PubMed Health⌕ Search

Biomedical subjects

J R Parratt

Publications and source records attributed to J R Parratt.

At least 127 records · Page 7Linked to original sources
PubMed1985

Effects of a combination of metoprolol and dazmegrel on myocardial infarct size in rats.

The effects of acute pretreatment with metoprolol, dazmegrel and a combination of these two drugs has been examined on myocardial infarct size in rats. Ischaemic damage was assessed 4 h after coronary artery occlusion in anaesthetized rats and after 48 h of ischaemia in conscious rats. Infarct size was measured histochemically (by using periodic-acid-Schiff diastase reaction for glycogen) and by standard histological examination (haematoxylin and eosin stain). There was some evidence of protection of the myocardium by metoprolol following 4 h of ischaemia (determined histologically) but this was not apparent 48 h after occlusion. When given alone, dazmegrel had no significant effects on infarct size assessed by either method. A clear reduction in the extent of glycogen depletion and histological damage was observed with the combination of metoprolol and dazmegrel 48 h after the onset of ischaemia. This protection was seen to occur in the horizontal plane of the heart, preventing the extension of the infarct towards the posterior wall of the left ventricle and showing some salvage of the epicardial surfaces.

Animals↗
PubMed1985

AH23848, a thromboxane antagonist, suppresses ischaemia and reperfusion-induced arrhythmias in anaesthetized greyhounds.

The effects of the thromboxane antagonist AH23848 (1 mg kg-1 i.v.) were examined in anaesthetized greyhounds prepared for occlusion of the left anterior descending coronary artery with subsequent reperfusion after 40 min of myocardial ischaemia. Pretreatment with AH23848 30 min before coronary artery occlusion reduced the number of ischaemia-induced extrasystoles to 339 +/- 111 compared with 736 +/- 153 in the control group. The incidence of ventricular fibrillation following reperfusion was also markedly reduced; 25% compared with 88% in the controls. Late intervention with AH23848, 25 min after the onset of myocardial ischaemia did not significantly alter the incidence of reperfusion-induced ventricular fibrillation; 70% of the control group died and 60% of those that received AH23848. The ischaemia-induced release of thromboxane A2 and prostacyclin was not altered by pretreatment with AH23848. The results suggest that blockade of thromboxane receptors before myocardial ischaemia is an effective antiarrhythmic strategy in this model.

Anesthesia↗
PubMed1985

The relationship between coronary artery occlusion-induced arrhythmias and myocardial cyclic nucleotide levels in the anaesthetized rat.

The aims of this study were to determine whether a relationship exists between the occurrence of coronary artery occlusion-induced arrhythmias in the anaesthetized rat and the levels of cyclic AMP and cyclic GMP in both normal and ischaemic myocardium, and to assess whether such arrhythmias were modified by pretreatment with the phosphodiesterase inhibitors, quazodine and isobutyl methylxanthine (IBMX), or with the butyryl derivatives of cyclic AMP and cyclic GMP. At 5 min after coronary artery ligation (when only a few arrhythmias had occurred) both cyclic AMP and cyclic GMP levels were elevated in normal myocardium whereas in ischaemic tissue only cyclic AMP was raised. As the peak of the arrhythmic activity and after cessation of the arrhythmias, i.e. at 10 and 30 min post-ligation respectively, levels of both nucleotides had fallen in ischaemic although not in normal tissue. The severity of these occlusion-induced arrhythmias was exacerbated by pretreatment intravenously with quazodine, IBMX, dibutyryl cyclic AMP and dibutyryl cyclic GMP. Pretreatment with IBMX was also shown to elevate significantly both cyclic AMP and cyclic GMP content of left ventricular tissue before occlusion. None of the drug pretreatments markedly affected mean arterial blood pressure but heart rate was significantly increased following quazodine and IBMX administration. We conclude that in the pentobarbitone-anaesthetized rat the occurrence of occlusion-induced arrhythmias was not accompanied by a rise in cyclic nucleotide content of the ischaemic myocardium but agents which may elevate either myocardial cyclic AMP or cyclic GMP levels exacerbate such arrhythmias.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Plasma catecholamines during endotoxin infusion in conscious unrestrained rats: effects of adrenal demedullation and/or guanethidine treatment.

We have examined the effect of E coli endotoxin infusion (41 micrograms kg-1 min-1 iv for 4 h) on plasma concentrations of epinephrine (E), norepinephrine (NE), and dopamine (DA) in the conscious unrestrained rat. Saline infusion did not change catecholamine concentrations from the preinfusion values of 230.8 +/- 32.9 pg ml-1 (E), 456.8 +/- 104.9 pg ml-1 (NE), and 49.0 +/- 19.9 pg ml-1 (DA). Endotoxin produced marked elevations in all three catecholamines. At 1 h, the plasma concentrations were 3,279 +/- 494.6 pg ml-1 (E), 1,670 +/- 137.0 pg ml-1 (NE), and 191.5 +/- 13.7 pg ml-1 (DA). Thereafter, concentrations of E decreased whereas concentrations of NE and DA increased. These increases were prevented by a combination of adrenal demedullation (28 days previously) and treatment with guanethidine (25 mg kg-1 iv, -24 h) ("sympathectomy"). Guanethidine alone markedly reduced the peak NE concentrations without affecting the E concentrations or the 1-h NE concentrations. Demedullation alone prevented the increase in E and reduced the 1-h NE concentrations. Survival in such "sympathectomized" animals was markedly reduced (survival at 4 h in rats receiving endotoxin alone, 100%: in "sympathectomized" animals receiving endotoxin, 12.5%). The tachycardia produced by endotoxin was attenuated in "sympathectomized" rats and mean arterial blood pressure fell rapidly. Endotoxin-induced hyperglycemia was prevented by "sympathectomy" and hypoglycemia was evident as early as 1 h after commencing the infusion. Endotoxin produced hypoinsulinemia in normal rats but did not change plasma insulin values in "sympathectomized" animals, although these animals showed a pre-endotoxin fasting hyperinsulinemia. An important protective role for catecholamines is suggested, especially in the early stages of shock.

Adrenal Medulla↗
PubMed1985

Metabolic and cardiovascular effects of endotoxin infusion in conscious unrestrained rats: effects of methylprednisolone and BW755C.

Infusion of Escherichia coli endotoxin (41.7 micrograms kg-1 min-1 i.v. for 4 h; 10 mg kg-1 total) in conscious unrestrained rats produced an increase in heart rate and a gradual decrease in arterial blood pressure. Initially plasma glucose was transiently elevated but fell to hypoglycaemic values in the 1-2 h before death. There was a marked elevation in the plasma concentrations of lactate, thromboxane B2, and 6-keto prostaglandin F1 alpha, (PGF1 alpha). Methylprednisolone treatment (two doses of 30 mg kg-1) significantly reduced mortality, provided the first dose was given before commencing the endotoxin infusion; there was no effect on mortality if it was given 2 h after starting the endotoxin infusion. Methylprednisolone pretreatment maintained arterial blood pressure and plasma glucose and prevented the increase in plasma lactate in rats given endotoxin. Methylprednisolone treatment did not modify the increase in plasma thromboxane B2 but attenuated the increase in plasma 6-keto PGF1 alpha concentrations. Pretreatment with BW755C, an inhibitor of both cyclooxygenase and lipoxygenase enzymes, completely prevented the increase in plasma prostanoid concentrations but did not improve survival or significantly modify any other detrimental effects of endotoxin. It is suggested that the beneficial effects of methylprednisolone in this model of endotoxin shock are not related to a reduction in the formation of pharmacologically active arachidonic acid metabolites.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

The effect of beta-adrenoceptor blockade and of thromboxane synthetase inhibition, alone and in combination, on arrhythmias resulting from myocardial ischemia.

The effects of pretreatment with metoprolol (2 mg/kg, i.v.), UK 38,485 (5 mg/kg, i.v.), and a combination of the two drugs were examined on early (0-0.5/hr) and late (0.5-4 hr) ischemic arrhythmias resulting from coronary artery ligation in the anesthetized rat. Metoprolol was administered at different times after the onset of ischemia to determine any relationship between antiarrhythmic effects and the time of administration. Studies with two other thromboxane synthetase inhibitors, dazoxiben and carboxyheptylimizadole, and a thromboxane analogue, U 46,619, were performed on the early arrhythmias to investigate a possible role of thromboxane A2 in the genesis of ischemic arrhythmias. Pretreatment and very early intervention with metoprolol caused a significant reduction in the incidence of ventricular fibrillation (VF) in the 0-0.5 hr period. The number of ventricular ectopic beats (VEBs) and the incidence of ventricular tachycardia (VT) during the 0.5-4 hr period were markedly reduced by both pretreatment and late intervention with metoprolol. VEBs and VT in the 0-0.5 hr phase were reduced by UK 38,485 and carboxyheptylimidazole and increased by U 46,619. Administration of a combination of the drugs produced a significant reduction in early VF and late VEBs.

Animals↗
PubMed1984

The effects of nafazatrom on arrhythmias and prostanoid release during coronary artery occlusion and reperfusion in anaesthetized greyhounds.

The effects of the antithrombotic drug nafazatrom (BAY g 6575) were investigated in chloralose-anaesthetized greyhounds subject to coronary artery occlusion and reperfusion. Pretreatment with nafazatrom 10 mg/kg p.o. did not significantly reduce the number of extrasystoles or the incidence of ventricular fibrillation (VF) during the first 30 min occlusion of the left anterior descending coronary artery. However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group). Both thromboxane B2 (TxB2) and 6-keto PGF1 alpha (breakdown products of TxA2 and prostacyclin respectively) were released from the acutely ischaemic myocardium in control dogs. Nafazatrom did not alter the release of TxB2 but the concentrations of 6-keto PGF1 alpha were elevated in blood draining from both the ischaemic and normal regions of the myocardium. The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats.

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.

Anesthesia↗
PubMed1984

An investigation into the characteristics of reperfusion-induced arrhythmias in the anaesthetized rat and their susceptibility to antiarrhythmic agents.

Reperfusion-induced arrhythmias were elicited in the pentobarbitone-anaesthetized rat by occlusion of the left main coronary artery and subsequent release. These arrhythmias were rapid in onset, occurring within 20 s after release of the ligature, and were of short duration (1-2 min). Their severity was dependent upon the duration of the preceding occlusion. A 5 or 15 min occlusion period produced the most severe arrhythmias on release, the incidence of ventricular fibrillation being 56 and 50% respectively. Evidence that reperfusion had occurred was provided by fluorescein dye distribution and intramyocardial temperature studies. The severity of reperfusion arrhythmias and mortality was unaffected by bilateral vagotomy, beta-adrenoceptor blockade by atenolol (2 mg kg-1 i.v.) or a combination of the two. The incidence of reperfusion-induced ventricular fibrillation was significantly reduced by Org 6001 (which blocks the fast inward sodium current), melperone (which acutely prolongs the cardiac action potential duration) and bepridil (which blocks both fast and slow inward currents). It was unaffected by nitroglycerine and the calcium antagonists verapamil, prenylamine and nifedipine. We have shown that reperfusion-induced cardiac arrhythmias can be consistently elicited in the anaesthetized rat and that they are particularly susceptible to drugs that can block the fast inward sodium current.

Anesthesia↗
PubMed1984

The effects of timolol on arrhythmias and prostanoid release during canine myocardial ischaemia and reperfusion.

Timolol (50 micrograms kg-1), administered intravenously to chloralose-anaesthetized open-chest greyhounds 30 min prior to occlusion of the left anterior descending coronary artery, reduced heart rate and mean arterial blood pressure. This dose caused a 20 fold increase in the dose of isoprenaline required to increase heart rate by 25 beats min-1. During the first 30 min of myocardial ischaemia the number of extrasystoles in the timolol-treated dogs (327 +/- 179) was less than in the control group (888 +/- 168) and none of the dogs that received timolol fibrillated. The haemodynamic changes induced by coronary artery occlusion (decreased cardiac output and stroke volume, increased peripheral vascular resistance) were similar in both control and timolol-treated dogs as were the increases in PCO2 and decreases in PO2 and pH in blood draining from the ischaemic myocardium. Timolol did not alter the release during myocardial ischaemia, of either thromboxane B2 or prostacyclin (measured as 6-keto PGF1 alpha). Reperfusion-induced ventricular fibrillation occurred in 7 out of 8 control dogs and in 5 out of 10 timolol-treated dogs. The overall survival following occlusion and reperfusion was improved by 10% to 50% by timolol.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Prostaglandins and thromboxane in the delayed phase of shock induced by Serratia marcescens endotoxin.

The cardiovascular and metabolic effects of an endotoxin derived from Serratia marcescens were examined in anaesthetized, spontaneously-breathing cats. There was a marked initial elevation of right atrial pressure (the result of pulmonary vasoconstriction) and decreases in systemic arterial pressure and in arterial PO2. The 'delayed' effects of endotoxin shock in this species (1-8 h) consisted of a reduced cardiac output and decreased urinary excretion. Blood pressure and myocardial contractility (assessed from measurement of left ventricular (LV) dP/dt and LV end-diastolic pressure) were maintained throughout this phase. There was evidence of a metabolic (lactic) acidosis largely compensated by hyperventilation. Plasma levels (both arterial and mixed venous blood samples) of prostaglandin (PG)E2, PGF2 alpha, 6-keto PGF1 alpha and thromboxane (TX)B2 were measured by radioimmunoassay techniques. Endotoxin administration caused substantial increases in the plasma levels of all four derivatives of arachidonic acid, especially between 1 and 6 h. Separation of the endotoxin-treated cats into survivors and non-survivors showed that the non-survivors had significantly higher circulating levels of PGE2, TXB2 and PGF2 alpha. It is suggested that TXB2 and PGF2 alpha might contribute to some of the detrimental effects of endotoxin (e.g. pulmonary, mesenteric, renal vasoconstriction; platelet aggregation with resulting organ failure) and that prostacyclin may be beneficial in endotoxin shock in this species.

Animals↗
PubMed1984

Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats.

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.

Animals↗
PubMed1984

Aspects of the cardiovascular pharmacology of exaprolol.

This study confirms that exaprolol is a potent beta-adrenoceptor antagonist, having a pA2 value of 9.8 for the inhibition of the inotropic and chronotropic responses of guinea-pig isolated atrial preparations to isoprenaline. In the anaesthetized cat, exaprolol blocks both the myocardial stimulatory and vasodilating effects of isoprenaline, suggesting that it is a non-selective antagonist at beta-adrenoceptors. Exaprolol also has direct electrophysiological effects on cardiac (Purkinje) tissue, reducing the rate of rise of phase 0 of the action potential. This direct action together with its marked blockade of beta-adrenoceptors may explain the drug's ability to markedly suppress the ischaemic ventricular arrhythmias that follow coronary artery occlusion in anaesthetized rats.

Action Potentials↗
PubMed1983

Cardioprotection with calcium antagonists by suppression of early ischaemia and reperfusion-induced arrhythmias.

This paper discusses the relevance of certain animal models for the production of ischaemia and reperfusion-induced ventricular arrhythmias to clinical problems of ischaemia, for example, sudden cardiac death. It then describes experiments in anaesthetised rats subjected to acute coronary artery occlusion in which nifedipine (administered both intravenously and orally) prevented the occurrence of ventricular fibrillation and markedly increased survival. In anaesthetised dogs, a continuous intravenous infusion of nifedipine reduced the severity and incidence of ventricular ectopic activity and also dramatically improved survival on reperfusion fro 12.5% (in the controls) to 88%. The mechanisms of this protection are discussed.

Animals↗
PubMed1983

Pharmacological agents to aid the clinician in combating myocardial ischaemia.

This paper summarizes the effects of various drugs (sodium channel inhibitors, alpha and beta-adrenoceptor blocking agents, calcium antagonists and substances that interfere in various ways with the metabolism of arachidonic acid (e.g. aspirin, dazoxiben, nafazatrom) on the early consequences of experimental acute myocardial ischaemia. Particular attention is paid to effects on the serious early arrhythmias that arise within a few minutes of the onset of ischaemia, on those ventricular arrhythmias that result from the subsequent reperfusion of the ischaemic myocardium and on the severity and extent of myocardial ischaemic damage. From these experimental studies conclusions are drawn regarding possible approaches to early intervention with drugs in clinical myocardial infarction. Among those agents where, based on results from studies in animals, early administration should prove beneficial are beta-adrenoceptor blocking drugs, calcium antagonists, drugs that inhibit thromboxane synthesis or its effects at receptor level, agents that 'promote' prostacyclin, nitroglycerin and analgesics with marked antiarrhythmic properties (e.g. meptazinol). However, the answer to the question as to which (if any) of these drugs should be given early in clinical infarction is still dependent upon the results of considerably more experimental and clinical studies.

Adrenergic beta-Antagonists↗
PubMed1983

Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetised greyhounds.

1 The effects of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on haemodynamics, blood gases, thromboxane and prostacyclin release and on arrhythmias were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. 2 Ten minutes after the administration of UK 37248 2 mg/kg intravenously, the plasma concentration of thromboxane B2 in the coronary sinus was significantly reduced whereas the 6-keto-prostaglandin F1 alpha concentration was increased. 3 UK 37248 did not significantly alter the number of arrhythmias or the incidence of ventricular fibrillation resulting from coronary artery occlusion. There was evidence, however, that in some drug-treated animals there may have been incomplete inhibition of thromboxane synthesis during coronary artery occlusion. 4 A further dose of 1 mg/kg UK 37248 was administered intravenously 5 min before the release of the 40 min coronary artery occlusion. Seven out of eight control dogs died in ventricular fibrillation following reperfusion whereas only one out of eight drug-treated animals fibrillated. 5 This latter result suggests that thromboxane may be an important factor in reperfusion induced ventricular fibrillation and that dazoxiben may be a useful drug in clinically related situations.

Anesthesia↗
PubMed1983

Effect of dazoxiben, a specific inhibitor of thromboxane synthetase, on acute pulmonary responses to E. coli endotoxin in anaesthetized cats.

1 The effects of acute pretreatment with the thromboxane synthetase inhibitor dazoxiben 5 mg/kg intravenously (UK 37248-01) were examined on the acute pulmonary responses of pentobarbitone-anaesthetized cats to E. coli endotoxin 2 mg/kg intravenously. 2 E. coli endotoxin in control, untreated, cats resulted in a marked pulmonary hypertension, an increase in intra-tracheal pressure (at a constant pulmonary inflation volume), an increase in both pulmonary arterial and aortic concentrations of thromboxane B2 (TXB2) and a reduction in systematic arterial PO2. 3 Dazoxiben prevented, or markedly reduced, the endotoxin-induced pulmonary release of TXB2, the decrease in systematic arterial PO2 and the pulmonary arterial hypertension, but did not modify the increase in intratracheal pressure. 4 These results may suggest that TXA2 is responsible for the endotoxin-induced pulmonary arterial hypertension but that some other arachidonic acid derivative (prostaglandin F2 alpha) is responsible for the reduced lung compliance that follows the acute administration of E. coli endotoxin.

Anesthesia↗