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M J Curtis

Publications and source records attributed to M J Curtis.

At least 37 records · Page 2Linked to original sources
PubMed1996

Effect of endogenous nitric oxide on cardiac systolic and diastolic function during ischemia and reperfusion in the rat isolated perfused heart.

Nitric oxide (NO) protects the heart against some forms of reperfusion-associated dysfunction (e.g. arrhythmias). Its role in protecting against other types of dysfunction is controversial. NO ameliorates polymorphonuclear cell-induced exacerbation of stunning. Here, whether endogenous NO protects against contractile dysfunction in a polymorphonuclear cell-free model has been tested. Isolated rat hearts (n = 6 per group) were perfused with Krebs solution for 15 min. They were then perfused with test solution: Krebs, or Krebs containing 100 microM NG-nitro-L-arginine methyl ester (L-NAME) (a concentration shown previously to significantly reduce NO content in coronary effluent), 100 microM L-NAME plus 10 mM L-arginine (the latter shown previously to be sufficient to surmount the effect of L-NAME), or 10 mM L-arginine alone. After 10 min of this, the hearts were subjected to 60-min normothermic global ischemia followed by reperfusion with the same test solution as before. A time-matched (sham) group was perfused continuously with Krebs. L-NAME hastened the onset of ischemic contracture (P < 0.05) and increased its peak value from 67.8 +/- 4.6 mmHg to 93.0 +/- 4.9 mmHg (P < 0.05). Both effects were prevented by co-perfusion with 10 mM L-arginine. Initially, reperfusion exacerbated diastolic contracture, but diastolic pressure at a constant ventricular volume fell from 112 +/- 27 mmHg to 73 +/- 19 mmHg between the 5th and 60th min of reperfusion in drug-free hearts, indicative of recovery from diastolic stunning. This recovery was not exacerbated or lessened by perfusion with L-NAME or L-arginine. Left ventricular developed pressure increased from 42 +/- 2 mmHg to 106 +/- 18 mmHg in controls between 5 and 30 min after the start of reperfusion, the latter value being indistinguishable from that in the sham group. At this time, the value in the L-NAME group was similar (78 +/- 18 mmHg). This indicated complete recovery from systolic stunning in both groups 30 min after the start of reperfusion. However, earlier after the start of reperfusion, there had been zero pressure development in the L-NAME group (P < 0.05 v the control group). This was associated with severe impairment of recovery of coronary flow, e.g. of only 18% of the mean coronary flow in controls 5 min after the start of reperfusion (P < 0.05). At 30 min after the start of reperfusion (when systolic function had recovered in the L-NAME group), flow recovery had increased in this group to 96% of the mean control values. The impairment in rates of recovery of systolic function and coronary flow in the L-NAME group were each prevented by coperfusion with L-arginine (P < 0.05). In conclusion, endogenous NO may delay the onset and reduce the magnitude of ischemic contracture but despite this, appears not to facilitate early recovery from systolic and diastolic stunning as a result of any direct action in the myocardium. The beneficial effect it does possess in this polymorphonuclear cell-free preparation is transient and results from mediation of rapid recovery of coronary flow during reperfusion.

Animals↗
PubMed1996

Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias?

Prolongation of the cardiac action potential duration is the hallmark of Class III antiarrhythmic activity. Action potential duration prolongation may be achieved by several means: enhancement of inward current and, more commonly, blockade of one or more of the many outward currents that are carried by K+. However, it is far from clear whether blockade of one particular K+ channel is more efficacious than blockade of another. The objective of this review is to consider this question with particular reference to ischaemic heart disease, a condition for which effective prevention of ventricular arrhythmias continues to be sought.

Animals↗
PubMed1996

Mechanism of 5-hydroxytryptamine-induced coronary vasodilation assessed by direct detection of nitric oxide production in guinea-pig isolated heart.

1. We assessed whether a submaximal concentration (1 microM) of 5-hydroxytryptamine (5-HT) releases nitric oxide (NO) from the coronary endothelium in guinea-pig perfused heart (n = 5 or 6/group) by direct detection of NO in coronary effluent, and determined whether this accounts for the associated coronary dilation. We also tested whether saponin is a selective and specific tool for examining the role of this mechanism in mediating agonist-induced coronary dilatation. 2. Continuous 5 min perfusion with 5-HT, or acetylcholine (ACh; 1 microM), substance P (1 nM) or sodium nitroprusside (SNP; 1 microM) increased coronary flow from baseline by 3.6 +/- 0.2, 3.4 +/- 0.2, 1.8 +/- 0.1 and 4.1 +/- 0.2 ml min-1 g-1, respectively (all P < 0.05). Coronary effluent NO content, detected by chemiluminescence, was correspondingly increased from baseline by 715 +/- 85, 920 +/- 136, 1019 +/- 58 and 2333 +/- 114 pmol min-1 g-1, respectively (all P < 0.05). 3. Continuous perfusion for 30 min with NG-nitro-L-arginine methyl ester (L-NAME) 100 microM reduced basal coronary effluent NO content by 370 +/- 32 pmol min-1 g-1 and coronary flow by 7.5 +/- 0.5 ml min-1 g-1 (both P < 0.05). Saponin (three cycles of 2 min of 30 micrograms ml-1 saponin perfusion interrupted by 2 min control perfusion) reduced basal coronary NO content by a similar amount (307 +/- 22 pmol min-1 g-1) but reduced basal coronary flow by only 0.6 +/- 0.2 ml min-1 g-1 (P < 0.05 versus the effect of L-NAME). 4. The increases in coronary flow in response to (5-HT), ACh and substance P were reduced (all P < 0.05) by 100 microM L-NAME to 1.2 +/- 0.3, 1.2 +/- 0.4 and 0.3 +/- 0.3 ml min-1 g-1, respectively. However, the flow increase in response to SNP was not reduced; it was in fact increased slightly to 4.8 +/- 0.4 ml min-1 g-1 (P < 0.05). 5. Similarly, after treatment with saponin, the increases in coronary flow in response to 5-HT, ACh and substance P were reduced to 2.1 +/- 0.3, 1.3 +/- 0.3 and 0.4 +/- 0.2 ml min-1 g-1, respectively (all P < 0.05). Again, the response to SNP was increased slightly to 4.6 +/- 0.5 ml min-1 g-1 (P < 0.05). 6. L-NAME and saponin also inhibited 5-HT, ACh and substance P-induced NO release (P < 0.05), without affecting equivalent responses to SNP. 7. For substance P, the change in coronary flow (delta CF) correlated with log10 delta NO in the presence and absence of saponin and L-NAME; delta CF = 1.2(log delta NO) 1.9; r = 0.92; P < 0.05. For 5-HT the relationship was delta CF = 2.2(log delta NO-2.7; r = 0.79; P < 0.05, indicating that 5-HT causes a disproportionately greater increase in coronary flow per release of NO. This was taken to indicate that 5-HT relaxes coronary vasculature in part by releasing NO, but in part by additional mechanisms. ACh resembled 5-HT in this respect. 8. Saponin had no effect on cardiac systolic or diastolic contractile function assessed by the construction of Starling curves with an isochoric intraventricular balloon. 9. In conclusion, despite its minimal effect on basal coronary flow, saponin is an effective tool for revealing endothelium-dependent actions of coronary vasodilator substances and has selectivity in that it does not impair endothelium-independent vasodilatation or cardiac contractile function. 5-HT dilates guinea-pig coronary arteries largely by the release of NO from the coronary endothelium.

Animals↗
PubMed1996

Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion.

With the knowledge of NO as an antiadhesion molecule, we performed studies to investigate the effects of NO on postischemic polymorphonuclear leukocyte (PMN)-medicated myocardial contractile dysfunction. Studies were performed with isolated perfused rat hearts subjected to 20 minutes of global ischemia and 45 minutes of reperfusion. Human PMNs (50 million) were infused over the first 5 minutes of reperfusion, and the recovery of left ventricular function was compared with baseline values. Infusion of PMNs alone (n = 10) led to a 61% reduction in left ventricular developed pressure (LVDP) and a 57% reduction in the pressure-rate product (PRP) at 45 minutes of reperfusion. Infusion of an NO donor, CAS-754 (n = 9), resulted in 80.2 +/- 6.7% recovery of LVDP and 77.0 +/- 8.6% recovery of PRP. Treatment with L-arginine (2.5 mmol/L, n = 10) resulted in a similar improvement in the postischemic contractile state of the heart. In contrast, NG-nitro-L-arginine methyl ester (L-NAME) treatment (250 mumol/L, n = 10) resulted in an exacerbation of contractile dysfunction, as evidence by a 93% reduction in LVDP at 45 minutes of reperfusion and a 91% reduction in PRP. The deleterious effects of L-NAME were prevented by L-arginine coperfusion. We failed to observe any cardioprotective effects when NO or L-arginine was administered to hearts subjected to 25 minutes of ischemia and 45 minutes of reperfusion in the absence of PMNs. In conclusion, PMN-mediated myocardial contractile dysfunction is attenuated by NO and exacerbated by blockade of NO synthesis.

Animals↗
PubMed1995

Contaminated fractures of the tibia: a comparison of treatment modalities in an animal model.

External fixation is the current standard treatment for skeletal stabilization of open tibial fractures, but intramedullary fixation techniques have become increasingly popular. The aim of this study was to compare, in an animal model, the susceptibility to infection of contaminated fractures stabilized with external fixation with that of contaminated fractures fixed with intramedullary locking nails with or without reaming. A unilateral osteotomy of the tibia was performed in 15 goats under general anesthesia. Each osteotomy was stabilized with either (a) a unilateral biplanar external fixator, (b) an 8 mm diameter intramedullary rod inserted without reaming of the medullary cavity, or (c) a 10 mm diameter rod inserted after reaming. A standardized inoculum of Staphylococcus aureus, 10(3) colony forming units per milliliter, was placed at each osteotomy site on a piece of absorbable gelatin sponge, to simulate contamination of an open fracture. Antibiotics were not administered. The animals were allowed full activity after the procedure. Fourteen days postoperatively, the animals were killed, radiographs of the tibiae were taken, and the tibiae were harvested in a sterile manner. Multiple specimens for quantitative microbiological analysis were taken from the fracture site and from sites 3 cm distal and 6 cm proximal to the fracture. Additional specimens of bone were taken for histological study. Clinical, radiographic, and microbiological analysis demonstrated that, in this animal model, there were significantly fewer and less severe infections in fractures fixed with external fixation than in those fixed with an intramedullary nail with or without reaming. There was marked cortical necrosis in tibiae that had been fixed with nailing and reaming.

Animals↗
PubMed1995

Further investigations into the mechanism of antifibrillatory action of the specific IK1 blocker, RP58866, assessed using the rat dual coronary perfusion model.

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the dual coronary perfusion model to assess pharmacological activity since, even in rat, a species with extremely low collateral flow, there is evidence of cross-flow between the left and right ventricles.

Animals↗
PubMed1995

Brief, intermediate and prolonged ischemia in the isolated crystalloid perfused rat heart: relationship between susceptibility to arrhythmias and degree of ultrastructural injury.

Isolated Langendorff-perfused rat hearts were used to assess susceptibility to reperfusion-induced arrhythmias after different durations of ischemia in relationship to structurally related impairment of heart function, and to examine whether phase two ischemia-induced arrhythmias occur in crystalloid perfused hearts. This was achieved by subjecting the hearts to 5 min reperfusion following either sustained (240 min), intermediate (30 min), or brief (10 min) regional ischemia. Sustained ischemia induced little arrhythmogenesis upon reperfusion (no ventricular fibrillation) and impairment of recovery of coronary flow (approximately 64% of uninvolved zone flow). Electron microscopic investigation of the ischemic region revealed severe degenerative damage of the ultrastructure of cardiac myocytes and capillary endothelial cells. In contrast, reperfusion following brief ischemia caused all hearts to develop ventricular fibrillation (VF), accompanied by a persisting hyperemia throughout the course of reperfusion (flow 149 +/- 33% of that in the uninvolved zone after 1 min of reperfusion). In this group, myocardial ultrastructure exhibited negligible i.e., almost complete reversal of injury, upon reperfusion. Intermediate (30 min) ischemia led to a high incidence of reperfusion arrhythmias (92% of hearts developing VF) and modest hyperemia (flow 111 +/- 22% of that in the uninvolved zone after 1 min of reperfusion). Moderate ultrastructural alterations and their further deterioration upon reperfusion were observed in some but not all hearts in this group. During ischemia, phase 1 arrhythmias were common (57% of hearts developed VF during the first 30 min). However, phase 2 arrhythmias were absent during 120-240 min ischemia in these isolated hearts. In conclusion sustained ischemia in the rat heart renders myocardium unviable with a consequent loss of susceptibility to reperfusion arrhythmias. Phase 2 ischemia-induced arrhythmias do not occur in this model, implicating an intact autonomic nervous system and/or circulating factors from blood (e.g., neutrophils) in phase 2 arrhythmogenesis.

Animals↗
PubMed1995

Protection by ITF 1300, a heparin ion-pair complex, against arrhythmias induced by regional ischemia and reperfusion in the isolated rat heart: possible mechanism of action.

We examined the effects of the heparin ion-pair complex ITF 1300 on ventricular fibrillation (VF) and other arrhythmias elicited by regional ischemia and by reperfusion in isolated rat hearts (n = 12 per group). During 30-min ischemia, 1, 3, and 10 mg/L ITF 1300 reduced the incidence of VF concentration dependently, with complete abolition of VF at the highest concentration (p < 0.05). Similar but weaker effects were observed for other arrhythmias [ventricular tachycardia (VT) and salvos]. Reperfusion-induced arrhythmias (elicited after 10- or 30-min regional ischemia) were affected similarly, with complete abolition of VF at the highest drug concentration (p < 0.05). Coronary blood flow (CBF), recovery of CBF during reperfusion, and occluded zone sizes were little affected (p = NS). ITF 1300 caused concentration-dependent bradycardia, PR interval widening, and QT widening. In further studies, we examined the roles of these changes in mediating the antiarrhythmic effects. Left atrial pacing at a rate close to control rate (300 beats/min) abolished the antiarrhythmic effects of ITF 1300 and the QT widening, indicating that bradycardia and QT widening were important in mediating the antiarrhythmic effects. Doubling the calcium concentration in the perfusion solution prevented ITF 1300-induced PR widening, indicating that calcium antagonist activity probably mediated the drug's effects on this variable. However, the antiarrhythmic effect of ITF 1300 was not affected by high calcium perfusion. ITF 1300 is an effective antiarrhythmic agent in a model of ischemic heart disease. Its effects are mediated primarily by heart rate-dependent QT widening and were not related to possible calcium antagonist activity.

Animals↗
PubMed1995

Pharmacological analysis in rat of the role of the ATP-sensitive potassium channel as a potential target for antifibrillatory intervention in acute myocardial ischaemia.

We tested the hypothesis that blockade of the ATP-sensitive K+ channel (IK(ATP)) is an antiarrhythmic mechanism in acute myocardial ischaemia, using an opener of the channel (10 microM RP 49356, RP) and a blocker of the channel (10 microM glibenclamide, GL) and a combination of the two drugs (GL+RP, 10 microM each) in a randomised blinded study. Isolated rat hearts (n = 8 per group) were subjected to 30-min left regional ischaemia. GL and GL+RP widened QT interval after 10-min ischaemia (197 +/- 39 and 203 +/- 20 ms, respectively vs. 154 +/- 12 ms in controls), whereas RP significantly shortened QT interval (123 +/- 6 ms). GL and GL+RP decreased coronary flow (p < 0.05). RP caused slight increase in flow during ischaemia. These effects are all consistent with modulation of vascular and cardiac IK(ATP). RP alone had no effect on ischaemia-induced arrhythmias. Neither did GL have any effect on the incidence of ventricular fibrillation (VF: 88 vs. 100% in controls). However, GL reduced the incidence of sustained VF (VF lasting continuously for > 2 min) to 14% vs. 88% in controls (p < 0.05). Therefore, GL had defibrillatory activity. Surprisingly, in view of these findings, the GL+RP combination significantly reduced the incidence of VF to 25% (from 100% in control hearts, p < 0.05) i.e., had an antifibrillatory effect. So, two agents that produce pharmacological effects attributable to block and opening of IK(ATP) when administered singly had no effects on the incidence of ischaemia-induced VF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1995

An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart.

1. After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 microM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P < 0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 microM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3. Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P < 0.05) to 50 +/- 10, 52 +/- 12 and 70 +/- 7 fmol mg-1 tissue wet weight, respectively from control values of 143 +/- 38, 147 +/- 43 and 156 +/- 15 fmol mg-1. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P < 0.05) to 366 +/- 102, 396 +/- 130 and 293 +/- 22 fmol mg-1 in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4. In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia.

Animals↗
PubMed1995

Effects of NO modulation on cardiac arrhythmias in the rat isolated heart.

It has been proposed that NO may function as an endogenous cardioprotectant. We have investigated whether modulation of NO levels (detected in coronary effluent by chemiluminescence) by a blocker of its synthesis, by supplementation of its precursor, and by administration of an NO donor can influence reperfusion arrhythmias in the isolated rat heart. Rat hearts were perfused with modified Krebs' solution and subjected to 5, 35, or 60 minutes of left regional ischemia followed by 10 minutes of reperfusion. NG-Nitro-L-arginine methyl ester (L-NAME), which blocks NO synthase, increased the incidence of reperfusion-induced ventricular fibrillation (VF) from 5% in the control condition to 35% after 60 minutes of ischemia (n = 20, P < .05). The profibrillatory effect of L-NAME was prevented in hearts coperfused with 1 or 10 mmol/L L-arginine (an NO precursor) but persisted in hearts coperfused with D-arginine (1 mmol/L). L-NAME did not increase VF susceptibility in hearts reperfused after 5 or 35 minutes of ischemia. L-NAME caused sinus bradycardia (264 +/- 10 versus 309 +/- 5 bpm in control groups, P < .05) and reduced coronary flow before ischemia (6.2 +/- 0.6 versus 9.2 +/- 0.6 mL.min-1.g-1 tissue in controls, P < .05). L-NAME reduced coronary effluent NO levels after 60 minutes of ischemia; during the first minute of reperfusion, values were reduced from 1457 +/- 422 to 812 +/- 228 pmol.min-1.g-1 (P < .05). This effect was prevented by coperfusion with L-arginine (10,344 +/- 1730 pmol.min-1.g-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Protection by cimetidine, but not ranitidine, implies that H2 receptors do not mediate arrhythmogenesis in a rat model of regional ischaemia and reperfusion in vitro.

OBJECTIVES: Evidence suggests that histamine may function as one of many endogenous biochemical mediators of ischaemia- and reperfusion-induced ventricular fibrillation (VF). The H2 receptor subtype has been hypothesised to mediate this action. Our objective was to test this hypothesis. METHODS: The hypothesis predicts that H2 antagonists should prevent VF. We tested this by evoking ischaemia- and reperfusion-induced VF using the isolated perfused rat heart (Langendorff preparation) and performing concentration-response studies with two H2 antagonists, cimetidine and ranitidine. RESULTS: Continuous perfusion with cimetidine at the highest concentration (10 microM) reduced the incidence of ischaemia-induced VF from 57% in controls to 8% (P < 0.05) and the incidence of reperfusion-induced VF from 78 to 38% (P < 0.05). Surprisingly, the incidences of ischaemia- and reperfusion-induced arrhythmias were not reduced by ranitidine over an equivalent concentration range (0.1-10 microM). Electrocardiographic (ECG) variables (PR and QT interval) were not altered by cimetidine or ranitidine at any concentration, suggesting that neither drug produced direct electrophysiological actions on fast inward sodium, L-type calcium or potassium currents (blockade of which would have led to ECG changes). CONCLUSION: Ranitidine does not possess antiarrhythmic activity during ischaemia or reperfusion in the isolated rat heart, indicating that specific H2 antagonism is unlikely to be an effective mechanism of VF suppression. Thus, if histamine functions as an arrhythmogenic factor, it is not likely to do so by activating H2 receptors. Furthermore, since ranitidine is marginally the more potent of the two drugs as an H2 antagonist, it would appear that cimetidine, which was found to protect against VF, possesses antiarrhythmic activity mediated by non-specific effects (i.e., not attributable to blockade of H2 receptors).

Animals↗
PubMed1994

Proximal femoral fractures: a biomechanical study to compare intramedullary and extramedullary fixation.

This study assesses the rigidity and strength of fixation provided by intramedullary and extramedullary devices for proximal femoral fractures. Stable and unstable intertrochanteric fractures were studied in paired femora after internal fixation with the Gamma nail and Richards 135 degrees classic hip-screw implants; in subtrochanteric fractures, the 95 degrees Richards condylar screw was studied in addition. Subsidence of the sliding screw within the plate and nail constructs was measured. Fixation of subtrochanteric fractures with the intramedullary Gamma nail was significantly stronger and more rigid than that with the extramedullary screw plate devices. Under conditions of simulated protected weight bearing, the 95 degrees condylar screw plate provided more rigid fixation than did the 135 degrees hip screw. There was no significant difference in the strength of fixation of stable and unstable intertrochanteric fractures between the Gamma nail and the hip screw, although the Gamma nail provided more rigid fixation.

Aged↗
PubMed1994

Anatomical restraints to dislocation of the second metatarsophalangeal joint and assessment of a repair technique.

The aim of this study was to determine the anatomical restraints to dislocation of the second metatarsophalangeal joint and to assess the biomechanical efficacy of a technique that is commonly used to stabilize this joint. Cadaveric feet were disarticulated at the ankle, with preservation of the long flexor tendons at the medial malleolus. The hindfoot was transfixed to an aluminum jig, and a contoured nylon block was secured to the dorsum of the second metatarsal. A Kirschner wire was passed transversely through the proximal phalanx and was attached to a wire loop through which a constant vertical displacement was applied with a universal testing machine. A preload of five newtons was applied, followed by a constant displacement of two millimeters per minute, and the load-displacement curves were measured. The volar plate and the collateral ligaments were divided in five feet each. In another ten feet, both of these structures were divided simultaneously. Each load cycle was repeated four times. The force required to dislocate the joint, in the position in which testing was performed, was reduced by a mean of 30 per cent when the volar plate was divided and by a mean of 46 per cent when the collateral ligaments were divided. Division of both of these structures created an unstable joint, which dislocated at an applied load of five to ten newtons. The metatarsophalangeal joint was then repaired with use of a flexor tendon transfer in all twenty feet. This repair technique restored the load-displacement curves to that of the normal toe.

Cadaver↗
PubMed1993

Anion manipulation, a novel antiarrhythmic approach: mechanism of action.

We recently reported that modulation of anion homeostasis by substitution of extracellular chloride by nitrate prevents ischaemia- and reperfusion-induced ventricular fibrillation (VF) in rat and rabbit in vitro by an unknown mechanism independent of haemodynamic changes but related to widening of QT interval (Ridley and Curtis 1991). In the present study we have examined three possible explanations for the mechanism: modification of membrane anion permeability, alteration of cyclic nucleotide homeostasis and alteration of intracellular pH. In isolated Langerdorff-perfused rat heart (n = 12/group), substitution of chloride in modified Krebs perfusion solution by anion surrogates (methylsulphate, bromide, nitrate or iodide) inhibited left regional ischaemia- and reperfusion-induced arrhythmias only when the membrane permeability of the surrogate was greater than that of chloride (e.g., nitrate, bromide, iodide); the least permeant anion, methylsulphate, was proarrhythmic during ischaemia. Rank order of arrhythmia susceptibility correlated with the relative permeability of each anion, with near abolition of both ischaemia- and reperfusion-induced VF (P < 0.05) by the most permeant anions (iodide and nitrate). Arrhythmia suppression occurring in the iodide and nitrate groups was accompanied by significant widening of QT interval at 90% repolarization, with effects substantially more marked during ischaemia than before ischaemia. In separate studies using the same model we determined cardiac cyclic (c) AMP and cGMP content and their molar ratios by radioimmunoassay of biopsies before, during and after ischaemia. There was no meaningful relation between cyclic nucleotide content and rank order of arrhythmia susceptibility ruling out changes in the former as a contributory mechanism to the latter. In further studies we measured intracellular pH in the isolated perfused rat heart by phosphorus NMR spectroscopy. Nitrate caused a slight intracellular acidosis which was exacerbated when hearts were made globally ischaemic, indicating that its antiarrhythmic activity was not a consequence of alkalinisation (e.g., via inhibition of chloride-bicarbonate exchange). To test for inherent adverse effects on cardiac contractile function we analysed Starling curves in isolated rat hearts perfused under conditions equivalent to those used for arrhythmia studies. There was no relationship between perfusion anion composition and systolic (developed pressure at constant intraventricular volume, and pressure-volume slope) or diastolic function (end-diastolic pressure at constant intraventricular volume). In conclusion, alteration of membrane permeability is a mechanism which may be sufficient to explain modulation of arrhythmias by manipulation of extracellular anion content, appears to be devoid of deleterious effects on contractile function, and may represent a focus for future antiarrhythmic drug development.

Animals↗