Physostigmine antagonizes ketamine-induced noradrenaline release from the medial prefrontal cortex in rats

Physostigmine is known to antagonize ketamine anesthesia. In this study, effects of physostigmine (0.1 mg kg⁻¹ i.p.) on ketamine (100 mg kg⁻¹ i.p.)-induced anesthesia time and noradrenaline release from the medial prefrontal cortex in rats were examined. Ketamine produced anesthesia for 27±1 min and increased noradrenaline release to 405% of the basal. Physostigmine significantly reduced anesthesia time to 23±1 min (p<0.05), and noradrenaline to 248% (p<0.05). Therefore, noradrenaline release may play an important role in ketamine anesthesia.     

Antithrombotic efficacy of single subcutaneous administration of a recombinant nematode anticoagulant peptide (rNAP5) in a canine model of coronary artery thrombolysis

We examined the adjunctive benefit of recombinant nematode anticoagulant peptide (rNAP5), a factor Xa inhibitor, in a canine model of recombinant (rt)-PA-induced thrombolysis. In anesthetized dogs, a stable occlusive thrombus was formed by electrolytic injury of the vessel wall, after which the animals were administered rt-PA (1.44 mg/kg, i.v.) and rNAP5 (0.1 mg/kg, s.c.; n=13), or rt-PA plus vehicle (1–2 ml, s.c.; n=13). Hemodynamic and coagulation parameters were monitored for 360 minutes. Single subcutaneous administration of rNAP5 resulted in a prolonged and sustained increase in the activated partial thromboplastin time (>10-fold), whereas prothrombin time was unchanged. The template bleeding time was not altered significantly throughout the protocol (maximum 1.4-fold). The incidence of reperfusion was similar in the two groups with a trend toward faster reperfusion in the rNAP5 group (34±4 minutes) compared to the vehicle group (63±15 minutes; p=0.07). After reperfusion, 80% of the vessels in the vehicle group reoccluded, whereas only 14% of vessels reoccluded in the rNAP5-treated group. Times to reocclusion were 65±21 minutes and 221±28 minutes, respectively (p<0.05). Single subcutaneous administration of rNAP5 sustained the coronary artery blood flow after reperfusion, such that at the end of protocol the flow was 47% of the preocclusion value as compared to the vehicle group in which the flow was 11% (p<0.05). Cyclic flow reductions were most prominent during rt-PA-induced reperfusion and were similar in both groups. The results indicate that a single subcutaneous administration of rNAP5 provides a sustained antithrombotic effect in maintaining the coronary artery patency during rt-PA-induced thrombolysis.     

The lupus anticoagulant is a risk factor for myocardial infarction (but not atherosclerosis): Hopkins Lupus Cohort

Antiphospholipid antibodies, both anticardiolipin and lupus anticoagulant, are common in SLE. We asked, in a prospective cohort, whether these antibodies are predictive of atherosclerosis and/or coronary artery disease. Methods: Three hundred eighty patients, 92% female, 49% Caucasian, 51% African-American, mean age 46.4±12.3 years are followed quarterly, with assessment of both anticardiolipin and lupus anticoagulant (dRVVT). These patients underwent both helical CT and carotid duplex. Results: Both the lupus anticoagulant and anticardiolipin are predictive of later venous or arterial thrombosis. Twenty years after diagnosis, SLE patients with the lupus anticoagulant (LA) have a 50% chance of a venous thrombotic event. Myocardial infarction occurs significantly more often in those with LA 22% vs. 9%, p=0.04. Neither anticardiolipin nor LA are associated with carotid IMT, carotid plaque, nor coronary calcium by helical CT. In aCL positive patients carotid IMT was 0.57±0.01 vs. 0.58±0.01 in aCL negative patients (p=NS); carotid plaque 0.47±0.13 vs. 0.32±0.10 (p=NS); and coronary calcium 65.4±37.4 vs. 65.4±30.2 (p=NS). In LA positive patients, carotid IMT was 0.59±0.03 vs. 0.59±0.02 in LA negative patients (p=NS); carotid plaque 0.07±0.02 (SE) vs. 0.80±0.02 (SE) (p=0.06); and coronary calcium 28.1±3.7 (SE) vs. 85.7±2.6 (SE) (p=NS). Conclusion: Antiphospholipid antibodies are not associated with subclinical atherosclerosis (carotid IMR, carotid plaque, helical CT coronary calcium), but are associated with actual thrombotic sequelae (myocardial infarction).     

The effect of valproic acid on the 5-hydroxyindoleacetic, homovanillic and lactic acid levels of cerebrospinal fluid

In this study the cisternal cerebrospinal fluid (CSF) contents of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were sequentially measured in free-moving rats which were administered 50–500 mg·kg⁻¹ valproic acid. Animals receiving 100–500 mg·kg⁻¹ valproic acid showed significant increases in CSF 5-HIAA and HVA content, with maximal accumulation rates of 1.80–2.10 and 0.25–0.30 nmol·ml⁻¹·h⁻¹, repectively, being reached at the 250 mg·kg⁻¹ dose. The combination of valproic acid 500 mg·kg⁻¹ and probenecid 300 mg·kg⁻¹ failed to increase the accumulation rates of 5-HIAA and HVA over those seen with valproic acid 500 mg·kg⁻¹ or probenecid 300 mg·kg⁻¹ alone. This pattern of change indicates that valproic acid and probenecid share a common site of action in blocking the clearance of 5-HIAA and HVA from CSF. The tranquillizer diazepam produced progressive increases in CSF 5-HIAA and HVA content which suggested a similar action to that of valproic acid and probenecid. The anticonvulsants phenytoin and phenobarbital produced selective increases in 5-HIAA, whereas the tranquillizer chlorpromazine produced proportionally larger increases in HVA, changes which seem to indicate a more selective effect of these drugs on the serotonergic or dopaminergic systems, respectively. Valproic acid was associated with increases in CSF lactate which occurred in the absence of similar increases of blood or tissue lactate. This indicated that valproic acid, like probenecid, can inhibit the monocar☐ylic acid transport system which removes lactate from the CSF.     

Sumatriptan modifies cortical free radical release during cortical spreading depression. A novel antimigraine action for sumatriptan?

Increases in concentration of brain NO are proposed to initiate and mediate migraine headache. Triggered by focal depolarisation, spreading depression (SD) represents a suitable mechanism for eliciting widespread release of nitric oxide. The current study examines the effect of sumatriptan, a 5-HT_1B/1D agonist and effective antimigraine therapy, on free radical release (nitric oxide and superoxide) in SD in the simple and complex cortices of the rat and cat. Following initiation of SD, sumatriptan pretreatment (300 μg kg⁻¹ i.v., 15 min prior to SD) modulated all phases of nitric oxide release associated with each SD in both cats and rats. As a result, superoxide levels were observed to significantly (ANOVA, post hoc LSD) increase versus vehicle treated animals (saline 1 ml kg⁻¹ i.v. 15 min prior to SD) during specific phases of each SD depolarisation. Averaged over all SD depolarisations, mean peak SD nitric oxide levels per depolarisation were 0.73±0.23 μM (n=29) in cats, and 0.42±0.09 μM (n=34) in rats. Sumatriptan significantly (Students t-test, P<0.05, two tailed hypothesis, P<0.05) modulated this increase in cortical nitric oxide concentrations to 0.32±0.06 μM (n=25) and 0.22±0.07 μM (n=37) in cats and rats. Sumatriptan appears to decrease the amplitude of nitric oxide release but enhances extracellular superoxide concentrations in both lissencephalic and gyrencephalic cortices during SD.     

Decreased plasma concentration of a novel anti-inflammatory protein--adiponectin--in hypertensive men with coronary artery disease

Aims: Recent studies indicate that adiponectin may have anti-inflammatory and anti-atherogenic properties, suggesting that hypoadiponectinemia can play a role in the pathogenesis of cardiovascular disease. Therefore the aim of the study was to assess plasma adiponectin concentration in hypertensive male patients with coronary artery disease (CAD). Associations of adiponectinemia with other cardiovascular risk factors were also analysed. Methods and results: The study included 99 consecutive male patients (median age 57 years) with hypertension and CAD who at the same time underwent coronary and renal angiography. The control group consisted of 62 BMI-matched healthy male blood donors (median age 48 years). Plasma adiponectin level was significantly lower in the CAD group as compared to the control group (4.01±0.18 vs. 4.88±0.24 μg/ml; p<0.01). There were no differences in plasma adiponectin concentration between hypertensive CAD patients with and without atherosclerotic renal artery stenosis. In the CAD group plasma adiponectin concentration correlated with levels of creatinine (r=0.56; p<0.001), HDL cholesterol (r=0.24; p<0.05), BMI (r=−0.33; p<0.001), glucose (r=−0.22; p<0.05) and triglycerides (r=−0.25; p<0.05). No correlation was found between plasma adiponectin and homocysteine concentrations. In a multivariate stepwise logistic regression model increasing concentrations of adiponectin were independently and significantly associated with a lower risk of CAD (OR 0.58 95% CI 0.42–0.81 p<0.001). Conclusions: Our results showed decreased plasma adiponectin concentration in the studied group of hypertensive men with CAD as compared to normotensive healthy subjects. This may suggest that decreased plasma adiponectin concentration is associated with a higher risk of CAD.     

Cyclophosphamide immunosuppression does not permit successful myoblast allotransplantation in mouse

Cyclophosphamide immunosuppression does not permit successful myoblast allotransplantation in mouse. Myoblast transplantation is a potential treatment for Duchenne muscular dystrophy. In one clinical trial, Duchenne patients were immunosuppressed with cyclophosphamide. We report here that myoblasts from transgenic mice expressing the β-galactosidase reporter gene transplanted in mdx mice failed to form new muscle fibres when cyclophosphamide (2 or 10 mg kg⁻¹ per day) was used for immunosuppression. At the lowest dose of cyclophosphamide (2 mg kg⁻¹ per day), some mdx recipient mice formed antibodies against donor myoblasts; however, no humoral immune reaction was observed at the highest dose (10 mg kg⁻¹ per day). The failure of transplantation under cyclophosphamide treatment was attributed to the low immunosuppressive activity at a low dose and to the toxic action at a high dose of this drug. These results could explain the lack of success of myoblast transplantation in a previous clinical trial.     

Effect of cryopreservation on endothelin-1 productions of human mammary artery

The aim of this study was to determine the ability of human mammary artery cells to maintain a metabolic activity by measuring the artery concentration of two vasoactive substances, endothelin-1 (ET-1) and cyclic guanosyl monophosphate (cGMP), and a neurohumoral substance—neuropeptide Y (NPY)—prior to and following cryostorage. Ten distal segments of internal mammary arteries were obtained at the time of surgery in patients who had undergone coronary artery bypass grafting. One ring of each vessel served as a fresh control for the other ring that was used in cryopreservation experiments. The arteries were frozen with liquid nitrogen at a controlled rate down to –130°C with an automatic freezing machine and were then stored in a liquid nitrogen vapor at −150°C. After mammary artery extraction, ET-1, cGMP, and NPY concentrations were studied before and after cryopreservation. Cryopreserved, compared to fresh arteries, exhibited an increase in ET-1 (11.11±1.61 vs. 3.09±0.06 pg/mg; p=0.004) and a decrease in cGMP (9.88±2.04 vs. 8.55±2.07 p moles/mg; p<0.02), whereas there was no significant NPY variation. An increase in ET-1 and decrease in cGMP was found in 10 out of 10 and 6 out of 10 of cryopreserved artery specimen, respectively. There was no significant correlation between ET-1 and cGMP production in fresh or in cryopreserved arteries. The present method of cryostorage is effective in preserving “hormonal” mammary artery activity. However, the particularly high ET-1 concentration without associated cGMP concentration may be deleterious by increasing smooth-muscle cell proliferation and vascular tone of cryopreserved arteries.     

Exercise induces a change in plasma fibrinogen concentration: fact or fiction?

This study examined the effect of exercise on plasma fibrinogen concentrations with simultaneous measurements of plasma volume changes. Eight moderately active males aged 26.6±3.6 years (mean±SD) completed maximal (VO₂max) and submaximal (75% VO₂max for 30 minutes) exercise trials separated by 7 days. Venous blood samples were obtained at rest, immediately postexercise, and following 30 minutes of recovery. Whole blood was analysed for haematocrit and haemoglobin, while citrated plasma was assayed for fibrinogen levels. Values of haematocrit and haemoglobin before and after exercise were utilised for the estimation of plasma volume changes. Plasma volume decreased (p<0.05) immediately following both maximal (−17.7±5.1%) and submaximal (−14.3±4.1%) exercise. Exercise resulted in decreased plasma fibrinogen levels (maximal exercise: from 266.3±14.5 to 222.2±23.9 mg·dL⁻¹; submaximal exercise: from 239.5±45.4 to 209.7±42.4 mg·dL⁻¹) only when postexercise raw data were corrected for the contraction of plasma volume. It is concluded therefore that changes in plasma volume in response to exercise should be taken into account when interpreting exercise effects on plasma fibrinogen concentration.     

Blood-brain barrier integrity and brain water and electrolytes during hypoxia/hypercapnia and hypotension in newborn piglets

This study examines the effects of hypoxia/hypercapnia and hypoxia/hypercapnia with hypotension (hypotensive-hypoxia/hypercapnia) on blood-to-brain transfer constants (K₁) for sodium and mannitol and brain water and electrolyte contents in newborn piglets. Hypoxia/hypercapnia was induced for 60 min with the piglets breathing a gas mixture of 15% carbon dioxide, 10–12% oxygen, and 73–75% nitrogen adjusted to achieve an arterial pH < 7.15, pO₂ < 40, and pCO₂ > 60 mmHg potension for 20 min by rapid phlebotomy to achieve a mean arterial blood pressure < 40 mmHg. Piglets were studied during 1 h of, and 24 h after resuscitation from hypoxia/hypercapnia (arterial pH 6.9 ± 0.18, pO₂ 36 ± 6 mmHg, pCO₂ 38 ± 8 mmHg, mean ± S.D.) and 10 min, and 24 h after resuscitation from hypotensive-hypoxia/hypercapnia (mean arterial blood pressure 28 ± 10 mmHg, mean ± S.D.). Values for K_t for sodium and mannitol, measured using the integral technique were 15.9 and 5.2 ml·g⁻¹·min⁻¹ × 10⁴ respectively, in 2–4-day-old controls, suggesting that the barrier is fully developed in newborn piglets. Values were not different during or after hypoxia/hypercapnia or 24 after hypotensive-hypoxia/hypercapnia. Ten to forty min after hypotensive-hypoxia/hypercapnia, there was a proportional decrease in the K₁ for sodium and mannitol of about 40%. These results suggest that the newborn piglet is similar to the adult with respect to impermeabiity of the blood-brain barrier to ions and small molecules and resistance of this barrier to systemic hypoxia/hypercapnia and hypotension. We suggest that acute decreases in K₁ for sodium and mannitol after hypotensive-hypoxia/hypercapnia reflect a reduction in capillary surface area.