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Biomedical subjects

J R Parratt

Publications and source records attributed to J R Parratt.

At least 37 records · Page 2Linked to original sources
PubMed1997

The case of low-dose aspirin for the prevention of myocardial infarction: but how low is low?

Although there is firm consensus that aspirin reduces the incidences (and severity) of reinfarction if given to patients after a myocardial infarction or in patients with unstable angina, there is disagreement about the optimum dose that should be used. We make the case that it could be considerably lower than the "medium dose" (75-320 mg daily) in current usage and put forward the view that a dose of 30 mg daily is sufficient. The arguments are based on the presystemic, exclusively pharmacokinetic inhibition of thromboxane synthesis in platelets by very low-dose aspirin and the importance of maintaining prostacyclin production by endothelial cells. Little attention has been in the past to the endogenous myocardial protection that results from prostacyclin generation. Such low doses have the additional advantage of not inducing gastrointestinal ulceration. We conclude that more extensive clinical trials with such "low-dose" aspirin preparations are warranted.

Aspirin↗
PubMed1997

Nitric oxide. A key mediator in sepsis and endotoxaemia?

A very large number of biologically active substances are released into the circulation under conditions of endotoxaemia and sepsis. One of the most important of these is nitric oxide. Under these conditions nitric oxide is produced through an induced enzyme (nitric oxide synthase) in a variety of tissues and the nitric oxide so generated is largely responsible for the loss of vascular reactivity, which occurs under these conditions, for the resulting unrelenting hypotension associated with the hypodynamic phase of septic shock. Nitric oxide also contributes to the myocardial depression in this condition. The question as to whether it is a worthwhile therapeutic approach to inhibit nitric oxide synthase is discussed with particular reference to the generation of inhibitors selective for the induced form of the enzyme. This approach has certain benefits but may also be detrimental. The fact that nitric oxide is not the key mediator involved in ultimate mortality in this condition is suggested by the failure to improve mortality in iNOS knockout mice given endotoxin.

Animals↗
PubMed1996

Nicorandil suppressed ventricular arrhythmias in a canine model of myocardial ischaemia.

These experiments were designed to explore the possibility that a K+ channel opener which also donates nitric oxide to the myocardium (nicorandil) may modify ischaemia-induced ventricular arrhythmias in a large animal model. In mongrel dogs anaesthetised with chloralose-urethane and thoracotomised, a side branch of the left anterior descending artery was catheterised for the local intracoronary infusion of nicorandil (2.5 micrograms kg-1 min-1 for 20 min prior to coronary artery occlusion and then continuing throughout the 25 min occlusion period). In this dose, nicorandil had no haemodynamic effects, increased coronary blood flow by up to 16% and significantly reduced the severity of ischaemia-induced arrhythmias (e.g. from nearly 500 ventricular premature beats in the controls to 160 +/- 60 in the nicorandil group). There was a significant reduction in the number of episodes of ventricular tachycardia during the ischaemic period and a reduced incidence of ventricular fibrillation following reperfusion resulting in a 42% survival from the combined ischaemia-reperfusion insult (cf. 0% in the control; P < 0.05). The marked changes that occurred in ST-segment elevation (mapped with epicardial electrodes) and in the inhomogeneity of electrical activation within the ischaemic area in control dogs was markedly reduced in those dogs administered nicorandil. We conclude that the local intracoronary administration of nicorandil reduces the severity of both ischaemia and the life-threatening arrhythmias that result from an abrupt reduction in coronary blood flow in this canine model. Possible mechanisms include an increase in coronary blood flow, a reduction in the severity of myocardial ischaemia and an ability of the compound to "donate' nitric oxide to the ischaemic area.

Animals↗
PubMed1996

The release of kininase from rat isolated hearts during myocardial ischaemia.

BK destroying activity was observed in rat isolated heart perfusates. BK was optimally degraded at pH 8.4 in rat heart. The results indicated that myocardial kinin degradation was due to ACE and a serine protease. These results suggest that bradykinin may have some cardioprotective role during myocardial ischaemia at acidic pH.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Captopril and norepinephrine-induced hypertrophy and haemodynamics in rats.

We wished to determine whether pretreatment with captopril, an angiotension-converting enzyme (ACE) inhibitor, modified the myocardial and haemodynamic consequences of chronic administration of norepinephrine (NE) in rats. Administration of NE (0.15 mg kg(-1) h(-1) by an osmotic minipump implanted subcutaneously for 28 days) resulted in left but not right ventricular hypertrophy. Captopril (250 but not 52 mu g kg(-1) h(1) administered for 28 days) significantly attenuated the development of left ventricular hypertrophy (weight of left ventricle to body weight ratio was 0.46 +/- 0.01 0.57 +/- 0.02, 0.53 +/- 0.02, and 0.51 +/- 0.01 for vehicle, NE, and NE plus low and high dose of captopril, respectively). Chronic administration of NE caused significant increases in systolic arterial blood pressure (BP: 194 +/- 11 vs. 130 +/- 6 mm Hg), systolic left ventricular pressure, heart rate (HR: 458 +/- 13 vs. 389 +/- 15 beats/min) and dP dt(-1)(max) P(-1), an index of myocardial contractility (202 +/- 29 vs. 91 +/- 3 s(-1)). Captopril (250 mu g kg(-1) h(-1) for 28 days) significantly reduced diastolic arterial BP (from 86 +/- 6 to 53 +/- 3 mm Hg). Concomitant administration of this dose of captopril together with NE prevented the NE-induced increase in systolic arterial BP but did not modify the increases in HR or dP dt(-1) max P(-1) (261 +/- 41 and 202 +/- 29 s(-1) in captopril and NE vs. NE-alone groups). Acute administration of NE (0.1-10 mu g kg(-1) intravenously, i.v.) produced less marked increases in cardiac contractility and in arterial BP in rats chronically pretreated with NE or NE plus captopril than in animals receiving vehicle or captopril alone. Chronic administration of NE and/or captopril did not significantly modify the haemodynamic effects of the acute administration of calcium chloride. We conclude that administration of captopril at 250 but not 52 mu g kg(-1) h(-1) for 28 days attenuates NE-induced cardiac hypertrophy and that this effect is associated with a decrease in systolic arterial BP. Captopril did not modify the reduced effects of acutely administered NE in rats treated with NE for a prolonged period.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Effect of nitric oxide synthase inhibition on myocardial contractility in anesthetized normal and endotoxemic dogs.

Nitric oxide (NO) produced by the induced NO synthase (NOS) enzyme has been implicated in the mechanisms of the circulatory changes that occur in the later stages of sepsis. As NO produced by the constitutive form of the enzyme is known to play a role in the regulation of normal circulation, we have performed a series of experiments to study the early circulatory effects of inhibition of NOS in a hyperdynamic endotoxemic dog model. Pentobarbital-anesthetized animals were used. Cardiac output (CO) was measured by thermodilution. Myocardial contractility (MC) was estimated from the slope of the left ventricular end-systolic pressure-diameter relationship obtained from sonomicrometer- and catheter-tip manometer signals in closed chest animals. All animals received a 15 mL/kg/h infusion of Ringer's lactate. A hyperdynamic response was elicited by a 2 h infusion of a total dose of 5.3 micrograms/kg Escherichia coli O55:B5 endotoxin (ETX). CO increased initially by about 25%, and total peripheral resistance decreased by 35%. These changes subsided in 60-90 min, after which a sustained decrease in CO occurred. MC elevated transiently by 25% after the first 30 min of ETX infusion, then decreased gradually below the control level. Administration of 2 mg/kg of the NOS inhibitor N-nitro-L-arginine (NNA) between the 45th and 55th min of the ETX infusion increased MC to the level in the control group, but accelerated the decline of the initially increased CO and caused a sustained increase in total peripheral resistance to about 50% above the control level. In normal (nonendotoxin treated) dogs, NNA also caused a similar increase in MC which, however, lasted at least 3 h. Left ventricular diameter increased in the NNA-treated groups. This increase also occurred in the endotoxin-only group but with a delay of about 2.5 h. Our results demonstrate the participation of constitutive NOS-produced NO in the early hyperdynamic response of endotoxemia. Suppression of NO is associated with increased myocardial contractility. NNA treatment may be favorable for the restoration of depressed cardiac contractility during endotoxemia, but this treatment is probably detrimental for the compensatory systemic flow (CO) increase.

Anesthesia↗
PubMed1996

Endotoxin-induced inhibition of mesenteric vasodilator responses to acetylcholine, bradykinin, and post-occlusion hyperemia in anesthetized rats.

The effects of endotoxin (20 mg kg-1 i.p.) on the mesenteric vascular responses to acetylcholine, bradykinin, sodium nitroprusside, and to transient occlusion of the superior mesenteric artery were examined in rats anesthetized with pentobarbitone. Mesenteric vasodilator responses to close arterial injections of acetylcholine and bradykinin were reduced at 1.5 h after endotoxin and almost abolished by 4 h; responses to sodium nitroprusside were unaffected. Occlusion of the superior mesenteric artery for 30, 60, or 120 s produced, on release of the occlusion, a time-dependent vasodilator response in the mesenteric circulation (post-occlusion hyperemia). This hyperemia was markedly reduced by nitro-L-arginine methyl ester (L-NAME); L-NAME did not modify acetylcholine-induced vasodilation. Endotoxin-pretreatment did not modify mesenteric post-occlusion hyperemia 1.5 h after administration but markedly reduced the response by 2.5 h. The administration of L-NAME to endotoxin-treated rats did not further attenuate the hyperemic responses. Mesenteric vasoconstrictor responses to phenylephrine were not modified by endotoxin, although systemic pressor responses to this agent were impaired. We concluded that endotoxin impairs endothelium and nitric oxide-dependent vasodilator responses in the mesenteric circulation.

Acetylcholine↗
PubMed1996

Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats.

This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg.kg-1.h-1) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 microgram.kg-1, intravenously [i.v.]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg.kg-1 i.v. 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin-treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L-arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.

Analysis of Variance↗
PubMed1996

Delayed protection against ischaemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin.

1. Bacterial endotoxin (lipopolysaccharide derived from Escherichia coli) was injected intraperitoneally in conscious rats in doses ranging from 0.5 to 2.5 mg kg-1. At various times afterwards the animals were anaesthetized and subjected to a 30 min period of left coronary artery occlusion. 2. Under these conditions the severity of ventricular arrhythmias was markedly suppressed, in comparison with saline-injected controls, but this was particularly marked with the higher doses (1.5 and 2.5 mg kg-1); the number of ventricular premature beats was reduced from 1687 +/- 227 over the 0.5 h coronary artery occlusion period to 190 +/- 46 in those rats administered 2.5 mg kg-1 endotoxin 8 h previously (P < 0.05). The duration of ventricular tachycardia was also significantly reduced (138 +/- 26 s to 8.9 +/- 4.2 s; P < 0.01) and there was a reduction in the incidence of ventricular fibrillation (from 56% to 10%). 3. The time course of this protection was studied following the administration of a single dose of 2.5 mg kg-1 of endotoxin by anaesthetizing rats 4, 8 or 24 h later. Protection was apparent at each time but was particularly marked at 8 h. 4. No rat given the highest dose of endotoxin (32 in all) died as a result of ventricular fibrillation, or from any other cause, during an occlusion, in contrast to a 26% mortality in the controls (P < 0.01). 5. Infarct size, measured following a 30 min period of coronary artery occlusion followed by a 3 h reperfusion period, was reduced both 8 and 24 h after the administration of 2.5 mg kg-1 endotoxin (reductions of 24.3 and 23.1% respectively; P < 0.05). Endotoxin had no significant effect on the area at risk. 6. The beneficial effects of endotoxin on infarct size and on ventricular arrhythmias were markedly attenuated by the prior administration of dexamethasone, 3 mg kg-1 given 1 h prior to endotoxin administration. Dexamethasone itself reduced infarct size (P < 0.05) but had no direct effect on arrhythmia severity following coronary artery occlusion. 7. The mechanisms of this "cross-tolerance' induced by bacterial endotoxin against ischaemia-reperfusion injury remain to be elucidated but the most likely mechanisms appear to be the induction of protective enzymes or proteins (e.g. nitric oxide synthase, cyclo-oxygenase (COX) 2) probably mediated by cytokine release.

Animals↗
PubMed1996

Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats.

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.

Animals↗
PubMed1995

Changes in intracellular pH close to term and their possible significance to labour.

The contractile pattern of uterine smooth muscle is markedly altered by even modest manipulations of intracellular pH (pHi); an acidification can abolish contractions, while alkalinization increases contractility. As at the end of gestation the uterus changes from being relatively quiescent to highly contractile, we investigated whether pHi changes with pregnancy in women. Isolated tissue was loaded with the pH-sensitive fluorophore, carboxy-SNARF. We found a significant alkalinization over the last few weeks of pregnancy. Such an increase in pHi will increase contractility of the uterus, and may therefore contribute to the mechanisms ensuring strong and efficient contractions occur during labour.

Adult↗
PubMed1995

Pronounced antiarrhythmic effects of preconditioning in anaesthetized dogs: is adenosine involved?

Although there is good evidence that adenosine contributes to the ability of ischaemic preconditioning to reduce myocardial ischaemic damage (infarct size) there is no evidence that it contributes to the marked antiarrhythmic effects of this endogenous protective mechanism. We have examined this in anaesthetized open-chest mongrel dogs by administering the non-selective adenosine receptor blocking drug 8-sulfophenyltheophylline (8-SPT) (1 mg/kg) given by intracoronary administration 10 min before both 5 min preconditioning coronary artery occlusions and also before the prolonged 25 min LAD occlusion i.e. in a total dose of 3 mg/kg. The only haemodynamic effect of 8-SPT was a reduction in coronary (LAD) blood flow and an increase in cardiovascular resistance. It was difficult to precondition dogs in the presence of 8-SPT; the number of ventricular premature beats was significantly higher (61 +/- 6 v 8 +/- 4; P < 0.01) during the initial preconditioning occlusion and the incidence of ventricular fibrillation during the preconditioning procedure was higher in the presence of the drug (5/11 v 4/20; P < 0.05). Nevertheless, it was still possible to precondition these dogs in the presence of the drug. No VF occurred during the prolonged occlusion (cf. 50% in the controls) and the number of episodes of ventricular tachycardia, and the number of ventricular premature beats in dogs preconditioned in the presence of 8-SPT was similar to those in dogs preconditioned without 8-SPT and significantly (P < 0.01 or P < 0.05) less than in control, non-preconditioned dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Delayed protection of the heart against ischaemia.

Ischaemic preconditioning is the protective adaptive mechanism produced by short periods of ischaemic stress that results in a marked resistance of the myocardium to prolonged periods of the same stress; however, this protection is transient. There is now evidence that protection resulting from preconditioning returns several hours later, and here James Parratt and Laszlo Szekeres highlight the possible importance of this concept, which may lead to novel approaches to the long-term protection of the heart against ischaemic injury.

Animals↗