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G F Baxter

Publications and source records attributed to G F Baxter.

At least 55 records · Page 3Linked to original sources
PubMed1997

Myocardial ischemic tolerance following heat stress is abolished by ATP-sensitive potassium channel blockade.

Heat stress is known to confer protection against ischemia, but the mechanisms involved are yet to be elucidated. Opening of ATP-sensitive potassium (K[ATP]) channels has been demonstrated to be involved in other endogenous forms of cardioprotection, in particular "classic" ischemic preconditioning and delayed preconditioning following treatment with the endotoxin derivative, monophosphoryl lipid A. We therefore speculated that there may be a role for K(ATP) channels in delayed heat stress-induced cardioprotection. This hypothesis was investigated in an in vivo rabbit model of acute myocardial infarction using two structurally dissimilar K(ATP) channel blockers, glibenclamide and sodium 5-hydroxydecanoate. Sodium pentobarbitone-anesthetized rabbits were subjected to either transient heat stress at 42 +/- 0.2 degrees C for 15 minutes or sham anesthesia. Twenty-four hours later, animals were reanesthetized ("Hypnorm" and sodium pentobarbitone) and a midline sternotomy and pericardiotomy were performed. An anterolateral branch of the circumflex coronary artery was occluded for 30 minutes and reperfused for 2 hours. The infarct-to-risk ratio was significantly limited in vehicle-treated rabbits from 41.3 +/- 4.0% in controls (n = 10) to 24.1 +/- 5.0% (n = 9; P = 0.014 by one-factor ANOVA) in heat-stressed hearts. This limitation in infarct size was abolished by 0.3 mg/kg i.v. glibenclamide or 5 mg/kg i.v. 5-hydroxydecanoate when administered 10 minutes prior to coronary occlusion (45.2 +/- 6.4%; n = 9 and 41.5 +/- 5.0%; n = 5, respectively.) The same doses of glibenclamide and 5-hydroxydecanoate in sham-anesthetized hearts had no effect (42.3 +/- 5.1%; n = 10 and 51.9 +/- 2.2%; n = 6, respectively). The adequacy of the heat stress protocol was confirmed by Western blot analysis of the inducible 72-kD heat stress protein. It is concluded, therefore, that K(ATP) channels appear to play a role in the heat stress response. The underlying mechanisms involved are, however, unclear.

Animals↗
PubMed1997

Time course of delayed myocardial protection after transient adenosine A1-receptor activation in the rabbit.

Ischaemic preconditioning of myocardium enhances tolerance to infarction in a biphasic manner. Adenosine A1-receptor activation has been implicated as a trigger of both the early the late phases of protection in rabbit myocardium. Delayed protection against myocardial infarction in vivo was previously shown to occur 24 h after transient adenosine A1-receptor activation with the selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA). Our studies examined the time course of CCPA-induced delayed myocardial protection and a possible mechanism of protection, the elevation of the cytoprotective inducible 72-kDa heat-shock protein (hsp70i). Rabbits were pretreated with a single dose of CCPA 100 micrograms/kg or saline i.v. Twenty-four, 48, 72, or 96 h after treatment, they were anaesthetised, and a left branch of the circumflex coronary artery was reversibly occluded for 30 min, followed by 120 min reperfusion. Infarct size was determined as a percentage of the myocardial risk volume by using triphenyltetrazolium staining. Approximately 50% reduction in infarct-to-risk volume ratio was observed 24, 48, and 72 h after CCPA pretreatment, compared with time-matched saline-pretreated controls. No infarct limitation was observed 96 h after CCPA pretreatment. Differences in infarct size were not related to differences in myocardial risk zone size or systemic haemodynamic parameters during the infarct protocol. Left ventricular tissue harvested from a separate cohort of animals pretreated with CCPA, 100 micrograms/kg, was assessed for content of hsp70i by Western blot analysis. The protein was not induced by CCPA treatment at any time point during the period in which cardioprotection was observed. We conclude that transient adenosine A1-receptor activation produces a delayed and prolonged period of enhanced resilience to ischaemia in rabbit myocardium. This is probably the result of an adaptive mechanism but does not involve elevation of hsp70i.

Adenosine↗
PubMed1997

Ischaemic preconditioning of myocardium.

Myocardium has the innate potential to adapt to transient sublethal ischaemia so that it becomes more resistant to a subsequent, more severe, ischaemic insult. The response is called ischaemic preconditioning and protection of the myocardium is manifested by a slowing of adenosine triphosphate decline, limitation of ischaemic necrosis and a reduction in dysrhythmia severity. Protection conferred by preconditioning occurs in two distinct temporal phases. An early phase of protection is observed immediately but wanes within two to three hours (classic preconditioning). This is followed many hours later by a second window of protection (delayed preconditioning). The cellular mechanisms underpinning both forms of protection are currently being intensively investigated. There is evidence that human myocardium can be preconditioned ex vivo and also in situ during elective procedures such as angioplasty and coronary artery bypass grafting. Furthermore, evidence points to the possibility that preconditioning occurs naturally in some ischaemic syndromes, particularly warm-up angina and preinfarction angina. Ultimately, investigation of the mechanisms of preconditioning may contribute to the development of rational therapies for protecting the ischaemic myocardium and, perhaps more importantly, enhance our understanding of the molecular basis of ischaemic heart disease.

Adaptation, Physiological↗
PubMed1996

Infarct limitation of the second window of protection in a conscious rabbit model.

OBJECTIVES: Myocardial protection associated with ischemic preconditioning (PC) wanes within an hour or two. It has recently been observed, however, that a delayed phase of protection appears about 24 h after ischemic PC in anesthetized rabbits and dogs which might be related to synthesis of cytoprotective proteins. We tested whether a second window of protection could be induced in conscious rabbits. METHODS: Rabbits chronically instrumented with a coronary artery occluder and ECG electrodes experienced a 30-min coronary occlusion followed by 3 h reperfusion. Infarct size was measured with triphenyltetrazolium chloride. RESULTS: 35.7 +/- 2.3% of the risk zone infarcted in control animals. PC with 4 cycles of 5-min coronary occlusion/10-min reperfusion 24 h prior to the 30-min ischemia decreased infarction to 24.1 +/- 1.4% of the risk zone (P < 0.01). During the 30-min occlusion 3 of 7 non-PC rabbits developed ventricular fibrillation, while this arrhythmia did not occur in the 7 PC animals (P < 0.1). Myocardial hsp70 content in PC rabbits was twice that in controls. Collateral blood flow was not different in the two groups. CONCLUSIONS: A second window of protection exists in conscious rabbits which minimizes both infarction and arrhythmias, and cytoprotective protein content is increased in the myocardium of protected animals.

Animals↗
PubMed1996

Protection of the myocardium by ischaemic preconditioning: mechanisms and therapeutic implications.

Preconditioning of the heart with brief periods of ischaemia protects the myocardium for up to 90 min against a more sustained ischaemic injury. A "second window of protection" occurs 24 hr after preconditioning with ischaemia. The cardioprotective effects of ischaemic preconditioning involve the release of mediators (adenosine, bradykinin, catecholamines, prostaglandins, endothelin-1), which either alone or in concert activate protein kinase C, which translocates to the cell membrane. This manuscript reviews (i) the cardioprotective effects of ischaemic preconditioning, (ii) the underlying mechanisms, (iii) the effects of ischaemic preconditioning of other tissues (skeletal muscle, brain and kidney), and (iv) the clinical implications.

Adaptation, Physiological↗
PubMed1996

Myocardial protection after monophosphoryl lipid A: studies of delayed anti-ischaemic properties in rabbit heart.

1. Monophosphoryl lipid A (MLA) is a non-pyrogenic derivative of Salmonella lipopolysaccharide. Administration of this agent at high doses to rats and at low doses to dogs was previously shown to confer marked protection against ischaemia-reperfusion 24 h later, although the cellular mechanisms of this delayed protection are obscure. We hypothesized that MLA pretreatment causes the induction of the 70 kDa cytoprotective stress protein HSP70i in the myocardium. If this were the case, protection against ischaemia-reperfusion injury would be observed both in vitro and in vivo. 2. Rabbits were pretreated with MLA 0.035 mg kg-1, i.v. or vehicle solution. For the in vitro study, hearts were isolated 24 h later and Langendorff-perfused with Krebs-Henseleit buffer at 37 degrees C. Global ischaemia was induced for 20 min followed by 120 min reperfusion. Recovery of post-ischaemic left ventricular function and lactate dehydrogenase efflux was similar in MLA and vehicle pretreated hearts and there was no significant difference in the percentage of infarction of the left ventricle determined by triphenyltetrazolium staining (MLA 22.4 +/- 5.2%, vehicle 24.8 +/- 5.1%). 3. When 30 min regional ischaemia and 120 min reperfusion was instituted in pentobarbitone-anaesthetized rabbits 24 h after pretreatment with MLA or vehicle, the percentage infarction within the risk zone was reduced from 42.6 +/- 5.7% in vehicle pretreated animals to 19.6 +/- 4.4% in MLA pretreated animals (P < 0.01). 4. Determination of myocardial HSP70i content by Western blot analysis showed that MLA treatment did not increase HSP70i immunoreactivity. 5. We conclude that MLA at this dose confers protection only against ischaemia-reperfusion injury in vivo and that this protection is not related to induction of HSP70i. Because protection was observed only in vivo it seems possible that the delayed protection conferred by MLA is mediated by effects on humoral or blood-borne factors.

Adjuvants, Immunologic↗
PubMed1995

Involvement of protein kinase C in the delayed cytoprotection following sublethal ischaemia in rabbit myocardium.

Rabbit hearts were preconditioned with four 5 min coronary artery occlusions 24 h before 30 min coronary occlusion with 120 min reperfusion. Preconditioning significantly reduced the percentage of myocardium infarcting within the risk zone from 49.1 +/- 4.3% to 31.8 +/- 3.5% (P < 0.05). When the protein kinase C (PKC) inhibitor, chelerythrine, was administered just before preconditioning, the delayed protection against infarction 24 h later was abolished. We conclude that the delayed cytoprotective response associated with ischaemic preconditioning of myocardium is likely to involve the early activation of one or more PKC subtypes.

Alkaloids↗
PubMed1994

Ischaemic preconditioning protects hypertrophied myocardium.

OBJECTIVE: Clinical and experimental evidence suggests that hypertrophied myocardium is more susceptible to injury from ischaemia than normal myocardium. This study was designed to investigate whether preconditioning confers protection on hearts with moderate hypertrophy. METHODS: Cardiac hypertrophy induced by hypertension was produced in rats by giving saline drinking fluid and subcutaneous deoxycorticosterone acetate for four weeks. After thoracotomy, localisation of the left main coronary artery and stabilisation, groups of hypertensive animals with cardiac hypertrophy (HT) and their age matched normotensive controls (NT) underwent a preconditioning protocol consisting of 5 min occlusion of the left main coronary artery followed by 10 min reperfusion. This was followed by 45 min ischaemia and at least 2.5 h reperfusion. Control animals in the hypertrophied and normotensive groups were treated identically but were not subjected to the preconditioning protocol. Thus there were four experimental groups: HT preconditioned (n = 8), HT control (n = 7), NT preconditioned (n = 7), and NT control (n = 7). Infarct size was measured using triphenyl tetrazolium chloride and was expressed as a percentage of the volume at risk, measured with fluorescent particles. RESULTS: Heart weight was greater (p < 0.01) in the HT groups than in the NT groups [HT preconditioned 1.7(SEM 0.06) g, HT control 1.71(0.02) g, NT preconditioned 1.3(0.04) g, NT control 1.31(0.03) g]. Infarct to risk volume ratio (I/R) was significantly lower (p < 0.05) in the preconditioned groups as compared with controls [HT preconditioned 19.1(1.5)% v HT control 67.1(5.6)%, and NT preconditioned 33.4(5.5)% v NT control 77.1(3.8)%]. There was no significant difference in the volume at risk of infarction between the four groups. CONCLUSIONS: Ischaemic preconditioning can induce myocardial protection in hypertrophied myocardium; this is the first study to demonstrate preconditioning in hypertrophy.

Animals↗
PubMed1994

Adenosine receptor involvement in a delayed phase of myocardial protection 24 hours after ischemic preconditioning.

BACKGROUND: We previously reported a delayed phase of protection against infarction 24 hours after ischemic preconditioning in the rabbit. In the present study, we investigated the possibility that this "second window of protection," like the well-described early phase of protection in the rabbit, might be associated with adenosine receptor activation. METHODS AND RESULTS: In the first series of experiments, we examined whether adenosine receptor blockade with 8-(p-sulfophenyl)-theophylline (SPT) during preconditioning could abolish the delayed protection against infarction 24 hours later. Open-chest rabbits were subjected to myocardial preconditioning (PC) with the four 5-minute coronary occlusions or they were sham operated on (SHAM). During these procedures, animals received either SPT (PC + SPT, n = 6; and SHAM + SPT, n = 6) or vehicle (PC + VEH, n = 12; and SHAM + VEH, n = 11). Twenty-four hours later, infarct development after a 30-minute coronary occlusion/120-minute reperfusion insult was assessed with triphenyltetrazolium staining. In vehicle-treated rabbits, the infarct-to-risk ratio (I/R) was reduced from 53.6 +/- 5.7% (SHAM + VEH) to 32.9 +/- 4.6% (PC + VEH) (P < .05), clearly indicating a delayed phase of protection. Although I/R was not significantly different between SHAM + VEH (53.6 +/- 5.7%) and SHAM + SPT (61.7 +/- 5.4%), in PC + SPT the delayed protection was abolished (I/R = 56.8 +/- 3.8%). In the second series of experiments, we examined if pharmacological adenosine A1 receptor stimulation could evoke a delayed phase of protection. Conscious rabbits were pretreated with intravenous boluses of saline or the A1 receptor-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA), and infarct size in response to 30-minute ischemia/120-minute reperfusion was assessed 24 hours later. I/R was 54.5 +/- 2.7% in saline-pretreated controls (n = 12). Pretreatment with 25 micrograms/kg CCPA (n = 6), 50 micrograms/kg CCPA (n = 6), or 100 micrograms/kg CCPA (n = 6) resulted in I/R ratios of 37.1 +/- 4.2% (P < .01), 37.7 +/- 2.2% (P < .01), and 26.3 +/- 5.7% (P < .01), respectively. In both series of experiments, there were no differences in systemic hemodynamics during the infarct protocol, assessed as rate-pressure product, between the different experimental groups. CONCLUSIONS: Twenty-four hours after repetitive brief coronary occlusions, susceptibility to infarction in rabbit myocardium is reduced, an effect that may have clinical relevance. Results of the present study suggest that this second window of protection following preconditioning may, like the early phase of protection, be initiated by an adenosine-related mechanism.

Adenosine↗
PubMed1993

Attenuation of reperfusion-induced ventricular fibrillation in the rat isolated hypertrophied heart by preischemic diltiazem treatment.

The ability of the calcium antagonist diltiazem to protect against reperfusion-induced arrhythmias in hypertrophied myocardium was studied. Hearts from normotensive and DOCA-salt hypertensive rats were Langendorff perfused and subjected to 10 minutes of stabilization, 10 minutes of left coronary artery occlusion, and 5 minutes of reperfusion. The incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion were determined and the effects of diltiazem or vehicle (given as a single bolus 3 minutes before coronary artery occlusion) were assessed in hypertrophied and normal hearts. In vehicle-treated (control) hypertrophied hearts, VF incidence was 91% compared with 67% in normal hearts, and the median duration of VF was 272 seconds (mean 207.4 +/- 32.3) compared with 27 seconds (mean 110.6 +/- 36.6; p < 0.05), respectively, suggesting that reperfusion VF is more severe in hypertrophied hearts. In normal hearts, diltiazem 18 micrograms reduced VT incidence from 92% to 55%, reduced VF from 67% to 27%, and sustained VF from 42% to 9%. In hypertrophied hearts, 18 micrograms diltiazem reduced the VT incidence from 100% to 58%, reduced VF from 91% to 25% (p < 0.01), and sustained VF from 82% to 8% (p < 0.01). Median VF duration in this group was reduced to 0 seconds (p < 0.05; mean 24.7 +/- 22.6). Diltiazem did not significantly affect heart rate or coronary flow rate decreases during ischemia. However, developed tension, at the onset of ischemia, was lower in diltiazem-treated groups than in the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Inhibition by diltiazem of left ventricle collagen proliferation during renovascular hypertension development in rats.

Diltiazem administered in drinking water (0.7 mg mL-1) to Goldblatt two kidney-one clip rats over 16 weeks did not prevent the development of hypertension and left ventricular hypertrophy (LVH). When the collagen content of the left ventricles was assayed (as hydroxyproline), it was found that the fibrosis, characteristic of LVH, was inhibited by diltiazem treatment, despite the fact that hypertension and LVH had developed. This study provides some indirect evidence for the notion that the collagen and myocyte compartments of the myocardium are under separate influences during LVH development in renovascular hypertension.

Animals↗