Biomedical subjects

N C Weber

Publications and source records attributed to N C Weber.

10 recordsLinked to original sources

PubMed2006

Xenon preconditioning differently regulates p44/42 MAPK (ERK 1/2) and p46/54 MAPK (JNK 1/2 and 3) in vivo.

BACKGROUND: Xenon (Xe) induces preconditioning (PC) of the rat heart in vivo via activation of p38 mitogen-activated protein kinase (MAPK). The role of ERK 1/2 and JNK 1/2 and 3 in Xe-PC has yet not been determined. METHODS: For infarct size measurements, anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Animals received Xe 70% during three 5 min periods with and without the ERK inhibitor PD 98059 (1 mg kg(-1), PD) or the JNK inhibitor SP 600125 (6 mg kg(-1), SP) (n=10 per group). Additional hearts were excised for western blot and kinase activity assay: without further treatment, after the first, the second and the third period of Xe-PC or at the end of the last washout phase (n=4 each). RESULTS: Infarct size (% of area at risk) was reduced from 46.2 (8.1)% to 28.4 (11.3)% after Xe-PC (P<0.01). PD completely abolished this effect [49.7 (11.4)%, P<0.01 vs Xe-PC]. The ratio of particulate/cytosolic phospho ERK 1/2 was time dependently increased during the PC protocol [ERK 1: 15 min: 2.4 (1.2), 25 min: 1.5 (0.3), 35 min: 1.6 (0.7), 45 min: 1.5 (0.5) vs Con 1.0 (0.5) and ERK 2: 15 min: 3.3 (1.8), 25 min: 2.0 (1.5), 35 min: 1.8 (1.7), 45 min: 0.9 (0.6) vs Con 0.8 (0.4)]. This finding was confirmed by a non-radioactive MAPK activity assay. In contrast SP had no effect on Xe-PC and the phosphorylation state of JNK was not influenced by Xe-PC. CONCLUSION: Besides the p38 MAPK, ERK 1/2 also is a mediator of Xe-PC. However, JNK is not involved, demonstrating a highly specific regulation of different kinases during Xe-PC.

Anesthetics, Inhalation↗

PubMed2005

The effect of anaesthetics on the myocardium--new insights into myocardial protection.

A variety of laboratory and clinical studies clearly indicate that exposure to anaesthetic agents can lead to a pronounced protection of the myocardium against ischaemia-reperfusion injury. Several changes in the protein structure of the myocardium that may mediate this cardioprotection have been identified. Ischaemia-reperfusion of the heart occurs in a variety of clinical situations including transplantations, coronary artery bypass grafting or vascular surgery. Ischaemia may also occur during a stressful anaesthetic induction. Early restoration of arterial blood flow and measures to improve the ischaemic tolerance of the tissue are the main therapeutic options (i.e. cardioplegia and betablockers). There exists increasing evidence that anaesthetic agents interact with the mechanisms of ischaemia-reperfusion injury and protect the myocardium by a 'preconditioning' and a 'postconditioning' mechanism. Hence, the anaesthesiologist may substantially influence the critical situation of ischaemia-reperfusion during surgery by choosing the appropriate anaesthetic agent. This review summarizes the current understanding of the mechanisms of anaesthetic-induced myocardial protection. In this context, three time windows of anaesthetic-induced cardioprotection are discussed: administration (1) during ischaemia, (2) after ischaemia-during reperfusion (postconditioning) and (3) before ischaemia (preconditioning). Possible clinical implications of these interventions will be reviewed.

Anesthetics, General↗

PubMed2004

Role of protein kinase C-epsilon (PKCepsilon) in isoflurane-induced cardioprotection.

BACKGROUND: Volatile anaesthetics precondition the heart against infarction, an effect partly mediated by activation of the epsilon isoform of protein kinase C (PKCepsilon). We investigated whether cardioprotection by activation of PKCepsilon depends on the isoflurane concentration. METHODS: Anaesthetized rats underwent 25 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups (n=10 in each group): isoflurane preconditioning induced by 15 min administration of 0.4 minimal alveolar concentration (MAC) (0.4MAC), 1 MAC (1MAC) or 1.75 MAC (1.75MAC) followed by 10 min washout before ischaemia. Each protocol was repeated in the presence of the PKC inhibitor staurosporine (10 microg kg(-1)): 0.4MAC+S, 1MAC+S and 1.75MAC+S. Controls were untreated (CON) and additional hearts received staurosporine without isoflurane (S). In a second set of experiments (n=6 in each group) hearts were excised before the infarct inducing ischaemia, and phosphorylation and translocation of PKCepsilon were determined by western blot analysis. RESULTS: Isoflurane reduced infarct size from a mean of 61(SEM 2)% of the area at risk in controls to 20(1)% (0.4MAC), 26(3)% (1MAC) and 30(1)% (1.75MAC) (all P<0.01 vs CON or S). This protection was partially reversed by administration of staurosporine in the 0.4MAC+S group (30[2]%; P<0.05 vs 0.4MAC) group, but not after administration of 1 MAC or 1.75 MAC isoflurane (26[2]% and 31[2]%, respectively). Thus 0.4MAC increased PKCepsilon phosphorylation, and this effect was blocked by staurosporine. Higher concentrations of isoflurane did not change PKCepsilon phosphorylation. PKCepsilon was translocated to the membrane fraction after administration of 0.4 MAC isoflurane, but not after 1.0 or 1.75 MAC. CONCLUSIONS: Although isoflurane preconditioning resulted in a reduction in infarct size at all concentrations used, the protection was mediated by phosphorylation and translocation of PKCepsilon only at 0.4 MAC.

Anesthetics, Inhalation↗

PubMed1997

Chronic cerebral hypoperfusion: pathological and behavioral consequences.

OBJECTIVE: Although the effects of acute ischemic insults to the brain are well known, the effects related to chronic ischemia are poorly delineated. The pathological and behavioral changes induced by a chronic noninfarctional reduction in cerebral blood flow of 25 to 50% maintained for 6 months were assessed. METHODS: In each of 18 male Sprague-Dawley rats, an arteriovenous fistula was created in the neck via an anastomosis between the right external jugular vein and the right common carotid artery to induce cerebral hypoperfusion. Nineteen age-matched animals comprised a control group. Six months after surgery, the animals were examined using light and electron microscopic techniques, as well as via a battery of behavioral tests (motor, open field, and T-maze). RESULTS: Examination of the hippocampus by using light microscopy revealed disorganization of the CA1 sector with an increased number of astrocytes. Transmission electron microscopy of the CA1 region demonstrated neurons with increased lipofuscin pigment and central nucleoli and astrocytes with more numerous cytosolic mitochondria. Motor performance testing revealed no gross motor deficits, although open-field assessment demonstrated increased exploratory behavior in rats with fistulas. Finally, T-maze testing results suggested that errors in working memory were more common in rats undergoing chronic cerebral hypoperfusion (P < 0.05). CONCLUSIONS: These findings suggest that chronic reductions in cerebral blood flow of a magnitude previously thought to be harmless to neurons (i.e., reduced by 25-50%) do alter neuronal structure and affect whole animal behavior. Such a scenario may be responsible for a symptomatology secondary to arteriovenous steal and severe carotid stenoses. The mechanisms are still unknown.

Animals↗

PubMed1997

Chronic cerebral hypoperfusion inhibits calcium-induced long-term potentiation in rats.

BACKGROUND AND PURPOSE: Long-term potentiation (LTP) in the rat hippocampus induced by tetanic stimulation is impaired by chronic cerebral hypoperfusion. The effects of chronic cerebral hypoperfusion on other forms of LTP are unknown. Such data could help delineate the pathways of cellular alteration caused by chronic cerebral hypoperfusion. The in vitro phenomenon of calcium-induced LTP was thus examined in rat hippocampal CA1 cells that had undergone chronic hypoperfusion with a reduction in cerebral blood flow of between 25% and 50% maintained for 26 weeks. METHODS: Ten Sprague-Dawley rats had a cervical arteriovenous fistula surgically constructed, and an additional 10 animals were used as age-matched controls. Hippocampal slices were prepared after 26 weeks of hypoperfusion, and in vitro extracellular field potential recordings were taken from the Schäffer collateral CA1 region. Properties of LTP induced through transient exposure to a hypercalcemic solution were analyzed. RESULTS: LTP was impaired in animals with an arteriovenous fistula (P < .05). Control animals demonstrated potentiation lasting for the entire 2 hours of recording, whereas fistula animals showed only transient potentiation (< 60 minutes) before returning to baseline values. CONCLUSIONS: Calcium-induced LTP is impaired by chronic cerebral hypoperfusion. This form of LTP is different from that induced by tetanic stimulation. It is the most sensitive test available for in vitro detection of the changes induced in neuronal function by chronic noninfarctional reductions in cerebral blood flow of 25% to 50% and may indicate that the most basic cellular parameters involving calcium homeostasis and metabolism are being altered. The precise mechanisms remain to be elucidated, and several postulates are discussed.

Action Potentials↗

PubMed1995

Chronic cerebral hypoperfusion in the rat: temporal delineation of effects and the in vitro ischemic threshold.

Acute reductions in cerebral blood flow of up to 50% do not affect neuronal function although it has been shown that reductions of a similar magnitude maintained for 26 weeks do induce neuronal changes. In vitro rat hippocampal LTP was evaluated after 10 weeks of cerebral hypoperfusion. An assessment was also made of the possible 'robustness' of hippocampal CA1 pyramidal neurons to combined in vitro hypoxic/ischemic insults because of previously shown differences in hemodynamic autoregulatory curves. No differences were found between controlled and chronically hypoperfused animals in either study. It is concluded that the changes in neuronal function induced by reductions in cerebral blood flow of less than 50% take time to develop and do not induce adaptive changes in affected neurons. The mechanism for these changes remains to be elucidated.

Animals↗

PubMed1995

Delayed referral of patients with aneurysmal subarachnoid haemorrhage.

OBJECTIVE: To determine the outcome of patients with subarachnoid haemorrhage and whether delays in their diagnosis and referral have been reduced over a 15-year period. DESIGN: A 15-year retrospective study of patients admitted to a tertiary neurosurgical unit between 1977 and 1992. SETTING: The Royal North Shore Hospital, Sydney. PATIENTS: 511 patients admitted with subarachnoid haemorrhage from ruptured intracranial aneurysms. RESULTS: Of 486 patients with at least a six-month follow-up, 66% made a good recovery and 19% died. Outcome was significantly influenced by the neurological condition of the patient at admission (P < 0.0001). There was no significant difference in the relative proportions of patients transferred late (three or more days after onset of symptoms) when those admitted before and after 1986 were compared. CONCLUSION: Delayed diagnosis and referral remain the major preventable problems in the management of patients with aneurysmal subarachnoid haemorrhage.

Aneurysm, Ruptured↗

PubMed1994

Chronic cerebral hypoperfusion and impaired neuronal function in rats.

BACKGROUND AND PURPOSE: Studies in acute cerebral ischemia have shown that reductions in cerebral blood flow of up to 50% do not lead to infarction or alterations in neuronal electric activity. Little is known about the effects of chronic reductions in cerebral blood flow. The purpose of this study was to evaluate neuronal electrophysiological function in brain that had been subjected to a chronic reduction of cerebral blood flow of less than 50%. Based on existing knowledge of thresholds of cerebral ischemia, neuronal electrophysiological function should be unaffected by hypoperfusion of this magnitude. METHODS: An arteriovenous fistula model in the rat was used to induce chronic cerebral hypoperfusion with reductions of cerebral blood flow of 25% to 50% as measured previously by 14C-labeled autoradiography. Using in vitro electrophysiological brain slice techniques, long-term potentiation in hippocampal CA1 neurons was examined extracellularly after 6 months of chronic noninfarctional cerebral hypoperfusion. Brains were also examined histologically at this time for evidence of cerebral infarction. RESULTS: There was no evidence of cerebral infarction. Long-term potentiation was produced in 9 of 12 control animals and only 2 of 8 hypoperfused animals. This difference was significant (P < .05) and demonstrated that long-term potentiation was impaired in animals with chronic hypoperfusion. CONCLUSIONS: Noninfarctional reductions in cerebral blood flow of up to 50% do impair neuronal function in chronic cerebral ischemia, a result quite distinct from that seen in acute ischemia. The threshold for neuronal dysfunction in chronic cerebral hypoperfusion is lower than that found in acute cerebral ischemia, suggesting that duration as well as severity of ischemic insult determines cellular viability. Chronic hypoperfusion may lead to a noninfarctional state with impaired neuronal function, a category of chronic cerebral ischemia not previously identified.

Action Potentials↗

PubMed1993

Complications of surgery for arteriovenous malformations of the brain.

A series of 112 patients undergoing complete surgical resection of arteriovenous malformations (AVM's) of the brain between 1974 and 1990 were analyzed for complications and 12-month outcomes. The cohort consisted of 44 patients with small AVM's (< 2 cm in diameter), 43 patients with medium-sized AVM's (2 to 4 cm in diameter), and 25 patients with large AVM's (> 4 cm in diameter). There was a 3.6% series mortality rate and an 18% morbidity rate. One of the four deaths was caused by normal perfusion pressure breakthrough. Analysis of logistic regression found that the most important factor influencing the occurrence of complications in this series was AVM size (p = 0.005) and that the occurrence of complications (p < 0.001) and the neurological grade at the time of surgery (p < 0.004) both significantly contributed to the outcome at 12 months. This study stresses the importance of defining complications in terms of rigid criteria when analyzing AVM series in order to allow for a correct evaluation of the risk:benefit ratio of surgery. Furthermore, it emphasizes the need for a separate analysis of the importance of complications upon outcome.

Adolescent↗

PubMed1986

A model of weak selection in the infinite alleles framework.

Ewens (1972) proposed a model in the infinite allele framework for populations with neutrality of all alleles at a particular locus. This paper proposes a generalisation of Ewens' result for situations where there is a form of weak selection. The models considered here are continuous time, discrete state space Markov processes.

Alleles↗