The endotoxin receptor on mononuclear phagocytes.
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Flow Cytometry↗
Biomedical subjects
J R Parratt
Publications and source records attributed to J R Parratt.
Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway.
The involvement of L-arginine-dependent nitric oxide (NO) production in the vascular failure observed in endotoxemia was investigated in male Wistar rats treated with Escherichia coli lipopolysaccharide (LPS). Contractile responses to norepinephrine (NE) were measured ex vivo in aortas isolated from rats treated with LPS (20 mg/kg ip, 4 h before experiments) and pressor responses to NE were recorded in vivo in rats infused with LPS (5 mg.kg-1.h-1 iv). LPS pretreatment induced a rightward shift of the concentration-response curve to NE and a reduction of the maximal contraction by approximately 43% and 54% (P less than 0.05) in aortic rings with and without functional endothelium, respectively. This was not modified by the presence of indomethacin (10 microM) during the contractile experiments. In contrast, in the presence of NG-monomethyl-L-arginine (L-NMMA, 300 microM) or methylene blue (10 microM), maximal contractions to NE were restored to control values whether functional endothelium was present or not. The effects of L-NMMA were reversed by L- but not by D-arginine. Additionally, the effects of LPS pretreatment on vascular contractility were potentiated by L-arginine. In vivo, LPS infusion produced a reduction in pressor responsiveness to NE (0.1-10 mg/kg), which was also abolished by L-NMMA (30 mg/kg iv). This effect of L-NMMA was reversed by L- but not by D-arginine (100 mg/kg iv). These results demonstrate that activation of the L-arginine pathway has a major role in the production of vascular hyporeactivity in endotoxemia, ex vivo as well as in vivo. Additionally, they suggest that endothelium-independent vascular production of NO may be involved.
Acetylcholine↗
Endotoxin-induced impairment of vascular reactivity in the pithed rat: role of arachidonic acid metabolites.
The effect of endotoxin on vascular reactivity was studied in pithed rats. Endotoxin infusion (1 mg kg-1 h-1) impaired pressor responses to noradrenaline, angiotensin II, BAY K 8644, and stimulation of the spinal sympathetic outflow. The loss of reactivity was prevented by pretreatment with the cyclooxygenase inhibitor flurbiprofen or the dual cyclooxygenase/lipoxygenase inhibitor BW755C. The effect of endotoxin in impairing vascular reactivity to noradrenaline was mimicked by prostaglandin E2 and platelet-activating factor but not by the prostacyclin analogue iloprost. Platelet-activating factor also impaired responsiveness to sympathetic stimulation. These results suggest a role for cyclooxygenase products and, possibly, platelet-activating factor in endotoxin-induced impairment of vascular reactivity.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Enzymes in normally perfused and ischaemic dog hearts which release a substance with kinin like activity.
The presence of amidases cleaving the tripeptide VAL.LEU.ARG.pNA, and liberating from human plasma kininogen substance(s) able to contract uterine smooth muscle and to lower blood pressure (uterus contracting and hypotensive activity), has been demonstrated in vascular and muscle tissues from normally perfused and ischaemic areas of dog hearts. Studies were carried out on blood free preparations of coronary arteries and veins and normally perfused and ischaemic ventricle. All the tissues were found to contain both acid optimum (pH 6) and alkaline optimum (pH greater than 9) enzymes forming uterus contracting substance (UCS, bioassayed on isolated uterus of rats in oestrus), the highest levels of both activities being found in arterial tissues and the least in ventricle. Enzyme levels in ischaemic or normally perfused ventricle did not differ significantly. Gel filtration (Sephacryl, S-300) of coronary artery extracts gave one peak each of acid optimum enzyme with a molecular weight of 38,300 +/- 800 daltons and alkaline optimum enzyme with a molecular weight of 92,100 +/- 4000 daltons. Both acid and alkaline enzyme fractions cleaved the tripeptide substrate with pH optima identical to those for UCS formation. The acid optimum activity, both of UCS formation and tripeptide cleavage, was inhibited by pepstatin but not by aprotinin or soybean trypsin inhibitor (SBTI). The alkaline optimum activity was inhibited by aprotinin and SBTI but not pepstatin. Both acid and alkaline optimum enzymes released a hypotensive agent from a plasma protein substrate. The molecular weight and response to inhibitors of the acid optimum enzyme were similar to a cathepsin, and those of the alkaline optimum enzyme were similar to plasma kallikrein.
Animals↗
Coronary vessels contain enzymes that liberate kinin-like vasodilator substances.
The presence of an acid optimum (pH 6) enzyme capable of generating a spasmogenic, vasodilator polypeptide from human plasma kininogen has been demonstrated in dog coronary arteries, veins and in the wall of the left ventricle. This enzyme also cleaved the tripeptide kallikrein substrate Val-Leu-Arg-pNA. Highest amounts were present in the coronary arteries. Gel filtration (Sephacryl S-300) of coronary artery extracts gave a peak for this acid optimum enzyme of 38, 300 +/- 800 Daltons. Its activity was inhibited by pepstatin but not by aprotinin or soya bean trypsin inhibitor. This enzyme, which is similar to a cathepsin, may play a role in the processing of peptide hormones in the heart and coronary vessels.
Animals↗
The effects of PAF antagonists on arrhythmias and platelets during acute myocardial ischaemia and reperfusion.
The aim of the study was to examine a possible role for platelet activating factor (PAF) in experimental myocardial ischaemia and reperfusion. Anaesthetized open-chest greyhounds were subjected to 40 min of coronary artery (LAD) occlusion followed by reperfusion. Blood samples for platelet counting were obtained from a local coronary vein draining the ischaemic region. Pretreatment with PAF antagonists BN52021 (5 mg kg-1 i.v.) or SRI63441 (10 mg kg-1 i.v.), 15 min prior to occlusion reduced the ventricular ectopic count during the ischaemic period from 614 +/- 82 (controls) to 296 +/- 145 (BN52021) and 474 +/- 200 (SRI63441). Both drugs also reduced the incidence of ventricular fibrillation (VF) (during ischaemia and reperfusion) from 90% (controls), to 50% (BN52021) and 43% (SRI63441). Ischaemia was accompanied by a 32 +/- 7% reduction in coronary venous platelets; this was attenuated by both BN52021 (-2 +/- 6%) and SRI63441) (-1 +/- 5%). These results suggest that PAF may contribute to ischaemia and reperfusion-induced arrhythmias by activating platelets.
Acute Disease↗
Cardiac electrophysiological effects of isoprenaline, phenylephrine, and noradrenaline on normal and mildly "ischaemic" sheep Purkinje fibers.
The aim of this study was to examine the electrophysiological effects of isoprenaline, phenylephrine, and noradrenaline on sheep Purkinje fibers in vitro, superfused either with a normal or with a modified physiological salt solution (PSS) designed to mimic some of the conditions occurring during mild myocardial ischemia (hyperkalemia, hypoxia, and acidosis). Intracellular microelectrode recording techniques were used to record resting and action potentials. Noradrenaline (10(-7) to 10(-5) M) and phenylephrine (10(-7) to 10(-5) M) prolonged the action potential of normal fibers in a concentration-dependent manner, the effect of phenylephrine being greater than that of noradrenaline. The only effect of isoprenaline (10(-7) to 10(-5) M) was a slight hyperpolarization. The modified PSS caused marked reductions in resting membrane potential, upstroke, and duration of the action potential. On these depressed fibers isoprenaline, noradrenaline, and phenylephrine all prolonged the action potential, and in the case of noradrenaline the duration of the abbreviated action potential was restored beyond control. This effect of noradrenaline and isoprenaline was more marked under ischemic than normal conditions, whereas the opposite was true of phenylephrine. In the presence of effective alpha- or beta-adrenoceptor blockade, the noradrenaline-induced prolongation of the "ischemia"-abbreviated action potential was attenuated. In some of the preparations exposed to simulated ischemia, noradrenaline caused inexcitability. In conclusion, isoprenaline, phenylephrine, and noradrenaline exhibited different electrophysiological effects on mildly "ischemic" sheep Purkinje fibers compared to their effects on normal fibers.
Acidosis↗
Electrophysiological effects of adenosine and adenosine triphosphate on sheep Purkinje fibres under normal and simulated ischaemic conditions.
1. The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated. 2. The only statistically significant effects of adenosine (10(-6)-10(4) M) and of ATP (10(-6)-10(-4) M) on normal action potential characteristics were a slight dose-dependent shortening of the action potential by adenosine and a depolarization by ATP, 10(-4) M. 3. Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential. 4. Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS. 5. Adenosine did not alter the noradrenaline-induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres. 6. Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.
Action Potentials↗
The effects of drugs interacting with opioid receptors on the early ventricular arrhythmias arising from myocardial ischaemia.
1. The effects of a range of opioid receptor agonists and antagonists with differing opioid receptor selectivities on ischaemia-induced arrhythmias in anaesthetised rats was investigated. 2. Naloxone was antiarrhythmic only at doses expected to antagonise kappa- and delta-receptors in addition to mu-receptors. 3. The opioid receptor antagonist Mr 2266, which is twice as potent at kappa-receptors as at mu-receptors dose-dependently reduced the incidence and severity of the arrhythmias resulting from coronary artery occlusion. 4. The opioid receptor antagonist M 8008 (1 mg kg-1), which is twice as potent at delta-receptors as at mu-receptors but has very little affinity for the kappa-receptor, did not exhibit any beneficial antiarrhythmic properties. 5. MrZ 2593, a quarternary complex of naloxone which does not readily cross the blood brain barrier, was antiarrhythmic which implies that the antiarrhythmic actions of opioid receptor antagonists may be mediated via peripheral opioid receptors. 6. The agonists, diamorphine, [Leu] enkephalin and U-50,488H exhibited no significant arrhythmogenic effects under the present experimental conditions. 7. It is tentatively suggested that blockade of peripheral kappa-receptors during acute myocardial ischaemia may result in an antiarrhythmic effect.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
The antiarrhythmic and cardiac electrophysiological effects of buprenorphine.
1. The effects of buprenorphine, given intravenously, on the incidence and severity of early acute coronary artery occlusion-induced arrhythmias were examined in anaesthetised rats. The electrophysiological effects of buprenorphine were also examined in sheep Purkinje fibres and rat papillary muscles, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2. In anaesthetised rats subjected to acute coronary artery occlusion, pretreatment with buprenorphine (1 mg kg-1 i.v.) markedly reduced the incidence of ventricular extra-systoles during the initial 30 min post-occlusion period. The incidence of ventricular fibrillation (VF) was also significantly reduced from 56% to 10%. 3. At the antiarrhythmic dose (1 mg kg -1), buprenorphine also attenuated the sudden fall in systemic arterial blood pressure induced by acute coronary artery ligation. 4. In normal sheep Purkinje fibres and rat papillary muscles, buprenorphine (10(-6)-10(-5) M) significantly reduced the action potential height and maximum rate of depolarisation of phase zero (MRD) and prolonged the duration of the action potential. 5. Superfusion of sheep Purkinje fibres and rat papillary muscles with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 6. In the presence of the modified compared with normal PSS, buprenorphine reduced the action potential height and MRD of both sheep Purkinje fibres and rat papillary muscles to a greater extent, although its ability to prolong the action potential duration was attenuated. 7. The antiarrhythmic effects of buprenorphine observed in vivo may be explained by its direct cardiac electrophysiological effects. Buprenorphine might be useful in relieving pain and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.
Anesthesia↗
Mediators of acute lung injury in endotoxaemia.
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Animals↗
Calcium antagonists in shock--a minireview of the evidence.
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Animals↗
Effect of dopexamine hydrochloride in the early stages of experimental myocardial infarction and comparison with dopamine and dobutamine.
The effect of dopexamine hydrochloride on myocardial performance, and on the susceptibility of the myocardium to generation of arrhythmias during the development of myocardial infarction has been compared with dopamine and dobutamine in 2 experimental models of myocardial ischemia. All 3 agents improved cardiac function in the presence of a developing infarct. Dopamine and dobutamine increased myocardial contractility (left ventricular dP/dt and left ventricular dP/dt/P), which would be expected to increase oxygen consumption and thus further compromise the ischemic myocardium. Dopexamine hydrochloride, however, improved cardiac function mainly by reducing afterload. The infusion of dopamine and dobutamine resulted in a high (100%) incidence of ventricular arrhythmias compared with only 63% with dopexamine hydrochloride. The effects of these agents on early ischemic arrhythmias after coronary artery ligation in anesthetized rats were also studied. Dopexamine hydrochloride reduced the incidence and severity of arrhythmias in the early stages of ischemia: At a dose of 0.25 micrograms/kg/min, the total number of ectopic beats was reduced to 375 +/- 175, from 1,250 +/- 330 in control rats (p less than 0.05). Dopexamine hydrochloride also significantly reduced mortality from ventricular fibrillation and there was a slight reduction in the incidence and duration of ventricular tachycardia and fibrillation.
Anesthesia↗
Alifedrine, a positive inotropic agent that moderately reduces the severity of ischaemia and reperfusion-induced ventricular arrhythmias.
The effects of alifedrine, a positive inotropic agent, were examined in greyhounds anaesthetised with chloralose. An intravenous dose of 0.3 mg kg-1 resulted in a substantial increase in myocardial contractility (increased dP/dtmax, cardiac output and stroke volume) without significantly affecting heart rate. The effects of alifedrine on the severity of arrhythmias resulting from both coronary artery occlusion and reperfusion were also determined. A mild antiarrhythmic effect was observed during early ischaemia when the incidence of ventricular tachycardia was reduced from 90% in controls to 50% in treated dogs. There was also a significant reduction in the number of extrasystoles appearing as ventricular tachycardia (from 511 +/- 138 to 151 +/- 84). The total number of extrasystoles during the first 30 min of ischaemia was also reduced, although not significantly, from 846 +/- 193 to 527 +/- 86. Following release of a 40 min coronary artery occlusion there was a marked reduction in reperfusion-induced ventricular fibrillation from 75% in controls, to 37% in the alifedrine-treated dogs. The overall survival from the combined occlusion-reperfusion insult was increased from 20% in controls to 50%. These results suggest that alifedrine has an unusual and useful spectrum of pharmacological activity in that it combines antiarrhythmic activity with an ability to improve cardiac function.
Animals↗
An antiarrhythmic effect of adenosine during myocardial ischaemia and reperfusion.
Adenosine (10 micrograms kg-1 min-1, infused into the lumen of the left ventricle) and dipyridamole (0.25 mg kg-1 intravenously, a dose that potentiated markedly the fall in arterial pressure in response to bolus doses of adenosine) each reduced the number of extrasystoles which occurred during the first 30 minutes following coronary artery occlusion in anaesthetised greyhound dogs (from 786 +/- 115 in control dogs to 156 +/- 44 in those treated with adenosine and to 388 +/- 167 with dipyridamole). Intracoronary adenosine (1 microgram kg-1 min-1, infused into the ischaemic area) however appeared to increase the number of extrasystoles to 1230 +/- 214. Left ventricular infusion of adenosine reduced the incidence of ventricular fibrillation (from 88 to 43%) when the ischaemic myocardium was perfused at the end of a 40 min occlusion period. In the dose used in this study (10 micrograms kg-1 min-1) adenosine caused a sustained fall in blood pressure but did not alter blood gases. In control dogs the levels of purine derivatives in blood draining the myocardium rendered ischaemic by coronary artery occlusion (local coronary venous samples) increased gradually during the ischaemic period (from 9 +/- 3 microM pre-occlusion to 25 +/- 7 microM post-occlusion). Dipyridamole increased the resting plasma concentration of purines prior to occlusion by approximately 90%; these remained raised for the occlusion period. These results support the suggestion that adenosine may act as a locally produced endogenous antiarrhythmic agent.
Adenosine↗
Pathophysiology of myocardial ischemia: importance of platelet-vessel wall interactions.
Clinical and experimental evidence for important interactions between platelets and vascular endothelium under conditions of myocardial ischemia is briefly summarized. The clinical evidence for a role of platelets in myocardial ischemia includes studies indicating alterations in platelet behavior and the therapeutic benefit of some antiplatelet drugs. Experimental evidence suggesting the importance of platelets in ischemia includes reductions in transmyocardial platelet number under these conditions, the cyclical reductions in coronary blood flow that result from intermittent intravascular platelet aggregation, and the relationship between induced platelet aggregation and cardiac arrhythmias. Evidence strongly suggesting the importance of platelet emboli and thromboxane generation as a major cause of reperfusion-induced ventricular arrhythmias is outlined.
Blood Platelets↗
The effects of L655,240, a selective thromboxane and prostaglandin endoperoxide antagonist, on ischemia- and reperfusion-induced cardiac arrhythmias.
The purpose of this investigation was to provide a detailed analysis of the effects of the thromboxane antagonist L655,240 (0.3 mg/kg i.v.) on early ischemia- and reperfusion-induced arrhythmias in a canine model of coronary artery occlusion. In a dose that abolished the pulmonary response to U46619, L655,240 attenuated markedly the severity of those arrhythmias that resulted from reperfusion of the myocardium; survival from the combined occlusion-reperfusion insult was increased from 10% in control animals to 70% in dogs administered L655,240. Drug intervention did not significantly alter the total number of arrhythmias during the period of ischemia, but a detailed analysis of the different types of arrhythmia that occurred during this period showed that L655,240 significantly reduced those arrhythmias in phase 1a (0-10 min of occlusion) without affecting the later phase 1b arrhythmias. This was particularly shown in the marked reduction in the number of salvos (couplets and triplets) during this period. Neither those arrhythmias occurring later in the ischaemia period (phase 1b) nor the total number of single ectopics and salvos or the incidence and duration of ventricular tachycardia was modified by L655,240. These results reveal that thromboxane antagonism protects especially against reperfusion-induced ventricular fibrillation and against early (phase 1a) ischemia-induced arrhythmias, possibly implicating a role for thromboxane in the genesis of these cardiac rhythm disturbances.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Eicosanoids and cardiac arrhythmias.
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Animals↗