PubMed Health⌕ Search

Biomedical subjects

J R Parratt

Publications and source records attributed to J R Parratt.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of chronic norepinephrine administration on cardiac function in rats.

We assessed the changes in the contractile response of rat hearts in vivo after chronic exposure to a range of doses of norepinephrine (NE) and determined whether free radical production played a role in these changes. Osmotic minipumps were implanted subcutaneously (s.c.) in male rats and delivered either NE (0.15-0.35 mg/kg/h) or acid saline for 10-28 days. The animals were then anaesthetised and prepared for haemodynamic measurement, and dose-response curves to acutely administered NE and calcium chloride were constructed. We analysed plasma for evidence of free radical activity by measuring the levels of thiobarbituric acid-reactive substances (TBARS). All doses of NE studied produced left, but not right, ventricular hypertrophy. Treatment with 0.25 mg/kg/h NE for 28 days produced signs of distress and, by 10 days, treatment with 0.35 mg/kg/h resulted in 33% mortality. Treatment with the two lower doses, but not the highest dose, of NE resulted in increases in basal left ventricular (LV) maximum rate of pressure generation and a marked increase in systolic, but not diastolic, arterial blood pressure (SBP, DBP). All doses of NE caused reduced responses to acutely administered NE but no marked change in the response to calcium chloride. Levels of plasma free radicals were increased only with the highest dose of NE. Over the concentration range studied, chronic administration of NE to rats causes beta-adrenoceptor downregulation and free radical production was associated only with the administration of a dose of NE that resulted in high mortality.

Analysis of Variance↗
PubMed1995

Effects of Bordetella pertussis toxin pretreatment on the antiarrhythmic action of ischaemic preconditioning in anaesthetized rats.

1. Bordetella pertussis toxin, which catalyses the ADP-ribosylation of certain guanine nucleotide binding proteins (G proteins), thus functionally uncoupling them from associated receptors, was examined to determine whether it modified the antiarrhythmic effect of ischaemic preconditioning in anaesthetized rats. 2. Pertussis toxin (25 micrograms kg-1, i.p., 48 h prior to heart isolation) attenuated the negative chronotropic effect of acetylcholine (ACh) in rat isolated Langendorff perfused hearts. ACh (10 microM) reduced heart rate by 4% in hearts taken from pertussis toxin-treated animals, compared to a reduction of 57% in hearts taken from animals treated only with vehicle. 3. In anaesthetized rats, ischaemic preconditioning (a single 3 min occlusion of the left main coronary artery followed by 10 min reperfusion) had a pronounced antiarrhythmic effect during a subsequent 30 min period of regional myocardial ischaemia. Compared to hearts receiving only a 30 min period of left coronary occlusion, there was a reduced mortality (67% and 0% for control and preconditioned groups, respectively; P < 0.01) and decreased incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF). Pretreatment with pertussis toxin (25 micrograms kg-1, i.p., 48 h previously) did not modify the arrhythmias associated with a 30 min period of regional myocardial ischaemia, neither did it modify the reduction in mortality (from 56% to 0%; P < 0.05) associated with preconditioning. Furthermore, the decrease in total ventricular premature beat count induced by preconditioning seen in controls (from 427 +/- 130 to 95 +/- 45) was also seen in pertussis toxin-treated rats (from 252 +/- 190 to 57 +/- 25). 4. These results suggest that receptor coupling to pertussis toxin-sensitive G proteins is not necessary for the antiarrhythmic effect of ischaemic preconditioning in this model.

Acetylcholine↗
PubMed1995

The effect of endotoxin on sympathetic responses in the rat isolated perfused mesenteric bed; involvement of nitric oxide and cyclo-oxygenase products.

1. The effects of endotoxin on the vasoconstrictor responses to sympathetic nerve stimulation (SNS) were investigated in the rat isolated perfused mesenteric bed. 2. Rats received either saline (0.1 ml h-1) or endotoxin (2.5 mg kg-1 h-1) intravenously for 4 h; the mesenteric beds were then isolated, perfused with Krebs and prepared for SNS (50 V, 3 ms, 7-40 Hz). 3. SNS caused a frequency-dependent vasoconstrictor response which was abolished by either tetrodotoxin (10(-7) M), prazosin (2.4 x 10(-7) M) or guanethidine (2.4 x 10(-7) M). 4. In mesenteric vascular beds removed from rats infused with endotoxin, there were markedly impaired vasoconstrictor responses to SNS, although responses to noradrenaline were not modified. 5. Removal of the endothelium with distilled water prevented endotoxin-induced impairment of vasoconstrictor responses to SNS, without modifying these responses in preparations from control rats. 6. Pretreatment with dexamethasone (3 mg kg-1 i.p. 1h before commencing endotoxin or saline infusions) did not modify responses to SNS in control rats but prevented the effects of endotoxin. 7. Both L-NAME (10(-3) M) and indomethacin (10(-5) M) restored responses to SNS in preparations from endotoxin-treated rats without modifying these responses in control preparations. However, co-administration of L-NAME and indomethacin markedly augmented responses in both control and endotoxin-treated preparations. 8. The effects of L-NAME were reversed by addition of L-arginine (10(-3) M). 9. The data suggest that endotoxin impairs the release of noradrenaline and that this effect is secondary to increased production of nitric oxide and prostanoids, possibly by the endothelium.

Animals↗
PubMed1995

Bradykinin as an endogenous myocardial protective substance with particular reference to ischemic preconditioning--a brief review of the evidence.

The present brief review summarizes the evidence for the possibility that endogenously released bradykinin plays a major role in protecting the heart against the consequences of acute myocardial injury. This evidence includes the facts that kinins are generated under myocardial ischemia; that when they are administered, they are cardioprotective (e.g., antiarrhythmic); that drugs that enhance the release of bradykinin from the ischemic heart reduce the ischemic injury and, conversely, drugs that block bradykinin receptors attenuate the reduction in ischemic injury resulting from the release of, or administration of, bradykinin. The possible mechanism of bradykinin in the cardioprotection afforded by ischemic preconditioning is summarized. Ischemic preconditioning can be defined as the marked reduction in the severity of ischemic changes that result from coronary artery occlusion when that occlusion is preceded by brief periods of myocardial ischemia, either regional or global, induced, for example, by complete or partial coronary artery occlusion or by rapid ventricular pacing. The possible mechanisms of cardioprotection elicited by bradykinin (and ischemic preconditioning) are summarized. The most likely is the generation of cyclic GMP within the ischemic myocardium following bradykinin-stimulated nitric oxide generation and release from endothelial cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Functional effects of intracellular pH alteration in the human uterus: simultaneous measurements of pH and force.

Changes in intracellular pH have differing effects on contraction in different types of muscle, and between species. Because of the large number of women requiring a caesarean section due to failure to progress in labour, it is important to know how the human myometrium responds to the changes in intracellular pH that may occur during labour. The pH-sensitive dye, carboxy-SNARF, was used to measure intracellular pH in small strips of human myometrium. Intracellular pH and tension were simultaneously recorded in pregnant and nonpregnant tissue. Intracellular pH was altered by the addition of weak acids and bases. Intracellular alkalinization caused an increase in the frequency and amplitude of contractions. Intracellular acidification led to an initial increase in the frequency and/or the amplitude of the contractions, followed by abolition of contractions. Alterations in intracellular pH had profound effects on contraction in human uterine smooth muscle. Possible mechanisms are discussed whereby pH could influence force production, and changes in contraction are related to the speed and extent of the change in intracellular pH.

Adult↗
PubMed1995

An acidic kininogenase in rat ventricular myocardium.

BACKGROUND: Canine ventricles have been reported to contain a cathepsin D-like kininogenase, which might confer protection on the heart during ischaemia. The aim of this study was to investigate the presence and levels of a similar kininogenase in normal and ischaemic rat hearts. METHODS: Aqueous extracts of rat ventricles were tested for the ability to release bradykinin-like immunoreactivity from human low-molecular-weight kininogen and high-molecular-weight kininogen at acidic pHs. The enzymes involved were separated using gel filtration followed by the testing of fractions for cleavage of D-Val-Leu-Arg-pNA and low-molecular-weight kininogen. Extracts from normal and ischaemic ventricles were compared for the ability to release bradykinin-like immunoreactivity from low-molecular-weight kininogen. Kinin levels in mixed venous blood were compared before and after ischaemia. By assessing their effect on isolated oestrous rat uteri and on protease inhibitors, further characterization of acidic kininogenases in the extracts was performed. RESULTS: Extracts of rat ventricles released bradykinin-like immunoreactivity only from low-molecular-weight kininogen. Using the isolated oestrous rat uterus, gel filtration and protease inhibitors, the enzyme involved was identified as a cathepsin D-like enzyme with an optimum pH of 4.7 and a molecular weight of 42.8 +/- 4.9 kDa. It is an arginine amidase and releases bradykinin-like immunoreactivity from low-molecular-weight kininogen. Ischaemia reduced the amount of bradykinin-like immunoreactivity released by the ventricular extract (P < or = 0.05) and increased levels of free kinin in venous blood from the right atrium. CONCLUSION: Rat ventricles contain a cathepsin D-like acidic protease that cleaves low-molecular-weight kininogen to release bradykinin-like immunoreactivity. The acidic protease may protect the heart during ischaemia.

Animals↗
PubMed1994

Protection of the heart by ischaemic preconditioning: mechanisms and possibilities for pharmacological exploitation.

Ischaemic preconditioning can be defined as the protective adaptive mechanism produced by short periods of ischaemic stress resulting in a marked, albeit temporary, resistance of the myocardium to a subsequent more prolonged period of that same stress. This protection includes reductions in ischaemic cellular damage and in life-threatening ventricular arrhythmias. The most likely mechanisms for this protection are discussed in this review by James Parratt and involve the release of endogenous substances from the ischaemic myocardium (for example, adenosine, bradykinin, nitric oxide and prostacyclin) with the possible involvement of ATP-dependent K+ channels, Gi proteins and protein kinase C. If we understood more fully the precise mechanisms of this pronounced protection, it should be possible to exploit them pharmacologically to ultimate therapeutic advantage.

Animals↗
PubMed1994

Prevention by dexamethasone of the marked antiarrhythmic effects of preconditioning induced 20 h after rapid cardiac pacing.

Dogs were paced, via a pacing electrode in the right ventricle, for four 5 min periods at a rate of 220 beats min-1. On the following day they were reanaesthetized, thoracotomized and the left anterior descending coronary artery occluded for 25 min. Pacing markedly reduced the severity of ischaemia-induced arrhythmias (e.g. reduction in VF from 45% in unpaced dogs to 10% in paced dogs; P < 0.05), an effect reversed by dexamethasone (4 mg kg-1 i.v., 45 min prior to pacing). This protection may be due to the induction of nitric oxide synthase or cyclo-oxygenase.

Animals↗
PubMed1994

Attenuation by dexamethasone of endotoxin protection against ischaemia-induced ventricular arrhythmias.

Ventricular arrhythmias from a 30 min occlusion of the left coronary artery were assessed in Langendorff perfused isolated hearts removed from rats administered either saline, or endotoxin derived from Escherichia coli (2.5 mg kg-1 i.p.) given either 2, 4, 8, 24 or 48 h previously. Arrhythmia severity was markedly reduced in those hearts removed from rats administered endotoxin with a maximum protection at 8h; there was a marked reduction in the incidence of ventricular fibrillation (from 54% to 4%) and in the number of ventricular premature beats during the occlusion period (e.g. from 1165 +/- 144 to 37 +/- 19; P < 0.01). Dexamethasone (3 mg kg-1, given 1 h prior to endotoxin or saline) markedly attenuated the protection afforded by endotoxin.

Animals↗
PubMed1994

Effects of NS-2, a new class 1 antiarrhythmic agent, and AFD-19, its active metabolite, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats: comparison with disopyramide and mexiletine.

We studied the antiarrhythmic effects of NS-2 (4-diisobutylamino-1,1-diphenyl-1-butanol maleate) and AFD-19 (active metabolite of NS-2) on early stage ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized male rats. These effects were compared with those of disopyramide and mexiletine. Drugs were intravenously administered either before or after coronary occlusion. When administered 5 min before occlusion, 3 mg/kg of NS-2 and AFD-19 exhibited equivalent anti-arrhythmic activity to that of 5 mg/kg of disopyramide and mexiletine, as assessed by reductions in the number of premature ventricular complexes and in the incidences of ventricular tachycardia and ventricular fibrillation. In a dose of 5 mg/kg, the antiarrhythmic effects of NS-2 and AFD-19 were more pronounced. When administered 5 min after coronary artery occlusion, only NS-2 and AFD-19 (in doses of 5 mg/kg) had significant antiarrhythmic effects. None of the drugs influenced the severe ventricular arrhythmias induced by reperfusion when administered 1 min before reperfusion. In conclusion, NS-2 might be effective in reducing the severity of the life-threatening ventricular arrhythmias that occur during acute myocardial infarction.

Amino Alcohols↗
PubMed1994

Platelet activating factor impairs pressor responses to noradrenaline in the anaesthetized rat but does not mediate endotoxin-induced hyporeactivity.

A nonhypotensive dose of endotoxin (Escherichia coli lipopolysaccharide, 250 micrograms kg-1 h-1) impaired both the pressor responsiveness to noradrenaline and its effects in reducing renal and hindquarter blood flow, measured using ultrasound Doppler flow probes. Platelet activating factor (PAF, 50 ng kg-1 h-1) similarly impaired pressor responsiveness to noradrenaline, although this effect was accompanied by marked hypotension. These actions of PAF were prevented by pretreatment with the PAF antagonists WEB 2086 (20 mg kg-1) or BN 50739 (10 mg kg-1) 15 min before commencing the infusion. However, neither antagonist modified the effect of endotoxin in impairing vascular responsiveness to noradrenaline. Thus, these results do not support a role for PAF in mediating endotoxin-induced vascular hyporeactivity, at least in the early stages of endotoxaemia.

Anesthesia↗
PubMed1993

Effects of the xanthine oxidase system on cardiac function in anaesthetised rats.

This investigation aimed to determine whether contractile dysfunction of the myocardium could be produced upon generation of free radicals in the anaesthetised rat. The enzyme xanthine oxidase, combined with its substrate purine and an iron source, was used to generate free radicals in the venous circulation. The suspended form of xanthine oxidase, with substrate, produced a transient, significant depression in the contractile indices dP dt-1 max and dP dt-1 P-1 and arterial blood pressure, 1146 +/- 87 mm Hg s-1, 9 +/- 1 s-1, and 18 +/- 1 mm Hg, respectively. This could not be attenuated by the enzymatic free radical scavengers superoxide dismutase and catalase. Furthermore, the suspended xanthine oxidase alone or its vehicle were able to produce a similar effect to that of the complete free-radical-generating system. The maximum soluble dose of the crystalline form of the enzyme when employed in the generating system had no effect upon administration despite its production of superoxide radicals in vitro. These results suggest that the haemodynamic effects of the free-radical-generating system containing the suspended form of xanthine oxidase were due to the effects of its vehicle and that the free-radical-generating system containing the crystalline form of the enzyme did not produce sufficient free radicals in vivo to modify myocardial contractility.

Animals↗
PubMed1993

Effects of R-PIA, a selective A1 adenosine agonist, on haemodynamics and ischaemic arrhythmias in pigs.

OBJECTIVES: Adenosine has previously been shown to protect against ischaemia induced ventricular arrhythmias. The aim of this study was to determine whether stimulation of A1 adenosine receptors with a selective agonist also protects against arrhythmias, and to attempt to elucidate the underlying mechanisms. METHODS: Large White/Welsh Landrace cross breed domestic pigs (25-40 kg) subjected to left anterior descending coronary artery occlusion were used. R-PIA [R(-)N6-(2-phenylisopropyl) adenosine; 5 micrograms.kg-1] was given prior to coronary artery occlusion and the effects on haemodynamic variables and early ischaemic arrhythmias in the absence and presence of right atrial pacing were studied. The three experimental groups were: solvent controls, n = 10; R-PIA without pacing, n = 10; R-PIA with atrial pacing, n = 10. Ex vivo assessment of platelet aggregation was also performed to determine any inhibitory effects of R-PIA on platelets. RESULTS: Administration of R-PIA without atrial pacing reduced the total number of ventricular ectopic beats induced by coronary occlusion, from 326(SEM 71) in controls to 121(30) (p < 0.05) and the incidence of ventricular fibrillation from 70% to 20% (p < 0.05). At the dose used, R-PIA reduced heart rate from 102(7) to 74(3) beats.min-1, with a consequent reduction in mean arterial blood pressure from 95(4) to 81(3) mm Hg. Atrial pacing following drug administration, at a rate of 109(5) beats.min-1, restored blood pressure and abolished the antiarrhythmic effects of R-PIA. Drug intervention had no effect on either ex-vivo platelet aggregation or coronary sinus oxygen content, suggesting a lack of activity at A2 adenosine receptors. CONCLUSIONS: An A1 adenosine receptor agonist exerts a marked protection against ischaemia induced ventricular arrhythmias and fibrillation in pigs. The reversal of this effect by restoring heart rate suggests that the drug induced bradycardia may be important in the antiarrhythmic action of R-PIA, possibly via an anti-ischaemic effect.

Animals↗
PubMed1993

Are ATP sensitive potassium channels involved in the pronounced antiarrhythmic effects of preconditioning?

OBJECTIVE: The aim was to determine whether the antiarrhythmic effects of preconditioning are modified by blockade of K+ATP channels with glibenclamide in a model (anaesthetised dogs) in which this procedure has previously been shown to prevent the effects of preconditioning in reducing myocardial infarct size. METHODS: 10 mongrel dogs were preconditioned by two 5 min occlusions of the left anterior descending coronary artery, separated by a 20 min reperfusion period, and then subjected, 20 min later, to a prolonged (25 min) occlusion and to subsequent reperfusion. In another 10 dogs glibenclamide (300 micrograms.kg-1) was given by intravenous injection both after the first preconditioning stimulus and before the prolonged occlusion. Control dogs (25) were subjected to a 25 min occlusion followed by reperfusion; five of these dogs also received glibenclamide. RESULTS: Preconditioning reduced the severity of ventricular arrhythmias, epicardial ST segment elevation, and the degree of inhomogeneity of conduction. The antiarrhythmic effect of preconditioning was attenuated by glibenclamide (twice as many ventricular premature beats and more episodes of ventricular tachycardia) but there was no modification of preconditioning induced reduction in ventricular fibrillation either during ischaemia or during reperfusion, or on survival (0% in controls; 50% in preconditioned dogs with or without glibenclamide). Glibenclamide did, however, prevent the effects of preconditioning on the inhomogeneity of conduction and, less markedly, on epicardial ST segment elevation. CONCLUSIONS: In a similar model to that in which it has previously been shown that glibenclamide prevents the effect of preconditioning in reducing myocardial infarct size (suggesting involvement of K+ATP channels), the most pronounced antiarrhythmic effects of preconditioning (reduction in ventricular fibrillation; increase in survival) were not modified by glibenclamide. This, and other evidence, suggests that the mechanisms of the protective effect of preconditioning in reducing the severity of arrhythmias and on infarct size are not the same.

Adenosine Triphosphate↗
PubMed1993

The antiarrhythmic effect of ischaemic preconditioning in isolated rat heart involves a pertussis toxin sensitive mechanism.

OBJECTIVE: The aims were to examine the effect of pretreatment with Bordetella pertussis toxin on the antiarrhythmic effect of ischaemic preconditioning in order to determine the possible involvement of inhibitory G proteins in this phenomenon; and (2) to characterise the model used by varying the duration of a single preconditioning occlusion of the left coronary artery, the reperfusion time, and the duration of the subsequent prolonged coronary artery occlusion. METHODS: Isolated rat hearts perfused with Krebs Henseleit solution at constant flow (8-10 ml.min-1) were subjected to a single preconditioning occlusion of the left coronary artery (either 1 or 3 min) followed, up to 60 min later, by a prolonged occlusion of 30 or 60 min (n = 56). The ventricular arrhythmias during occlusion were compared to those from control rats in which the artery was occluded for 30 or 60 min but without preconditioning (n = 29 and 14 respectively). RESULTS: Protection against ventricular arrhythmias was most pronounced when a 3 min preconditioning occlusion was used followed by a 10 min reperfusion period: reduction in ventricular premature beats (VPB) during the 30 min occlusion from 514(SEM 119) in control hearts to 79(29) in preconditioned hearts (p < 0.01). This protection was still apparent when the reperfusion time was extended to 30 min [VPB 52(16); p < 0.01] but lost when reperfusion was extended to 1 h. Rendering Gi proteins non-functional (ascertained by responses to acetylcholine) resulted in loss of this antiarrhythmic effect of preconditioning [VPB 241(93) v 226(120) for non-preconditioned hearts]. CONCLUSIONS: The antiarrhythmic effects of preconditioning can be demonstrated in isolated rat hearts perfused at constant flow with an artificial medium and this protection is lost following treatment with Bordetella pertussis toxin 48 h previously.

Animals↗