Predictors of Stroke, Myocardial Infarction or Death within 30 Days of Carotid Artery Stenting: Results from the International Carotid Stenting Study.

OBJECTIVES: Stroke, myocardial infarction (MI), and death are complications of carotid artery stenting (CAS). The effect of baseline patient demographic factors, processes of care, and technical factors during CAS on the risk of stroke, MI, or death within 30 days of CAS in the International Carotid Stenting Study (ICSS) were investigated. METHODS: In ICSS, suitable patients with recently symptomatic carotid stenosis > 50% were randomly allocated to CAS or endarterectomy. Factors influencing the risk of stroke, MI, or death within 30 days of CAS were examined in a regression model for the 828 patients randomized to CAS in whom the procedure was initiated. RESULTS: Of the patients, 7.4% suffered stroke, MI, or death within 30 days of CAS. Independent predictors of risk were age (risk ratio [RR] 1.17 per 5 years of age, 95% CI 1.01-1.37), a right-sided procedure (RR 0.54, 95% CI 0.32-0.91), aspirin and clopidogrel in combination prior to CAS (compared with any other antiplatelet regimen, RR 0.59, 95% CI 0.36-0.98), smoking status, and the severity of index event. In patients in whom a stent was deployed, use of an open-cell stent conferred higher risk than use of a closed-cell stent (RR 1.92, 95% CI 1.11-3.33). Cerebral protection device (CPD) use did not modify the risk. CONCLUSIONS: Selection of patients for CAS should take into account symptoms, age, and side of the procedure. The results favour the use of closed-cell stents. CPDs in ICSS did not protect against stroke.

Carotid Anatomy Does Not Predict the Risk of New Ischaemic Brain Lesions on Diffusion-Weighted Imaging after Carotid Artery Stenting in the ICSS-MRI Substudy.

INTRODUCTION: The International Carotid Stenting Study (ICSS, ISRCTN25337470) randomized patients with recently symptomatic carotid artery stenosis > 50% to carotid artery stenting (CAS) or endarterectomy. CAS increased the risk of new brain lesions visible on diffusion-weighted magnetic resonance imaging (DWI-MRI) more than endarterectomy in the ICSS-MRI Substudy. The predictors of new post-stenting DWI lesions were assessed in these patients. METHODS: ICSS-MRI Substudy patients allocated to CAS were studied. Baseline or pre-stenting catheter angiograms were rated to determine carotid anatomy. Baseline patient demographics and the influence of plaque length, plaque morphology, internal carotid angulation, and external or common carotid atheroma were examined in negative binomial regression models. RESULTS: A total of 115 patients (70% male, average age 70.4) were included; 50.4% had at least one new DWI-MRI-positive lesion following CAS. Independent risk factors increasing the number of new lesions were a left-sided stenosis (incidence risk ratio [IRR] 1.59, 95% CI 1.04-2.44, p = .03), age (IRR 2.10 per 10-year increase in age, 95% CI 1.61-2.74, p < .01), male sex (IRR 2.83, 95% CI 1.72-4.67, p < .01), hypertension (IRR 2.04, 95% CI 1.25-3.33, p < .01) and absence of cardiac failure (IRR 6.58, 95% CI 1.23-35.07, p = .03). None of the carotid anatomical features significantly influenced the number of post-procedure lesions. CONCLUSION: Carotid anatomy seen on pre-stenting catheter angiography did not predict of the number of ischaemic brain lesions following CAS.

Mechanism of Procedural Stroke Following Carotid Endarterectomy or Carotid Artery Stenting Within the International Carotid Stenting Study (ICSS) Randomised Trial.

OBJECTIVE: To decrease the procedural risk of carotid revascularisation it is crucial to understand the mechanisms of procedural stroke. This study analysed the features of procedural strokes associated with carotid artery stenting (CAS) and carotid endarterectomy (CEA) within the International Carotid Stenting Study (ICSS) to identify the underlying pathophysiological mechanism. MATERIALS AND METHODS: Patients with recently symptomatic carotid stenosis (1,713) were randomly allocated to CAS or CEA. Procedural strokes were classified by type (ischaemic or haemorrhagic), time of onset (intraprocedural or after the procedure), side (ipsilateral or contralateral), severity (disabling or non-disabling), and patency of the treated artery. Only patients in whom the allocated treatment was initiated were included. The most likely pathophysiological mechanism was determined using the following classification system: (1) carotid-embolic, (2) haemodynamic, (3) thrombosis or occlusion of the revascularised carotid artery, (4) hyperperfusion, (5) cardio-embolic, (6) multiple, and (7) undetermined. RESULTS: Procedural stroke occurred within 30 days of revascularisation in 85 patients (CAS 58 out of 791 and CEA 27 out of 819). Strokes were predominately ischaemic (77; 56 CAS and 21 CEA), after the procedure (57; 37 CAS and 20 CEA), ipsilateral to the treated artery (77; 52 CAS and 25 CEA), and non-disabling (47; 36 CAS and 11 CEA). Mechanisms of stroke were carotid-embolic (14; 10 CAS and 4 CEA), haemodynamic (20; 15 CAS and 5 CEA), thrombosis or occlusion of the carotid artery (15; 11 CAS and 4 CEA), hyperperfusion (9; 3 CAS and 6 CEA), cardio-embolic (5; 2 CAS and 3 CEA) and multiple causes (3; 3 CAS). In 19 patients (14 CAS and 5 CEA) the cause of stroke remained undetermined. CONCLUSION: Although the mechanism of procedural stroke in both CAS and CEA is diverse, haemodynamic disturbance is an important mechanism. Careful attention to blood pressure control could lower the incidence of procedural stroke.

Risk Factors For Stroke, Myocardial Infarction, or Death Following Carotid Endarterectomy: Results From the International Carotid Stenting Study.

OBJECTIVES: Carotid endarterectomy (CEA) is standard treatment for symptomatic carotid artery stenosis but carries a risk of stroke, myocardial infarction (MI), or death. This study investigated risk factors for these procedural complications occurring within 30 days of endarterectomy in the International Carotid Stenting Study (ICSS). METHODS: Patients with recently symptomatic carotid stenosis >50% were randomly allocated to endarterectomy or stenting. Analysis is reported of patients in ICSS assigned to endarterectomy and limited to those in whom CEA was initiated. The occurrence of stroke, MI, or death within 30 days of the procedure was reported by investigators and adjudicated. Demographic and technical risk factors for these complications were analysed sequentially in a binomial regression analysis and subsequently in a multivariable model. RESULTS: Eight-hundred and twenty-one patients were included in the analysis. The risk of stroke, MI, or death within 30 days of CEA was 4.0%. The risk was higher in female patients (risk ratio [RR] 1.98, 95% CI 1.02-3.87, p = .05) and with increasing baseline diastolic blood pressure (dBP) (RR 1.30 per +10 mmHg, 95% CI 1.02-1.66, p = .04). Mean baseline dBP, obtained at the time of randomization in the trial, was 78 mmHg (SD 13 mmHg). In a multivariable model, only dBP remained a significant predictor. The risk was not related to the type of surgical reconstruction, anaesthetic technique, or perioperative medication regimen. Patients undergoing CEA stayed a median of 4 days before discharge, and 21.2% of events occurred on or after the day of discharge. CONCLUSIONS: Increasing diastolic blood pressure was the only independent risk factor for stroke, MI, or death following CEA. Cautious attention to blood pressure control following symptoms attributable to carotid stenosis could reduce the risks associated with subsequent CEA.

Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study.

OBJECTIVE: Cranial nerve palsy (CNP) and neck haematoma are complications of carotid endarterectomy (CEA). The effects of patient factors and surgical technique were analysed on the risk, and impact on disability, of CNP or haematoma in the surgical arm of the International Carotid Stenting Study (ICSS), a randomized controlled clinical trial of stenting versus CEA in patients with symptomatic carotid stenosis. MATERIALS AND METHODS: A per-protocol analysis of early outcome in patients receiving CEA in ICSS is reported. Haematoma was defined by the surgeon. CNP was confirmed by an independent neurologist. Factors associated with the risk of CNP and haematoma were investigated in a binomial regression analysis. RESULTS: Of the patients undergoing CEA, 45/821 (5.5%) developed CNP, one of which was disabling (modified Rankin score = 3 at 1 month). Twenty-eight (3.4%) developed severe haematoma. Twelve patients with haematoma also had CNP, a significant association (p < .01). Independent risk factors modifying the risk of CNP were cardiac failure (risk ratio [RR] 2.66, 95% CI 1.11 to 6.40), female sex (RR 1.80, 95% CI 1.02 to 3.20), the degree of contralateral carotid stenosis, and time from randomization to treatment >14 days (RR 3.33, 95% CI 1.05 to 10.57). The risk of haematoma was increased in women, by the prescription of anticoagulant drugs pre-procedure and in patients with atrial fibrillation, and was decreased in patients in whom a shunt was used and in those with a higher baseline cholesterol level. CONCLUSIONS: CNP remains relatively common after CEA, but is rarely disabling. Women should be warned about an increased risk. Attention to haemostasis might reduce the incidence of CNP. ICSS is a registered clinical trial: ISRCTN 25337470.

9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways.

Prostaglandin (PG) D2, the predominant prostanoid released from activated mast cells in humans is initially metabolized by reduction of the C-11 keto function to yield 9 alpha,11 beta-PGF2. In this study the airways effects of 9 alpha,11 beta-PGF2 were compared with those of its epimer 9 alpha,11 alpha-PGF2 (PGF2 alpha) and PGD2. 9 alpha,11 beta-PGF2 was a potent contractile agonist of isolated guinea pig trachea and 4-mm human airways in vitro; the potencies of the PGs relative to PGD2 (= 1.00) being 0.65 (NS) and 4.08 (P less than 0.001) for 9 alpha,11 beta-PGF2, and 0.52 (P less than 0.01) and 2.40 (P less than 0.001) for PGF2 alpha, respectively. When inhaled by asthmatic subjects, 9 alpha,11 beta-PGF2 was a potent bronchoconstrictor agent, being approximately equipotent with PGD2 and 28-32 times more potent than histamine (P less than 0.01). These studies suggest that 9 alpha,11 beta-PGF2 is at least equipotent with PGD2 as a bronchoconstrictor agonist, and in being a major metabolite of PGD2, could contribute to the bronchoconstrictor effect of this mast cell-derived mediator in asthma.

Percutaneous transluminal angioplasty and stenting for carotid artery stenosis.

BACKGROUND: Endovascular treatment by transluminal balloon angioplasty or stent insertion may be a useful alternative to carotid endarterectomy. OBJECTIVES: To assess the benefits and risks of endovascular treatment compared with carotid endarterectomy or medical therapy. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched 14 March 2007) and the following bibliographic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2007), MEDLINE (1950 to March 2007), EMBASE (1980 to March 2007) and Science Citation Index (1945 to March 2007). We also contacted researchers in the field. SELECTION CRITERIA: We selected randomised trials of endovascular treatment compared with endarterectomy or medical therapy for carotid artery stenosis. DATA COLLECTION AND ANALYSIS: One review author independently applied the inclusion criteria, extracted data and assessed trial quality. Search results were validated by a second review author. MAIN RESULTS: Data were available from 12 trials (3227 patients) but not all contributed to each analysis. The primary outcome comparison of any stroke or death within 30 days of treatment favoured surgery (odds ratio (OR) 1.39, P = 0.02, not significant (NS) in the random-effects model). The following outcome comparisons favoured endovascular treatment over surgery: cranial neuropathy (OR 0.07, P < 0.01); 30 day neurological complication or death (OR 0.62, P = 0.004, NS in the random-effects model, with significant heterogeneity). The following outcome comparisons showed little difference between endovascular treatment and surgery: 30 day stroke, myocardial infarction or death (OR 1.11, P = 0.57 with significant heterogeneity); stroke during long-term follow up (OR 1.00). Comparison between endovascular treatment with or without protection device showed no significant difference in 30 day stroke or death (OR 0.77, P = 0.42 with significant heterogeneity). Analysis of stroke or death within 30 days of the procedure in asymptomatic carotid stenosis showed no difference (OR 1.06, P = 0.96). In patients not suitable for surgery, there was no significant difference in 30 day stroke or death (OR 0.39, P = 0.09 with significant heterogeneity). AUTHORS' CONCLUSIONS: The data are difficult to interpret because the trials are heterogeneous (different patients, endovascular procedures, and duration of follow up) and five trials were stopped early, perhaps leading to an over-estimate of the risks of endovascular treatment. The pattern of effects on different outcomes does not support a change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis.

Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis.

BACKGROUND: Surgery for vertebral artery stenosis is technically difficult, potentially hazardous and is not considered in most centres. There is growing evidence from case series that vertebral artery stenosis may be treated endovascularly by percutaneous transluminal angioplasty and stenting. This may be a feasible alternative to surgery to relieve symptoms caused by significant stenosis. OBJECTIVES: The objective of this review was to assess the safety and efficacy of vertebral artery percutaneous transluminal angioplasty, with or without stenting, combined with medical care, compared to medical care alone, in patients with vertebral artery stenosis. SEARCH STRATEGY: We searched the Cochrane Stroke Group's trials register (last searched 28 July 2004). In addition we searched the following bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to July 2004), EMBASE (1980 to July 2004), and Science Citation Index (1981 to July 2004). We also contacted researchers in the field, and balloon catheter and stent manufacturers. SELECTION CRITERIA: We selected randomised trials of endovascular treatment of vertebral artery stenosis combined with best medical therapy, compared with best medical therapy alone, in patients with symptomatic or asymptomatic vertebral artery stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, extracted data and assessed trial quality. MAIN RESULTS: One completed randomised trial was found. In one subgroup of this trial, 16 patients with symptomatic severe vertebral artery stenosis were randomised to endovascular treatment (n = 8) or medical treatment alone (n = 8). There were no strokes in any arterial territory or deaths from any cause in either group within 30 days of treatment (endovascular group) or 30 days of randomisation (medical group). In the endovascular group, two patients had a posterior circulation TIA at the time of the procedure. In the endovascular group, the mean vessel stenosis at follow up was 47% (range 0% to 80%). Patients were followed up for a mean of 4.5 years in the endovascular group and 4.9 years in the medical group. There were no further vertebrobasilar territory strokes in either group for the duration of follow up. Morbidity and mortality was related to carotid and coronary artery disease in this study. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to assess the effects of percutaneous transluminal angioplasty with or without stenting or primary stenting for vertebral artery stenosis.

A comparison of the effects of three substance P antagonists on tachykinin-stimulated [3H]-acetylcholine release in the guinea-pig ileum.

The potencies of three tachykinin antagonists [D-Pro4,D-Trp7,9,10]SP(4-11), [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP(1-11) and [D-Arg1,D-Trp7,9,Leu11]SP(1-11) (spantide) against eledoisin were examined in the guinea-pig ileum myenteric plexus, where a continuous superfusion system was employed to examine evoked release of [3H]-acetylcholine [( 3H]-ACh]); effects on mechanical activity of the preparations were also measured. Eledoisin was chosen as the standard tachykinin agonist since the rank order of potency observed in evoking release was eledoisin, kassinin, substance P, physalaemin; on this basis is may be presumed that an 'SP-E' type receptor was involved in the release process. The two undecapeptide antagonists both significantly reduced the response to eledoisin (10 nM) as assessed by both [3H]-ACh release and mechanical activity which under these conditions was largely dependent on ACh release, and the response levels could be restored by increasing the concentration of eledoisin to 100 nM. The pA2 values for the two antagonists were estimated as 5.3 for [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP(1-11) and 5.2 for [D-Arg1,D-Trp7,9,Leu11]SP(1-11). [D-Pro4,D-Trp7,9,10]SP(4-11) was markedly less potent with a pA2 value of less than 4.8. All three antagonists possessed considerable inherent stimulatory activity as measured both by [3H]-ACh release and mechanical activity, [D-Pro4,D-Trp7,9,10]SP(4-11) being the most active in this respect, a 10 microM concentration producing 50% of the response seen with 10 nM eledoisin. These findings are discussed both in relation to tachykinin receptor classifications and limitations in the use of such antagonists in the study of the role of tachykinins in neurotransmission.

An examination of the pharmacology of two substance P antagonists and the evidence for tachykinin receptor subtypes.

The potencies of two tachykinin antagonists [D-Pro4,D-Trp7,9,10]-SP(4-11) and [D-Arg1,D-Pro2, D-Trp7,9,Leu11]-SP(1-11) against four tachykinins were examined in a range of smooth muscle preparations, including guinea-pig ileum and bladder and rat colon muscularis mucosae and duodenum. Parallel shifts in the log dose-response curves of all the tachykinins tested were observed in all tissues, except in the case of the guinea-pig bladder where [D-Pro4, D-Trp7,9,10]-SP(4-11) was without effect at concentrations up to 32 microM. The slopes of the Schild plots for the two antagonists did not differ significantly from unity, with the exception of [D-Pro4, D-Trp7,9,10]-SP(4-11) in the rat duodenum, which may indicate a heterogeneous receptor population in this tissue. The antagonists displayed agonist selectivity in the case of the guinea-pig ileum where log dose-response curves to substance P and physalaemin were shifted less than those to eledoisin and kassinin. Rank orders of potency for eledoisin, kassinin, physalaemin and substance P in the five preparations studied allowed classification of the tissues by the predominant receptor type according to the 'SP-P' and 'SP-E' scheme. It is concluded that [D-Pro4, D-Trp7,9,10]-SP(4-11), in particular, displays tissue selectivity that may indicate different receptor populations, but classification of receptor and tissue types on this basis does not fully correspond with classifications based on agonist potencies. Such schemes should therefore be treated with caution at this stage.

Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction.

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation.

BACKGROUND: Ischemic preconditioning, an endogenous protection mechanism, occurs in many organs, including lungs. The efficacies of differing ischemic durations in protecting the lung are unknown. We compared the ability of three preconditioning protocols to protect rat lungs during storage. METHODS: Function was measured in five groups of perfused, ventilated rat lungs. Group 1 lungs underwent control perfusion (60 minutes) without storage. Groups 2 through 5 underwent the following prestorage protocols: group 2, 20 minutes of perfusion; group 3, 10 minutes of perfusion, 5 minutes of cessation of ventilation and perfusion (ischemia), and 5 minutes of reperfusion; group 4, 5 minutes of perfusion, 10 minutes of ischemia, and 5 minutes of reperfusion; and group 5, 2 periods of 5 minutes of ischemia and 5 minutes of reperfusion. Lungs were then flushed with, and immersed (6 hours) in modified bicarbonate buffer (4 degrees C). Lung function was reassessed during 40 minutes of reperfusion (37 degrees C). Subsequently we examined preconditioning by stopping ventilation or perfusion separately. RESULTS: After reperfusion, lungs in group 2 had a compliance of 0.015+/-0.002 mL/cm H2O (mean +/- SE, n = 10), significantly lower than lungs in group 1 (0.063+/-0.002 mL/cm H2O). Ischemic preconditioning was protective, with lungs in groups 3, 4, and 5 having compliances greater (p<0.05) than those in group 2. Preconditioning by cessation of ventilation alone was also effective. CONCLUSIONS: Preconditioning attenuates deterioration in lung compliance on reperfusion to a degree dependent on the protocol used.

Theophylline improves functional recovery of isolated rat lungs after hypothermic preservation.

BACKGROUND: Raising intracellular cyclic adenosine monophosphate levels protects lungs from ischemia-reperfusion injury. We hypothesized that the phosphodiesterase inhibitor theophylline would protect lungs during storage. METHODS: Rat lungs were perfused with modified bicarbonate buffer mixed with rat blood (4:1 vol/vol) (37 degrees C) and ventilated (80 breaths/min). After 20 minutes of perfusion during which vascular resistance and airway compliance were measured, lungs were flushed with and then immersed in bicarbonate buffer (4 degrees C) alone or containing theophylline (30 to 1,000 micromol/L). After 6 hours of storage, lung function was reassessed during 40 minutes of reperfusion. RESULTS: Lungs stored in the presence of theophylline had improved lung function on reperfusion. After 40 minutes of reperfusion, pulmonary compliance was 0.008+/-0.004 mL/cm H2O, 0.022+/-0.010, 0.037+/-0.007, 0.044+/-0.006, and 0.073+/-0.003 mL/cm H2O, and vascular resistance was 3.84+/-0.40 cm H2O x min x mL(-1), 3.64+/-0.78, 2.12+/-0.35, 2.22+/-0.25, and 1.90+/-0.38 cm H2O x min x mL(-1) in lungs stored in the presence of 0, 30, 100, 300, or 1,000 micromol/L theophylline, respectively. Similar improvements were obtained for wet to dry weight ratio and gas exchange. CONCLUSIONS: Theophylline merits investigation as a potentially beneficial addition to solutions for the flushing and storage of human lungs for transplantation.

The interaction of endothelin receptor responses in the isolated perfused rat lung.

UNLABELLED: To gain more insight into the complex pulmonary interactions of endothelins (ET), we studied airway and vascular responses to endothelins in isolated perfused rat lungs in the presence of the novel ET(B)-receptor antagonist BQ788. In particular we focused on airway responses and on prostacyclin release. The effectiveness of BQ788 in our system was shown by its ability to concentration-dependently prevent vasoconstriction (IC50 0.1 microM), bronchoconstriction (IC50 0.1 microM) and prostacyclin production (IC50 < 0.1 microM) induced by the ET(B)-receptor agonist IRL1620 (1 nmol). Airway responses to ET-1: ET-1-induced bronchoconstriction was aggravated by BQ123 (1 or 8 microM), while BQ788 pretreatment (1 or 8 microM) showed no significant effect. Simultaneous treatment with 8 microM BQ123 and BQ788 attenuated the ET-1-induced bronchoconstriction. Vascular responses to ET-1: ET-1 (1 nmol)-induced vasoconstriction was potentiated by BQ788 (1 or 8 microM), but attenuated by the ET(A)-receptor antagonist BQ123 (1 microM). In the presence of BQ788 diminished amounts of the stable prostacyclin metabolite 6-keto-PGF1alpha were detected in the perfusate. Simultaneous treatment with 8 microM BQ123 and BQ788 completely prevented the ET-1-induced vasoconstriction. CONCLUSIONS: Both ET(A)- and ET(B)-receptors contribute to ET-1-induced vasoconstriction and bronchoconstriction. The ET-1-induced vasoconstriction is attenuated by stimulation of ET(B)-receptors, a response that is partly mediated by prostacyclin. Due to the mutual interactions between ET(A)- and ET(B)-receptors, simultaneous inhibition of both receptors is required to prevent the deleterious effects of ET-1 on lung functions.

Comparison of potency of substance P and related peptides on [3H]-acetylcholine release, and contractile actions, in the guinea-pig ileum.

A range of tachykinins including substance P were studied for their ability to contract the guinea-pig ileum longitudinal muscle preparation on brief exposure (20S) to the peptides, and their ability to evoke the release of [3H]-acetylcholine (ACh) from previously labelled stores within the myenteric plexus. With respect to their immediate spasmogenic activity, none of the peptides differed greatly in potency from substance P. Atropine did not modify the response to the tachykinins suggesting that the release of ACh does not contribute to the contraction resulting from brief exposure to the peptides. In the release studies, all tachykinins used produced a dose-related, calcium-dependent release of [3H]-ACh but the differences in potency were much greater. Eledoisin was the most potent and its evoked release of ACh was unaffected by hyoscine, hexamethonium, guanethidine and naloxone suggesting the release is not mediated via, or modulated by, opiate or autonomic neuronal influences. The two orders of tachykinin potency found suggest that the two processes, initial contraction and ACh release, may be principally mediated via two distinct subclasses of substance P receptor designated SP-P and SP-E respectively.

Effect of urodilatin on platelet-activating factor-induced bronchoconstriction, vasoconstriction and edema formation in isolated rat lung.

In the isolated perfused rat lung, perfusion with platelet-activating factor causes bronchoconstriction, vasoconstriction and edema formation. The bronchoconstriction and vasoconstriction are largely mediated by thromboxane, whereas the edema formation is due to enhanced vascular permeability unrelated to eicosanoids. Since natriuretic peptides are known to relax smooth muscle and were suggested to attenuate enhanced vascular permeability, we investigated the effect of urodilatin on the PAF-induced alterations in lung function. Pretreatment with urodilatin (0.25 microM or 0.75 microM) reduced the PAF-induced increase in airway and vascular resistance by approximately 50%. Urodilatin pretreatment, however, was completely ineffective against the PAF-induced increase in weight gain and in vascular permeability, as assessed by the vascular filtration coefficient. Furthermore, urodilatin failed to affect the release of thromboxane into the perfusate in PAF-exposed lungs. Thus, urodilatin relaxes airway and vascular smooth muscle, but fails to reduce edema formation in PAF-perfused rat lungs.

Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG) D2, 9 alpha,11 beta-PGF2 and PGF2 alpha.

The rank orders of potency of prostaglandin D2, prostaglandin F2 alpha, 9 alpha,11 beta-prostaglandin F2 and the stable thromboxane A2 mimetics U-46619 and ONO-11113 were determined in guinea-pig trachea and human bronchus in vitro. In both tissues the thromboxane mimetics were markedly more potent than the other prostanoids with EC50 values in the nanomolar range. The prostanoid antagonists BW-245C, EP-092 and GR-32191 attenuated the contractile responses to all of the prostanoid agonists and TXA2 mimetics tested in guinea-pig tracheal spirals, although agonist selectivity was seen. Contractile responses to methacholine in the guinea-pig trachea were unaffected by any of the antagonists employed. BW-245C antagonised the effects of all prostanoid agonists tested in human bronchial spirals, the pA2 values obtained were similar to those seen in the guinea-pig trachea when U-46619 and 9 alpha,11 beta-PGF2 were employed as the agonists. However, significant differences were found between the two tissues when PGD2 and PGF2 alpha were tested against BW-245C. EP-092 produced pA2 values against prostanoid agonists in the human bronchus similar to those seen in the guinea-pig trachea, as did GR-32191. It is concluded that whilst the contractile responses of guinea-pig and human airways smooth muscle to prostaglandin D2, and the other prostanoids are mediated predominantly via thromboxane (TP) receptors, it can be inferred that other receptor populations may contribute to the contractile response. The presence of these minor subpopulations may account for the agonist selectivity seen both within and between tissues from different species.

Hypothermic preservation of isolated rat lungs in modified bicarbonate buffer, EuroCollins solution or St Thomas' Hospital cardioplegic solution.

OBJECTIVES: Inadequate preservation solutions limit lung storage times and, consequently, transplant programs. To address this problem we established an isolated, ventilated and perfused rat lung preparation. Here we report the effects of hypothermic storage in EuroCollins solution, St Thomas' Hospital cardioplegic solution and a modified bicarbonate buffer solution. METHODS: Lungs from male Wistar rats (230-330 g) were perfused via the pulmonary artery with modified bicarbonate buffer (37 degrees C, 15 ml/min, constant flow) and ventilated by positive pressure (tidal volume:1.6-1.8 ml, 80 breaths/min). Vascular resistance (pulmonary artery pressure:perfusate flow ratio) and airways compliance (tidal volume:tracheal pressure ratio) were measured. After a control perfusion period (20 min), lungs were flushed with, then immersed in, bicarbonate buffer (4 degrees C) for varying periods (0-24 h). After storage, lung function was assessed during 20 min reperfusion. Having established a suitable period for study, storage in EuroCollins, St Thomas' Hospital cardioplegic solution or bicarbonate buffer were compared. RESULTS: Pulmonary compliance (ml/cmH2O) was significantly (P < 0.05) reduced in lungs stored for 6 h in modified bicarbonate buffer (0.026 +/- 0.008), EuroCollins solution (0.013 +/- 0.002) or St Thomas' Hospital solution (0.025 +/- 0.005) compared to unstored lungs (0.068 +/- 0.007). Vascular resistance, (1.32 +/- 0.13 cmH2O/ml per min) in unstored lungs, was similar in lungs stored in St Thomas' Hospital solution but increased significantly in lungs stored in modified bicarbonate buffer (3.22 +/- 0.78 cmH2O/ml per min) or EuroCollins solution (4.66 +/- 0.57 cmH2O/ml per min). CONCLUSIONS: Hypothermic storage of rat lungs for 6 h in modified bicarbonate buffer or St Thomas' Hospital solution causes less increase in vascular resistance on reperfusion than EuroCollins solution.

Percutaneous transluminal angioplasty and stenting for carotid artery stenosis.

BACKGROUND: Carotid artery stenosis may be treated endovascularly by percutaneous transluminal balloon angioplasty with or without stent insertion or by primary stenting. Endovascular treatment may be a useful alternative to carotid endarterectomy (CEA), particularly for lesions not suitable for surgery. OBJECTIVES: The objective of this review was to assess the benefits and risks of endovascular treatments compared with carotid endarterectomy (in patients suitable for surgery) or medical therapy (in patients not suitable for surgery). SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched 1 September 2003). In addition we searched the following bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to June 2003), EMBASE (1980 to June 2003) and Science Citation Index (1981 to June 2003). We also contacted researchers in the field and balloon catheter and stent manufacturers. SELECTION CRITERIA: We selected randomised trials of carotid endovascular treatment compared with carotid endarterectomy, or endovascular treatment plus best medical therapy compared with best medical therapy alone, in patients with symptomatic or asymptomatic carotid artery stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, extracted data and assessed trial quality. MAIN RESULTS: Two completed trials comparing endovascular treatment with carotid endarterectomy involving 608 patients were found. In addition there were two trials which fulfilled the inclusion criteria and which were stopped early (242 patients), and a third trial which has completed randomisation and 30 day follow up of 307 patients. Four trials are ongoing. Meta analysis of the data from the included studies found no significant difference between the odds of death or any stroke at 30 days post procedure (Odds Ratio [OR] endovascular:surgery 1.26, 95% Confidence Interval [CI] 0.82 to 1.94). The odds of death or disabling stroke at 30 days were similar in the endovascular and surgical group (OR 1.22, CI 0.61 to 2.41). At one year following procedure, there was no significant difference between the two groups in preventing any stroke or death (OR 1.36,CI 0.87 to 2.13). Endovascular treatment significantly reduced the risk of cranial neuropathy (OR 0.12, CI 0.06 to 0.25). There was no significant difference between the two groups when the risk of death, any stroke or myocardial infarction was considered (OR 0.99, CI 0.66 to 1.48). There was substantial heterogeneity between the trials for four of the five outcomes. REVIEWERS' CONCLUSIONS: Data from randomised trials comparing endovascular treatment for carotid artery stenosis with carotid endarterectomy suggest that the two treatments have similar early risks of death or stroke and similar long term benefits. However, the substantial heterogeneity renders the overall estimates of effect somewhat unreliable. Furthermore, two trials were stopped early because of safety concerns, so perhaps leading to an over-estimate of the risks of endovascular treatment. On the other hand, endovascular treatment appears to avoid completely the risk of cranial neuropathy. There is also uncertainty about the potential for restenosis to develop and cause recurrent stroke after endovascular treatment. The current evidence does not support a widespread change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis. There is a strong case to continue recruitment in the current randomised trials comparing carotid stenting with endarterectomy.

Synthetic inhibitors of tissue kallikrein: effects in vivo in a model of allergic inflammation.

We have recently developed synthetic low molecular weight inhibitors of both tissue and plasma kallikreins. Several of these were evaluated in vivo in the ovalbumin-sensitised guinea pig for their ability to prevent the bronchoconstriction elicited by antigen challenge. The selective tissue kallikrein inhibitor CH-694 (but not the selective plasma kallikrein inhibitor CH-684) caused highly significant falls in airways resistance when it was administered at 10 mg/kg intraperitoneally 15 min before and 90 min after challenge. There was also a highly significant fall in the tissue kallikrein activity measured in broncho-alveolar lavage fluid. Inhibitors of tissue kallikrein may prove effective in the treatment of allergic inflammation in man.