reduction in systemic arterial blood pressure. Over the next 2 h shock was characterized by a reduced cardiac output, tachycardia, reduced arterial pH and an increased level of lactate. The survival rate at the end of the 8 h experimental period was only 10%. The protease inhibitor aprotinin (Trasylol), given as a continuous intravenous infusion 1000 kallikrein inhibitor units (k.i.u.) kg-1h-1 together with a bolus of 40,000 k.i.u. kg-1, significantly inhibited the severity and incidence of the initial endotoxin response (increase in right atrial pressure and systemic hypotension), perhaps suggesting the direct or indirect involvement of kinins. Aprotinin did not reduce the delayed effects of endotoxin (sustained reduction in cardiac output, lacticacidosis), nor did it improve survival at 8 h. Indeed, there was some evidence that aprotinin exaggerated the delayed effects of endotoxin in this model.

Animals↗

PubMed1985

The effects of metoprolol and dazmegrel, alone and in combination, on arrhythmias induced by coronary artery occlusion in conscious rats.

The effects of metoprolol and the thromboxane synthetase inhibitor dazmegrel, alone and in combination, were examined in a model of coronary artery occlusion in conscious rats. In a dose (2 mg kg-1), intravenously, that resulted in a marked bradycardia (of 50-80 beats min -1) metoprolol did not influence the incidence or severity of the ventricular arrhythmias that occur in the first 20 min following occlusion, nor did it improve survival (assessed at both 20 min and 16 h). In a dose (5 mg kg-1), intravenously, that in another conscious rat model involving tissue hypoperfusion inhibited thromboxane production, dazmegrel also did not modify ischaemic arrhythmias or survival. In contrast, metoprolol and dazmegrel (2 mg kg-1 and 5 mg kg-1 i.v.) when given together prior to coronary artery occlusion, produced a significant reduction in mortality both at 20 min and 16 h (e.g. from 60-75% in the control, metoprolol alone and dazmegrel alone groups and only 25% in the combined-treatment group). This was due to a decrease in the incidence of terminal ventricular fibrillation. The results suggest that a combination of beta-adrenoceptor blocking drug with a drug that inhibits thromboxane synthesis may offer more protection against ischaemia-induced ventricular fibrillation than either drug used alone. They suggest a role for both catecholamines and thromboxane in the genesis of ischaemia-induced ventricular fibrillation.

Animals↗