Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport.

The neurotransmitter noradrenaline is removed from the extracellular space by neuronal and extraneuronal transport mechanisms. In the past, further functional and biochemical characterisation of the corticosterone-sensitive extraneuronal transporter was hampered by the lack of highly potent inhibitors. Here we describe a new class of selective and highly potent inhibitors of the extraneuronal noradrenaline transporter. Clonal Caki-1 cells possess the human type of extraneuronal noradrenaline carrier. The effect of various steroids and steroid-like compounds on initial rates of specific 3H-noradrenaline transport in Caki-1 cells was investigated. None of these steroids had an inhibitory potency higher than that of corticosterone which hitherto was generally accepted as the most potent inhibitor of the extraneuronal noradrenaline transport. On the other hand, a variety of quinoline and isoquinoline derivatives interacted with the extraneuronal noradrenaline transporter. Several cationic quinolines that belong to the chemical class of the cyanine dyes turned out to be very potent inhibitors of 3H-noradrenaline transport in Caki-1 cells. The isocyanines, 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) and 1-methyl-1'-isopropyl-2,4'-cyanine as well as the pseudoisocyanines 1,1'-diethyl-2,2'-cyanine (decynium22) and 1-isopropyl-1'-ethyl-2,2'-cyanine (iprecynium22) were most potent with IC50's of 14, 62, 16, and 18 nmol/l, respectively. The inhibitory potency on extraneuronal noradrenaline transport of 1-methyl-1'-isopropyl-2,4'-cyanine was determined also in isolated organs, namely the isolated incubated rabbit aorta and the isolated perfused rat heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of body position on tissue-pO2, cerebral perfusion pressure and intracranial pressure in patients with acute brain injury.

It is a common practice to position head-injured patients in bed with the head elevated above the level of the heart in order to reduce intracranial pressure (ICP). This practice has been in vivid discussion since some authors argue a horizontal body position will increase the cerebral perfusion pressure (CPP) and therefore improve cerebral blood flow (CBF). However, ICP is generally significantly higher in the horizontal position. The aim of this study was to evaluate changes in regional microcirculation using tissue pO2 (ti-pO2), as well as changes in cerebral perfusion pressure (CPP) and intracranial pressure induced by changes in body position in patients with head injury. The effect of 0 degree and 30 degrees head elevation on ti-pO2. CPP, ICP and arterial blood pressure (MABP) was studied in 22 head injured patients during day 0-12 after trauma. The mean ICP was significantly lower at 30 degrees head elevation than at 0 degree (14.1 + 8.6 vs. 19.9 + 8.3 mmHg). While MABP was unaffected by head elevation, CPP was slightly higher at 30 degrees than at 0 degree (76.5 + 13.5 vs. 71.5 + 13.2 mmHg). However, regional ti-pO2 was unaffected by body position (30 degrees vs. 0 degree: 24.9 + 13.1 vs. 24.7 + 12.9 mmHg). In addition, there was no change in the time course after trauma concerning these findings in the individual patients. The data indicate that a moderate head elevation of 30 degrees reduces ICP without jeopardizing regional cerebral microcirculation as monitored using a polarographic ti-pO2 microcatheter.

Intraoperative microdialysis and tissue-pO2 measurement in human glioma.

The amino acid glutamate is one of the major neurotoxins in the pathogenesis of neuronal death after ischemia or trauma. Microdialysis studies in both man and animal have shown elevated extracellular levels after primary lesions. Monitoring of cerebral tissue oxygenation (p(ti)O2) has been used in recent years to detect and prevent episodes of low cerebral oxygenation, e.g. after trauma or subarachnoid hemorrhage. Intraoperative monitoring of p(ti)O2 combined with microdialysis in the peritumoral edema has been chosen to study the responses of glutamate and oxygen levels during resection. In 7/9 patients p(ti)O2 was below "critical" 10 mm Hg. Elevating inspiratory oxygen concentration to 100% led to an increase of p(ti)O2 by 2.5-4 fold and a decrease of glutamate and aspartate by 50-80%. A close correlation between p(ti)O2 and microdialysis glutamate levels was not clearly shown due to frequent intraoperative manipulations.

Multimodal hemodynamic neuromonitoring--quality and consequences for therapy of severely head injured patients.

Fifty-five head injured patients (GCS < 8) were studied at an average of 7.5 +/- 3.4 days on the ICU to check quality of hemodynamic monitoring and the consequences for therapy. Multimodal neuromonitoring included intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), endtidal CO2 (EtCO2) as well as brain tissue--pO2 (p(ti)O2), regional oxygen (rSO2) and jugular venous oxygen saturation (SjO2). Regional p(ti)O2 as well as global SjO2 were sensitive technologies to detect hemodynamic changes. However analyzing reliability and good data quality regional p(ti)O2 (up to 95%) was superior to jugular bulb oximetry (up to 50%). Longterm-measurements of rSO2 using near infrared spectroscopy reached, if possible, a restricted reliability (good data quality up to 70%) and sensitivity in comparison to p(ti)O2. Especially p(ti)O2 enabled detection of critical p(ti)O2 (< 15 mm Hg) in up to 50% frequency during the first days after trauma and a second peak after day 6 to 8 according to evidence of CPP insults. Knowledge of baseline p(ti)O2 and CO2-reactivity allowed minimizing risk of ischemia by induced hyperventilation and improvement on cerebral microcirculation after mannitol administration could be individually recognized.