Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.

BACKGROUND AND PURPOSE: The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). METHODS: Fifty-five consecutive patients with relapsing-remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. RESULTS: Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 µm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). CONCLUSIONS: This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.

Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme.

Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47-59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5-3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3-3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support.

Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy.

Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from multiple sclerosis. We describe the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. Our findings support autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. Adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab.

Degradation of bradykinin, a cardioprotective substance, during a single passage through isolated rat-heart.

Angiotensin converting enzyme (ACE) inhibitors have cardioprotective effects in different species including human. This cardioprotective effect is mainly due to the inhibition of bradykinin (BK) degradation rather than inhibition of the conversion of angiotensin I to angiotensin II. Bradykinin, a nonapeptide, has been considered to be the potential target for various enzymes including ACE, neutral endopeptidase 24.11, carboxypeptidase M, carboxypeptidase N, proline aminopeptidase, endopeptidase 24.15, and meprin. In the present study, the coronary vascular beds of Sprague Dawley rat isolated hearts were perfused (single passage) with Krebs solution alone or with different concentrations of BK i.e. 2.75x10(-10), 10(-7), 10(-6) and 10(-5) M solution. Percent degradation of BK was determined by radioimmunoassay. The degradation products of BK after passing through the isolated rat-hearts were determined using RP-HPLC and mass spectroscopy. All the four doses of BK significantly decreased the perfusion pressure during their passage through the hearts. The percentage degradation of all four doses was decreased as the concentration of drug was increased, implying saturation of a fixed number of active sites involved in BK degradation. Bradykinin during a single passage through the hearts degraded to give [1-7]-BK as the major metabolite, and [1-8]-BK as a minor metabolite, detected on HPLC. Mass spectroscopy not only confirmed the presence of these two metabolites but also detected traces of [1-5]-BK and arginine. These findings showed that primarily ACE is the major cardiac enzyme involved in the degradation of bradykinin during a single passage through the coronary vascular of bed the healthy rat heart, while carboxypeptidase M may have a minor role.

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.

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.

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.

Failure of cyclo-oxygenase inhibition to protect against arrhythmias induced by ischaemia and reperfusion: implications for the role of prostaglandins as endogenous myocardial protective substances.

STUDY OBJECTIVE: It has been suggested that the balance between the release from the heart of prostacyclin and thromboxane A2 is a major determinant of the severity of arrhythmias during ischaemia and reperfusion. This has been examined in a dog model. DESIGN: Three different cyclo-oxygenase inhibitors in doses adequate to prevent formation of both prostacyclin and thromboxane--aspirin (7 mg.kg-1), flurbiprofen (3 mg.kg-1), and sodium meclofenamate (2 mg.kg-1) with or without nafazatrom or dazmegrel--were given prior to a combined occlusion-reperfusion insult, and the severity of resulting arrhythmias examined. MATERIAL: Adult greyhound dogs were used: controls n = 29; aspirin n = 10; flurbiprofen n = 10; sodium meclofenamate +/- nafazatrom or dazmegrel n = 22. MEASUREMENTS AND MAIN RESULTS: None of the interventions modified the severity of ischaemic arrhythmias induced by coronary artery occlusion and release. The numbers of ventricular extrasystoles during the 40 min occlusion period were similar in all groups: controls 653(SEM 109); aspirin 690(187); flurbiprofen 454(132); meclofenamate 833(218). Ventricular fibrillation from the combined occlusion-reperfusion insult was also similar; controls 83%; aspirin 80%; flurbiprofen 80%; meclofenamate 100%. In the doses used all three inhibitors prevented the increase in plasma concentrations of thromboxane A2 [from 104(23) to 166(34) pg.ml-1] and prostacyclin [from 450(80) to 720(110) pg.ml-1] seen in control untreated dogs subjected to coronary artery occlusion. The addition of sodium meclofenamate to either nafazatrom (10 mg.kg-1 orally) or dazmegrel (3 mg.kg-1 intravenously), which when given alone are markedly protective, abolished this protection. CONCLUSION: The results show the importance of maintaining prostacyclin release in modifying the severity of ischaemic and reperfusion arrhythmias, and again suggest that prostacyclin is an "endogenous antiarrhythmic substance".

Transient ischaemia induced by rapid cardiac pacing results in myocardial preconditioning.

STUDY OBJECTIVE: The aim was to determine whether rapid ventricular pacing can protect against the ventricular arrhythmias occurring during a subsequent coronary artery occlusion. DESIGN: The effect was examined of two 2 min periods of pacing (300 beats.min-1) in chloralose-urethane anaesthetised dogs on a subsequent 25 min coronary artery occlusion. Ventricular arrhythmias, ST segment elevation, and inhomogeneity of conduction were analysed. EXPERIMENTAL MATERIAL: 25 anaesthetised mongrel dogs in a restricted body weight range were used. MEASUREMENTS AND MAIN RESULTS: Preocclusion pacing reduced the severity of occlusion induced ST segment elevation, degree of inhomogeneity, and arrhythmias: ventricular premature beats were reduced from 528(SEM 40) to 136(45), and there were lower incidences of ventricular fibrillation (0% v 47%) and ventricular tachycardia (30% v 80%). CONCLUSIONS: Rapid ventricular pacing "preconditions" the myocardium in a manner similar to that following short coronary artery occlusions. Short periods of ischaemia no matter how induced protect the heart against the arrhythmogenic effect of a prolonged coronary artery occlusion.

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.

Protective effects of preconditioning of the ischaemic myocardium involve cyclo-oxygenase products.

STUDY OBJECTIVE: The aim was to determine whether short (preconditioning) occlusions of a coronary artery protect against the arrhythmias occurring during a subsequent more prolonged occlusion and to examine whether the observed protection is mediated by the release of a product of the cyclo-oxygenase pathway of arachidonic acid metabolism. DESIGN: The effects were examined of two short (5 min) coronary artery occlusions, in chloralose-urethane anaesthetised dogs, on a subsequent prolonged (25 min) occlusion; analysis of ischaemia and reperfusion induced arrhythmias and of epicardial ST segment changes was performed. EXPERIMENTAL MATERIAL: 46 anaesthetised mongrel dogs in a restricted body weight range were used. MEASUREMENTS AND MAIN RESULTS: Preconditioning reduced the incidence and severity of ischaemic arrhythmias during a 25 min occlusion. Ventricular premature beats (VPB) reduced from 445 (SEM 140) to 96(22) (p less than 0.01), ventricular fibrillation (VF) from 4/10 to 0/20 (p less than 0.05), and ventricular tachycardia from 9/10 to 6/20 (p less than 0.05). VF following reperfusion was reduced from 6/6 to 6/10 (p less than 0.05). Preconditioning thus increased survival from the prolonged ischaemia-reperfusion insult from 0% to 40%. The protective effect of preconditioning was lost in the presence of the cyclo-oxygenase inhibitor sodium meclofenamate (2 mg.kg-1), eg, VPBs 367(95), VF during occlusion 1/9 and during reperfusion 8/8, survival 0%. CONCLUSIONS: Short, preconditioning periods of myocardial ischaemia protect the myocardium against the arrhythmogenic effects of a more prolonged occlusion. That this protection is lost if the cyclo-oxygenase pathway is blocked suggests a protective role for prostanoids, most likely prostacyclin, as endogenous myocardial protective substances.

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.

Antiarrhythmic effects of preconditioning in anaesthetised dogs and rats.

OBJECTIVE: The aim was to determine the relationship of the duration of short coronary artery occlusions and of the reperfusion period to the extent of the antiarrhythmic effect of preconditioning. METHODS: A prolonged occlusion of a coronary artery in 102 anaesthetised rats and 55 anaesthetised dogs was preceded by a variable number of preconditioning coronary artery occlusions, of varying duration and with variable reperfusion periods between them and the prolonged occlusion. RESULTS: Preconditioning in both species reduced the severity of ischaemia induced arrhythmias, epicardial ST segment changes, and alterations in the degree of inhomogeneity of conduction during a subsequent prolonged coronary artery occlusion, provided that the reperfusion time was less than 30 min (in rats) and 1 h (in dogs). This antiarrhythmic effect of preconditioning was marked; eg, in dogs following two preconditioning occlusions survival from a combined ischaemia-reperfusion insult was 40% (cf, 0% in the controls). CONCLUSIONS: Short preconditioning periods of myocardial ischaemia protect the myocardium against the arrhythmogenic effects of a more prolonged occlusion. The optimum time for this preconditioning occlusion in rats is 3 min and protection is still apparent 30 min later. In dogs, the protective effect is especially clear with two short (5 min) coronary artery occlusions. The protection in this species lasts for less than 1 h.

Enzymes in normally perfused and ischaemic dog hearts which release a substance with kinin like activity.

The presence of amidases cleaving the tripeptide VAL.LEU.ARG.pNA, and liberating from human plasma kininogen substance(s) able to contract uterine smooth muscle and to lower blood pressure (uterus contracting and hypotensive activity), has been demonstrated in vascular and muscle tissues from normally perfused and ischaemic areas of dog hearts. Studies were carried out on blood free preparations of coronary arteries and veins and normally perfused and ischaemic ventricle. All the tissues were found to contain both acid optimum (pH 6) and alkaline optimum (pH greater than 9) enzymes forming uterus contracting substance (UCS, bioassayed on isolated uterus of rats in oestrus), the highest levels of both activities being found in arterial tissues and the least in ventricle. Enzyme levels in ischaemic or normally perfused ventricle did not differ significantly. Gel filtration (Sephacryl, S-300) of coronary artery extracts gave one peak each of acid optimum enzyme with a molecular weight of 38,300 +/- 800 daltons and alkaline optimum enzyme with a molecular weight of 92,100 +/- 4000 daltons. Both acid and alkaline enzyme fractions cleaved the tripeptide substrate with pH optima identical to those for UCS formation. The acid optimum activity, both of UCS formation and tripeptide cleavage, was inhibited by pepstatin but not by aprotinin or soybean trypsin inhibitor (SBTI). The alkaline optimum activity was inhibited by aprotinin and SBTI but not pepstatin. Both acid and alkaline optimum enzymes released a hypotensive agent from a plasma protein substrate. The molecular weight and response to inhibitors of the acid optimum enzyme were similar to a cathepsin, and those of the alkaline optimum enzyme were similar to plasma kallikrein.

Acid optimum kininogenases in canine myocardium and aorta.

OBJECTIVE: Canine coronary artery was recently reported to contain a cathepsin like acid optimum enzyme and a kallikrein like alkaline optimum enzyme which cleaved from a crude kininogen preparation a vasodilator uterus contracting substance. The aim of this study was to seek the presence of similar acid optimum enzymes in canine ventricular myocardium and in a large systemic artery, the aorta. METHODS: Aqueous canine tissue extracts were tested for the ability at different pHs to release uterus contracting substance (using rat isolated oestrous uterus) from a kininogen preparation. After gel filtration, the extracts were tested for the presence of arginine-amidase activity (substrate: D-Val.Leu.Arg.pNA) and enzymic activity forming bradykinin like immunoreactivity. Tissues were obtained from anaesthetised greyhounds which had been used in control studies and had received no other drug treatment. RESULTS: Ventricular extracts released uterus contracting substance optimally at pH 5.2-5.4, but not at alkaline pH, neither was bradykinin like immunoreactivity formed at alkaline pH. Inhibitor studies and gel filtration showed this activity to be due to a cathepsin-D-like enzyme, molecular weight (MW) 42.6 (SD 0.9) kd, which was an arginine amidase and released bradykinin like immunoreactivity from a plasma kininogen. Aortic extracts showed two pH related peaks of uterus contracting substance formation, at pH 5.2 and (unlike myocardium) at pH 8. Also unlike myocardium, aortic extracts gave two acid optimum kininogenase peaks on gel filtration, with MW 42(4.6) kd and 252(39) kd, respectively. Both peaks released bradykinin like immunoreactivity. CONCLUSIONS: Canine aorta contained an alkaline optimum and two acid optimum enzymes, while ventricle contained only a cathepsin-D-like acid optimum enzyme, all of which could form bradykinin like immunoreactivity. The ability of the ventricular enzyme to form a kinin in the slightly acid conditions of myocardial ischaemia may have a protective role.

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.

Effect of dopexamine hydrochloride in the early stages of experimental myocardial infarction and comparison with dopamine and dobutamine.

The effect of dopexamine hydrochloride on myocardial performance, and on the susceptibility of the myocardium to generation of arrhythmias during the development of myocardial infarction has been compared with dopamine and dobutamine in 2 experimental models of myocardial ischemia. All 3 agents improved cardiac function in the presence of a developing infarct. Dopamine and dobutamine increased myocardial contractility (left ventricular dP/dt and left ventricular dP/dt/P), which would be expected to increase oxygen consumption and thus further compromise the ischemic myocardium. Dopexamine hydrochloride, however, improved cardiac function mainly by reducing afterload. The infusion of dopamine and dobutamine resulted in a high (100%) incidence of ventricular arrhythmias compared with only 63% with dopexamine hydrochloride. The effects of these agents on early ischemic arrhythmias after coronary artery ligation in anesthetized rats were also studied. Dopexamine hydrochloride reduced the incidence and severity of arrhythmias in the early stages of ischemia: At a dose of 0.25 micrograms/kg/min, the total number of ectopic beats was reduced to 375 +/- 175, from 1,250 +/- 330 in control rats (p less than 0.05). Dopexamine hydrochloride also significantly reduced mortality from ventricular fibrillation and there was a slight reduction in the incidence and duration of ventricular tachycardia and fibrillation.

Bradykinin and endothelial-cardiac myocyte interactions in ischemic preconditioning.

Myocardial ischemia results in the release of a variety of vasoactive substances from coronary vascular endothelial cells and/or from cardiac myocytes. Some of these substances appear to be protective and include nitric oxide and bradykinin. One hypothesis for the pronounced antiarrhythmic effects of preconditioning involves the early generation of bradykinin and, subsequently, nitric oxide. Evidence for early bradykinin release has come from clinical studies involving patients undergoing coronary angioplasty where, in 4 of 5 patients, there was evidence for elevated kinin levels in coronary sinus blood either during balloon inflation (i.e., ischemia) or deflation (reperfusion). The levels reached are sometimes considerable (increases 10-20 fold). The second piece of evidence comes from dogs subjected to a preconditioning stimulus (2 x 5 min periods of ischemia), followed 20 min later by occlusion of the same artery for a 25-min period. This preconditioning procedure markedly reduces ischemia-induced ventricular arrhythmias and, although under resting conditions there was little difference between arterial and coronary sinus bradykinin levels (125 +/- 22 and 157 +/- 41 pg/mL, respectively), there was a marked increase in coronary sinus levels in preconditioned dogs before the prolonged occlusion (637 +/- 293 pg/mL compared with 114 +/- 18 pg/mL in nonpreconditioned dogs); levels at the end of the prolonged occlusion in the preconditioned dogs were also higher (577 +/- 305 pg/mL compared with 162 +/- 34 pg/mL in control dogs). Other evidence for the involvement of bradykinin and nitric oxide comes from studies in which the generation, or effects, of these mediators have been suppressed (e.g., with the bradykinin B2 receptor blocking agent icatibant, with inhibitors of the L-arginine-nitric oxide pathway, and by methylene blue). The conclusion is that early bradykinin release is protective under conditions of ischemia, is presumably enhanced during therapy with angiotensin-converting enzyme (ACE) inhibitors and is suppressed under conditions of endothelial dysfunction.

Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines.

1. The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8-12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2-4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the beta-adrenoceptor blocking drug alprenolol.2. The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.3. Over the 2-3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.4. The predominant delayed effect of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess-20 mEq/litre). Arterial pO(2) and pCO(2) were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.5. The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2-3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.

The haemodynamic effects of prolonged oral administration of oxyfedrine, a partial agonist at beta-adrenoceptors: comparison with propranolol.

1 Haemodynamic changes have been studied in cats after the chronic oral administration of oxyfedrine (14 mg/kg for 3-4 weeks) or of placebo (lactose). The initial part of the study was carried out under double-blind conditions. The arterial blood pressure was between 19 mmHg (diastolic) and 27 mmHg (systolic) higher in the oxyfedrine treated animals, but there were no differences between the two groups with regard to cardiac output, left ventricular dP/dt max, heart rate or systolic ejection time.2 In cats similarly treated with propranolol (4 mg/kg) there was a slight (12%), but significant, reduction in cardiac output.3 Isoprenaline dose-response curves were shifted to the right in the cats administered oxyfedrine as well as in those administered propranolol. The degree of shift was five-fold (positive chronotropic response) and 20-fold (decrease in diastolic blood pressure) in the oxyfedrine group and 10- and 80-fold, respectively, in the propranolol group.4 In contrast to the partial blockade of the effects of isoprenaline, the haemodynamic response to oxyfedrine was largely unaltered, both in the cats pretreated with propranolol and in those pretreated with oxyfedrine. The pressor response to noradrenaline was potentiated in the cats pretreated with oxyfedrine.5 These results provide an explanation for the anti-anginal action of oxyfedrine. Some degree of beta-adrenoceptor blockade is achieved without a reduction in cardiac output or left ventricular dP/dt max. The relevance of these findings to the haemodynamic situation in angina is discussed.