Biomedical subjects
Publications and source records attributed to L Dumont.
Peritoneal insufflation with CO2 has been associated with profound cardiorespiratory disturbances, which may modify cerebral blood flow (CBF), particularly in hypertensive patients in whom CBF autoregulation is altered. We report a case of bilateral mydriasis during laparoscopic gastrectomy in a patient with chronic hypertension followed by a coma lasting several hours and we shortly discuss the possible mechanisms involved.
BACKGROUND AND OBJECTIVES: Febrile nonhemolytic transfusion reactions frequently accompany platelet transfusions and may be due to accumulation of cytokines mediating inflammation during storage of platelet concentrates (PCs). We wished to determine whether PCs collected using the COBE(R) SpectraTM Apheresis System (Version 4) were sufficiently leukocyte reduced (LR) to limit cytokine accumulation during storage. MATERIALS AND METHODS: Cytokine accumulation - interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha) - and release of platelet alpha-granule - P-selectin, transforming growth factor-beta1 (TGF-beta1), platelet-derived growth factor AB (PDGF-AB), von Willebrand factor (vWf) - or dense granule (serotonin) markers were investigated during a 7-day storage period comparing apheresis-collected, LR PCs (LR PCs) and random donor platelets prepared from whole blood (WB). RESULTS: Leukocyte counts were reduced 99.95% comparing LR PCs (5.7 x 10(5)/l) and WB PCs (1.09 x 10(9)/l). Little or no accumulation of leukocyte-derived cytokines was observed in LR PCs during storage in contrast to WB PCs. A reduction in the release of platelet alpha-granule proteins, such as P-selectin, TGF-beta1 and PDGF-AB, was observed on day 0 for LR PCs compared to WB PCs with little or no difference observed from day 3 to 7. Plasma vWf levels were higher in LR PCs compared to WB PCs on days 0-7. CONCLUSION: Leukocyte levels in PCs collected with the COBE Spectra Apheresis System are sufficiently low to limit cytokine production during 7 days of storage.
Combined use of tacrolimus (FK506) with sirolimus (rapamycin [RAPA]) was examined in a model of vascularized heart allograft in the rat. For prevention of acute rejection, three different combinations of low doses of FK506 and RAPA from day 1 up to day 14 after transplantation produced significantly longer cardiac allograft survival than each agent alone (P<0.05). Identical results were observed in a model of reversal of ongoing acute rejection, where two combinations of low doses of FK506 and RAPA from day 4 up to day 18 after surgery also demonstrated significantly longer graft survival than each immunosuppressant alone (P<0.05). All the low-dose-treated groups in these two models presented significantly longer heart graft survival than naive controls (P<0.05), confirming that both agents are potent immunosuppressants in the models chosen. These results also indicate that, in contrast with in vitro studies, the combined use of FK506 and RAPA in vivo did not produce antagonism, but rather had synergistic effect in prolonging the allograft survival as compared with each agent alone. It appears likely that the abundance of FKBP-12 available for binding in vivo prevents inhibitive competition of the two agents for their receptor.
OBJECTIVES: Several studies suggest that regulation of coronary vasomotion is abnormal in heart failure, but controversies exist as to whether an altered endothelium-dependent dilation of the coronary vasculature contributes to these abnormalities. In the present study we evaluated the coronary reactivity to endothelium-dependent and -independent vasoactive substances in a model of chronic heart failure. METHODS: Isolated hearts from > 200-day-old cardiomyopathic hamsters (UM-X7.1) and age-matched normal Syrian hamsters were mounted on a Langendorff apparatus and retrogradely perfused at constant pressure (100 mmHg). Heart rate, left ventricular developed pressure (LVP) and coronary flow (CF) were measured. A first group of normal and failing hearts were challenged with increasing doses of acetylcholine (Ach), 1-1000 nM, and sodium nitroprusside (SNP), 0.01-10 microM. A second group was challenged with Ach (100 nM) and SNP (1 microM) before and during infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Finally, normal and failing hearts were challenged with Ach (100 nM) before and during infusion of indomethacin (10 microM) or tetraethylammonium (1 mM). RESULTS: Myocardial contractility and coronary flow were significantly impaired in failing hearts (LVP = 32 +/- 5 vs. 50 +/- 4 mmHg in normal hearts; CF = 4.7 +/- 0.6 vs. 6.7 +/- 0.6 ml/min in normal hearts). Coronary flow increases with increasing doses of Ach (EC50 = 84 +/- 15 nM for failing hearts and 100 +/- 3 nM for normal hearts, P = ns). At concentrations exceeding the EC50, failing hearts were more sensitive to the coronary dilator effects of Ach. The reduction in coronary flow elicited by L-NAME was similar in normal (-41 +/- 2%) and failing hearts (-40 +/- 3%); in both normal and failing hearts, the acetylcholine vasodilator response was not significantly affected by L-NAME. Indomethacin infusion resulted in a slight increase in coronary flow and significantly reduced the coronary dilator effects of acetylcholine. Tetraethylammonium had no significant effects on basal coronary perfusion of normal and failing hearts. However, in the latter group, acetylcholine vasodilator response was significantly attenuated. CONCLUSION: Results obtained in isolated failing hamster hearts allow us to conclude that (1) significant coronary dysfunctions are present in this model of chronic heart failure, (2) neither the NO-synthase nor the cyclo-oxygenase pathway contributes to these coronary dysfunctions, and (3) an adequate coronary vasodilator response appears to be present in this model of chronic heart failure.
BACKGROUND: Several studies suggest that coronary perfusion is abnormal in heart failure. The fact that these deficits may results in an altered coronary reserve remains controversial. Therefore, coronary adaptability to short-duration ischemia and the resultant myocardial reactive hyperemia were investigated in a model of chronic heart failure. METHODS AND RESULTS: Experiments were performed in normal and failing hamster hearts (UM-X7.1, aged > 225 days). Heart rate, left ventricular developed pressure, and coronary flow were recorded continuously before and after each 30-second ischemia in isolated perfused heart preparations. Studies were conducted under control conditions and in the presence of four inhibitors of potential mediators of the reactive hyperemia response: the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (30 microM), the adenosine antagonist 8-(p-sulfophenyl)theophylline (50 microM), the K+ cyclic adenosine triphosphate-dependent channel antagonist glibenclamide (10 microM), and the cyclooxygenase inhibitor indomethacin (10 microM). Baseline hemodynamic parameters were all significantly impaired in failing hearts. Under control conditions, failing hearts were able to respond adequately to a 30-second ischemia: repayment-to-debt ratio averaged 1.02 +/- 0.09 as compared with 1.10 +/- 0.09 in normal hearts (P = NS). All inhibitors significantly reduced basal coronary perfusion except for indomethacin. Of the four inhibitors of potential mediators of the myocardial reactive hyperemic response, only glibenclamide and indomethacin impaired the repayment-to-debt ratio. In their presence, repayment-to-debt ratio was reduced by 40% of the baseline response (P < .01) without significant difference between normal and failing hearts. On the contrary, NG-nitro-L-arginine methyl ester and 8-(p-sulfophenyl)theophylline did not alter the repayment-to-debt ratio. CONCLUSIONS: These observations demonstrate the capacity of the failing heart to tolerate short-duration ischemia despite the presence of significant alterations in its basal coronary perfusion. In addition, results suggest that activation of K+ adenosine triphosphate-dependent channels and the presence of cyclooxygenase by-products are important determinants of coronary adaptation to short-duration ischemia in this model of chronic heart failure.
Recent evidence suggests that newer vasoselective dihydropyridine calcium antagonists are not cardiodepressant and may be useful in the treatment of heart failure. No data are available on the efficacy of clentiazem, a vasoselective benzothiazepine-like calcium antagonist, in this pathological condition. Therefore, our objective was to assess coronary and cardiac sensitivity to clentiazem in an experimental model of chronic heart failure (cardiomyopathic hamster, UM-X7.1, > 200 day old). Left ventricular developed pressure (LVP) and coronary flow changes were assessed in isolated, perfused failing hearts and in normal Syrian hamster hearts. Clentiazem dose-response curves for both coronary dilation and negative inotropic effects were determined under control conditions and in the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Baseline hemodynamics indicate a significant reduction in both LVP and coronary perfusion in failing hearts. Cardiac sensitivity to the negative inotropic effects of clentiazem were similar in normal and failing hearts (IC50 = 677 nM and 734 nM, respectively). However, the clentiazem-induced increase in coronary flow was significantly attenuated in failing hearts (EC50 = 56 +/- 9 nM vs. 15 +/- 3 nM in normal hearts, p < 0.01). To better characterize the reduced coronary sensitivity to clentiazem in the presence of heart failure, the contributions of the NO synthase and the cyclooxygenase pathways were evaluated. Although coronary sensitivity to clentiazem was significantly reduced in the presence of L-NAME, this attenuation was of the same magnitude in normal and failing hearts, suggesting that coronary "desensitization" to clentiazem in failing hearts does not involve the NO synthase pathway. Experiments carried in the presence of indomethacin indicate that the reduced coronary sensitivity to clentiazem observed in failing hearts does not involve the cyclooxygenase pathway. In conclusion, reduced coronary sensitivity to the vasoselective calcium antagonist clentiazem was observed in the failing hamster heart, while no exacerbation of clentiazem's cardiodepressant actions was present. Although the mechanisms involved in the vascular desensitization to clentiazem are still unknown, our findings may provide an additional explanation for the variable efficacy of calcium antagonists in the treatment of heart failure.
BACKGROUND: Obesity is an important respiratory risk factor after abdominal surgery. Laparoscopic surgical techniques seem beneficial in obese patients in terms of respiratory morbidity, with a faster return to normal respiratory function. However, there is little information about intraoperative respiratory mechanics and about patient tolerance to abdominal insufflation in the morbidly obese. METHODS: We studied respiratory mechanics and arterial blood gases in 15 morbidly obese patients (mean BMI = 45) undergoing laparoscopic gastroplasty under general anaesthesia and controlled ventilation. Respiratory mechanics were analysed using side-stream spirometry. RESULTS: When compared to preinsufflation values, servocontrolled abdominal insufflation to 2.26 kPa caused a significant decrease in respiratory system compliance (31%), a significant increase in peak (17%) and plateau (32%) airway pressures at constant tidal volume with a significant hypercapnia but no change in arterial O2 saturation. Respiratory system compliance and pulmonary insufflation pressures returned to baseline values after abdominal deflation. CONCLUSION: These alterations in pulmonary mechanics are less than those observed with comparable degrees of abdominal inflation in non-obese patients, and were well tolerated. From the point of view of intraoperative respiratory mechanics, laparoscopic surgery is safe in morbidly obese patients.
In the presence of severe rejection, cardiac allograft perfusion has been shown to be impaired. Since a functionally reversible vasoconstrictor component has been identified in this condition and rejection does not reverse if ischemia does not, we hypothesized that diltiazem may be beneficial in this condition. Experiments were performed on dogs with heterotopic heart transplants and chronic instrumentation for the assessment of allograft perfusion. Two groups of cardiac allograft recipients were studied: untreated recipients and recipients treated with the calcium antagonist diltiazem (180 mg twice daily, orally). Allograft blood flow was monitored daily along with plasma diltiazem levels. The lymphoproliferative response to mitogens was studied at selected intervals until terminal rejection. Contractile function of the graft was assessed daily by palpation. Without immunosuppression, terminal rejection was observed within 7 days. Rejection was confirmed by histology; cellular infiltration and myocyte necrosis were present in all cardiac allografts but to a significantly lesser degree in diltiazem-treated recipients. The mean blood flow of heterotopically implanted hearts was in the range of 35-50 ml/min, which decreased steadily in untreated recipients. In contrast, significant improvement of allograft perfusion was observed in diltiazem-treated recipients at days 4-6 after transplantation. Diltiazem also significantly attenuated mitogen-induced lymphocyte proliferation at peak sensitivity (2 days after transplantation). Diltiazem plasma concentrations were in the therapeutic range (30-60 ng/ml) before and after cardiac transplantation. Results of the present study demonstrate beneficial effects of diltiazem in the course of severe cardiac rejection. Such findings support its use during rejection when maintenance of graft blood flow and myocyte protection may be important for myocardial function and viability.
BACKGROUND: In nonobese patients, peritoneal insufflation has consistently been shown to influence parameters of preload and afterload as well as cardiac output. Obese patients have an abnormal and particular cardiovascular status. The aim of this study was to investigate the hemodynamic changes induced by an increase of intra-abdominal pressure in morbidly obese patients (MOP). METHODS: Standard general anesthesia was administered to 15 informed MOP (body mass index > 40 kg/m2) scheduled for laparoscopic gastroplasty. Hemodynamic parameters were measured by thermodilution through a pulmonary artery catheter and through invasive blood pressure monitoring. RESULTS: CO2 insufflation with an intra-abdominal pressure of 17 mmHg caused a significant increase of mean arterial pressure (MAP) (33%, P = 0.005), mean pulmonary arterial pressure (MPAP) (40%, P = 0.001), pulmonary capillary wedge pressure (PCWP) (41%, P = 0.001), and central venous pressure (CVP) (55%, P = 0.001). The increase in diastolic filling pressures could be due to an increase in the filling volume or to a decrease in diastolic compliance. Ventricular volumes were not measured but we speculate that the rise in CVP, PCWP and MPAP is due to an increase in intrathoracic pressure as judged by the increase of pulmonary airway pressure. Stroke volume fell slightly (11%, P = 0.008), because of a reduction in transmural pressure and a fall in effective preload. Cardiac output rose slightly (16%, P = 0.005) because of an increase in heart rate (15%, P = 0.014) probably induced by sympathetic stimulation, which only became fully operative after 15 minutes. CONCLUSIONS: When compared to nonobese patients our obese patients tolerated the pneumoperitoneum surprisingly well, without experiencing fall in cardiac output. The hemodynamic consequences of peritoneal insufflation seem to be different in obese and nonobese patients.
We studied the voltage dependence of the inhibitory effects of the Ca2+ antagonist Mg2+, compared to nifedipine, on the transsarcolemmal Ca2+ uptake into primary monolayers of smooth muscle cells obtained from pig coronary arteries. The cellular Ca incorporation was analyzed by liquid scintillation. Depolarization was produced by elevation of K+0. The data suggest that depolarization known to improve the inhibition by organic Ca2+ antagonists of L-type voltage-gated Ca2+ channels attenuates the Ca2+ antagonism of Mg2+ at vascular smooth muscle cells.
Limited recovery of contractile function and loss of coronary reactivity have been observed following prolonged hypothermic storage and transplantation of the heart. Since lipid peroxidation has a significant role in these deficits, we investigated the cardioprotective effects of a 21-aminosteroid. U74389G, 3 mg/kg i.v., was given daily for 2 consecutive days to donor Lewis rats before the hearts were harvested and to recipient Lewis rats for 3 consecutive days after heart transplantation. Donor hearts were preserved for 4 hr in cold saline (4 degree C) before transplantation. Left ventricular developed pressure (LVP), basal coronary perfusion, and coronary reactivity to endothelium-dependent dilation (bradykinin, 0.1 microM) or endothelium-dependent dilation (sodium nitroprusside, 0.5 microM) were studied in isolated, buffer-perfused heart, using a modified Langendorff model. Cold preservation alone significantly reduced LVP and coronary perfusion. Coronary reactivity to bradykinin and sodium nitroprusside was also significantly impaired. In U74389G-treated donor hearts, 4 hr of cold ischemia did not alter contractile function, coronary perfusion or endothelial reactivity, although the response to sodium nitroprusside did not fully recover. In untreated recipients, in vivo reperfusion (transplantation) resulted in reduced LVP and perfusion deficits. Treating donors and recipients with U74389G improved left ventricular contractibility and coronary perfusion, although endothelium-dependent and -independent coronary reactivity remained affected. These results indicate that the lazaroid U74389G exerts significant cardioprotection during both preservation and transplantation of the heart. Donor and recipient pretreatment is mandatory for maximal efficacy with U74389G.
Aprikalim, a K+ ATP channel opener, is a potent vasodilator with demonstrated cardioprotective properties against ischemia/reperfusion injury. It is still unknown if K+ ATP channel openers exert their beneficial effects via interaction with oxygen-derived free radicals. Therefore, we investigated the cardioprotective effects of aprikalim against oxygen-derived free radicals. Isolated rabbit hearts were perfused at constant pressure (85 cm H2O) or constant flow (30-35 ml/min). Heart rate, left ventricular developed pressure (LVDP), and either coronary flow or coronary perfusion pressure (CPP) were monitored. Free radicals were produced by electrolysis of the perfusate (0.6 mA, direct current), and 10 microM aprikalim was infused before and after exposure to free radicals. In the constant perfusion pressure experiments, 10 min of exposure to free radicals resulted in a significant reduction of heart rate (137 to 129 beats/min), LVDP (112 to 91 mmHg) and coronary flow (37 to 29 ml/min); coronary flow was more markedly impaired than contractile function. Acetylcholine-induced coronary dilation was also significantly attenuated in the presence of free radicals. After 30 min of recovery, both coronary flow and LVDP were still significantly decreased while acetylcholine-induced coronary dilation had fully recuperated. Aprikalim completely abated the coronary and cardiac depressant actions of free radicals. Constant flow experiments indicated that exposure to free radicals increased CPP (+40%, p < 0.05), an effect totally suppressed by aprikalim. These results demonstrate that aprikalim reverses the cardiodepressant actions of free radicals. The cardioprotection it afforded involves both contractile function and the coronary vasculature. Acetylcholine-induced coronary dilation was blunted by free radicals, an indication of complex interactions at the coronary endothelial level.
Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.
Neurotoxicity of spinally administered hyperbaric 5% lidocaine is becoming a serious concern in view of the recent literature. We report a case of probable neurotoxicity of hyperbaric 5% lidocaine, followed by an aseptic meningitis. This case report emphasizes the danger of using hyperbaric 5% lidocaine in a too high dose while performing spinal anesthesia.
In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.
Although hypothermia and cardioplegic cardiac arrest provide effective protection during cardiac surgery, ischemia of long duration, poor preoperative myocardial function, and ventricular hypertrophy may lead to heterogeneous delivery of cardioplegic solutions, incomplete protection, and impaired postischemic recovery. Calcium antagonists are potent cardioprotective agents, but their efficacy in the presence of cold cardioplegia is still controversial, especially in heart failure, since it is often believed that failing hearts are more sensitive to their negative inotropic and chronotropic actions. However, recent data have demonstrated that the benzothiazepine-like calcium antagonists diltiazem and clentiazem, in selected dose ranges, elicit significant cardioprotection independently of intrinsic cardiodepression, thus lending support to their use in cardioprotective maneuvers involving the failing heart. We therefore evaluated the cardioprotective interaction of diltiazem, clentiazem, and cold cardioplegia in both normal and failing ischemic hearts. Hearts were excised from 200- to 225-day-old cardiomyopathic hamsters (CMHs) of the UM-X7.1 line and age-matched normal healthy controls. Ex vivo perfusion was performed at a constant pressure (140 cmH2O; 1 cmH2O = 98.1 Pa) according to the method of Langendorff. Heart rate, left ventricular developed pressure (LVDP), and coronary flow were monitored throughout the study. Global ischemia was produced for 90 min by shutting down the perfusate flow, followed by reperfusion for 30 min. Normal and failing CMH hearts were either untreated (control) or perfused at the onset of global ischemia with one of the following combinations: cold cardioplegia alone (St. Thomas' Hospital cardioplegic solution, 4 degrees C, infused for 2 min), cold cardioplegia + 10 nM diltiazem, or cold cardioplegia + 10 nM clentiazem. The cardiac and coronary dilator properties of 10 nM diltiazem and 10 nM clentiazem alone were investigated in separate groups of isolated preparations. Failing CMH hearts had lower basal LVDP (42 +/- 2 vs. 77 +/- 2 mmHg (1 mmHg = 133.3 Pa) for normal hearts, p < 0.05), while coronary flow was only slightly reduced (5.6 +/- 0.2 vs. 6.2 +/- 0.2 mL/min for normal hearts). Following 90 min global ischemia, coronary flow was increased in both groups, but the peak hyperemic response declined only in failing CMH hearts (+50 +/- 17 vs. +82 +/- 17% in normal hearts). In normal hearts, LVDP virtually recovered within 5 min of reperfusion but steadily decreased thereafter (-37 +/- 4% at 30 min). In contrast, in failing CMH hearts, LVDP significantly decreased early during reperfusion but improved over time (-19 +/- 7% at 30 min). In normal hearts, the addition of diltiazem or clentiazem to cold cardioplegic solutions resulted in improved postischemic contractile function for the duration of reperfusion (85 +/- 4% vs. only 71 +/- 6% for cardioplegia, p < 0.05). The post-ischemic increase in coronary flow was similar in all groups. In failing CMH hearts, the addition of diltiazem or clentiazem afforded no significant contractile benefit at reperfusion. In nonischemic normal hearts, infusion of diltiazem or clentiazem (10 nM) alone increased coronary flow (+6 +/- 1% for diltiazem and +24 +/- 3% for clentiazem) without significant negative inotropic or chronotropic effects. In nonischemic failing CMH hearts, infusion of diltiazem or clentiazem did not elicit cardiodepression. In contrast their coronary dilator actions reverted to vasoconstriction (diltiazem) or were significantly attenuated (clentiazem). From these experiments we can conclude that, compared with the normal heart, the failing CMH heart adapted differently to global ischemia.
Methaemoglobinemia is a rare but well known complication of the use of prilocaïne in locoregional anaesthesia. We report a case of methaemoglobinemia following the administration of a low dose of prilocaïne for an interscalenic bloc. We suggest some hypotheses to explain this phenomenon. This case illustrates the necessity of pulse oximetry monitoring in all patients receiving prilocaïne during locoregional anaesthesia.
An extracellular elastase, termed Myxococcus xanthus alkaline protease 1 (MAP1), has been purified from M. xanthus DK1622 culture supernatants by a combination of ion-exchange and affinity chromatographies. It consists of a single peptide chain of 39 kDa. The elastolytic activity was totally suppressed by 10 mM 1,10-phenanthroline and the enzyme may then be classified as a metalloprotease. Its pH optimum was estimated to be 8.2 with both elastin-orcein and succinyl-Ala3 p-nitroanilide as substrates. Despite its low pI (5.2), MAP1 was adsorbed on elastin at 80%, a result which privileges hydrophobic interactions between MAP1 and elastin rather than salt bridges, as for known basic elastases. About 80% of the original amidasic and elastolytic activities were conserved after a 30-min prior incubation of the enzyme at 40 degrees C; however, 70% of the amidasic activity is measured, instead of 15% for the elastolytic activity, after 30 min at 50 degrees C. Thermal denaturation at this temperature may prevent adsorption of the enzyme on elastin without any important change of the elastase structure. MAP1 readily hydrolyzes the Gly23-Phe24 bond in the oxidized insulin B chain; the peptide bonds Ala14-Leu15, Leu15-Tyr16, Phe24-Phe25, Phe25-Tyr26 are also cleaved, suggesting a primary specificity of the enzyme for hydrophobic or aromatic residues at the first amino acid towards the C-terminus from the cleavage site (P'1 position) [Schechter, I. & Berger, A. (1967) Biochem. Biophys. Res. Commun. 27, 157-162]. This hypothesis is consistent with the fact that Ala2-Phe-Ala and Ala3-Phe-Ala are hydrolyzed even though tri-alanine to hexa-alanine oligomers are not. The evidence of an elastase with the same molecular mass and pI as MAP1 is given during fruiting body development in submerged culture of M. xanthus. The fact that aromatic amino acids have been found to be the most representative of A-signal [Kuspa, A., Plamann, L. & Kaiser, D. (1992) J. Bacteriol. 174, 3319-3326] is consistent with the hypothesis that, regarding its specificity, MAP1 is likely to play a role in development of myxobacteria.