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).     

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

The objective of this study was to test the hypothesis if thrombolysis induced by recombinant tissue-type plasminogen activator, (rt-PA) could be facilitated by inhibiting carboxypeptidase U (CPU, active Thrombin Activatable Fibrinolysis Inhibitor, TAFIa) activity. The efficacy of rt-PA alone, or in combination with the carboxypeptidase inhibitor MERGETPA, was compared in a dog model of coronary artery thrombosis. Twenty dogs were randomised in two groups, one received rt-PA, 1 mg kg⁻¹, as intravenous infusion over 20 min starting 30 min after thrombus formation, and the other group received rt-PA, 1 mg kg⁻¹, as group one with the addition of MERGEPTA 5 mg kg⁻¹ starting 25 min prior to coronary artery occlusion and followed by infusion of 5 mg kg⁻¹ h⁻¹ until the end of experiment. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Both groups had similar baseline characteristics with respect to haemodynamic parameters, i.e., heart rate, blood pressure and coronary artery blood flow. Coadministration of rt-PA and MERGETPA resulted in significant decrease in time to lysis (15±1.5 min vs. 20±1.7 min, p=0.03), increased patency time (87±16 min vs. 46±12 min, p=0.047) and increased coronary blood flow during patency (1131 mL h⁻¹ vs. 405 mL h⁻¹, p=0.015), compared to rt-PA alone. These results indicate that an inhibitor of CPU activity may have a beneficial effect in patients undergoing thrombolytic therapy by attaining shorter time to reperfusion and improved coronary patency.     

Vitamin E improves fibrinolytic activity in patients with coronary spastic angina

Introduction: The fibrinolytic system has a major role as a defense mechanism against thrombus formation. Net fibrinolytic activity in plasma reflects the balance between tissue-type plasminogen activator and plasminogen activator inhibitor (PAI). PAI is the main factor determining overall fibrinolytic activity. Materials and methods: We examined the effects of oral administration of vitamin E, an antioxidant, on fibrinolytic activity and oxidative stress in patients with coronary spastic angina. Forty patients with coronary spastic angina were randomly assigned into two treatment groups, either vitamin E group (-tocopherol acetate, 400 mg/day) or placebo group by means of computerized system. PAI activity and thioredoxin, a marker of oxidative stress, levels were measured before and at the end of 1 month treatment. Results: Before treatment, the levels of PAI activity and thioredoxin were increased in patients with coronary spastic angina as compared with control subjects (n=17) (PAI activity levels: 13.6±1.4 vs. 7.6±2.2 IU/ml, p<0.05, thioredoxin levels: 22.8±1.7 vs. 16.0±1.4 ng/ml, p<0.05). In patients with coronary spastic angina, administration of vitamin E decreased both PAI activity and thioredoxin levels (PAI activity levels: 14.7±1.7 to 7.5±1.6 IU/ml, p<0.01, thioredoxin levels: 23.3±2.4 to 15.1±2.5 ng/ml, p<0.01), whereas placebo had no effect on these variables. Conclusions: Oral administration of vitamin E improved fibrinolytic activity and the improvement was associated with a decrease in oxidative stress. Administration of vitamin E is possible to be an effective adjunct therapy of coronary spasm in the absence of coronary atherosclerosis.     

Proton magnetic resonance spectroscopy in children with acute central nervous system injury

Single voxel proton magnetic resonance spectroscopy (¹H-MRS) was used in 30 infants and children with acute central nervous system injuries to determine the value of changes in specific metabolite ratios in predicting outcome. The mean age of all patients was 38 ± 52 months and the mean time of study after insult was 7 ± 5 days. ¹H-MRS was determined in the occipital gray and parietal white matter (8 cm³ volume, STEAM sequence with TE = 20 ms, TR = 3,000 ms). Data were expressed as ratios of different metabolite peak areas including N-acetylaspartate (NA), choline-containing compounds (Ch), creatine and phosphocreatine (Cr), and lactate (Lac). Statistically significant differences were observed when patients with good/moderate (G/M) outcomes (n = 17; mean age: 46 months) were compared to patients with bad outcomes (n = 10; mean age: 26 months). NA/Cr and NA/Ch were significantly lower in the bad outcome group (NA/Cr = 1.15 ± 0.38; NA/Ch = 1.18 ± 0.52) compared to the G/M group (NA/Cr = 1.41 ± 0.28, P < .05; NA/Ch = 1.98 ± 0.81, P < .01). Lactate was present in 80% of bad outcome patients and in none of the G/M group (P < .0001). Using a linear discriminant analysis and combining 4 clinical variables (Glasgow Coma Scale score, initial pH and glucose, number of days unconscious at time of ¹H-MRS) allows classification of 94% of patients into their correct outcome group. Use of spectroscopy variables (NA/Cr, NA/Ch, Ch/Cr, presence of lactate) alone correctly classified 81% of patients. The combination of clinical and ¹H-MRS variables correctly classified 100% of patients. Our findings suggest that ¹H-MRS adds information which, in combination with clinical examination, may be useful in outcome assessment in children with serious acute central nervous system injury.     

Myo-inositol in depressive and healthy subjects determined by frontal H-magnetic resonance spectroscopy at 1.5 tesla

Myo-inositol (mI) as a precursor in the phosphatidylinositol second messenger system has been reported to be reduced in depression. By means of proton-magnetic resonance spectroscopy (¹H-MRS) the mI levels in the frontal brain were investigated in vivo in the present study. Twenty-two patients (mean age: 42.8±10.7 years) with depressive episodes according to ICD 10 (HAMD score> 17) were compared to 22 healthy subjects (28.0±5.3 years). Two voxels (30×20×20 mm³) in the frontal lobes were examined in a Siemens Magnetom SP 4000 at 1.5 T (STEAM sequence: TR = 3500 ms, TE = 55 ms). With the total creatine (Cr) as an internal standard, mI\Cr ratios were calculated to follow the mI levels. In the left frontal lobe, mI\Cr was 0.43±0.06 in depressive patients and 0.46±0.07 in healthy subjects; concerning the right frontal lobe, mI\Cr was 0.46±0.08 and 0.48±0.06, respectively. There were neither significant differences between the two groups nor between the hemispheres. Since there was a significant positive correlation (R = 0.6) between the age and the mI\Cr in the right frontal lobe of depressed patients, age matched pairs analysis was performed (n = 2×10, in each group: nine females, one male, < 40 years). In the right frontal lobe, the patients mI\Cr of 0.40±0.05 was now significantly lower than the controls mI\Cr of 0.45±0.06. However, most of the patients were on antidepressive medication. Interestingly, it was exactly this group of patients which showed significantly lower mI levels.

We regard our investigation as a pilot study which suggests an influence of age and antidepressants on mI levels and should be taken into consideration in further investigations in depressive patients.     

Blunted dexamethasone-induced growth hormone responses in acute mania

Dynamic endocrine testing using a variety of probes has revealed abnormalities of the somatotropic axis in bipolar mania. In health, acute administration of dexamethasone (DEX) results in the secretion of growth hormone (GH) by possibly inhibiting somatostatin tone. We elected to determine DEX/GH responses in acute mania. Eight male bipolar manics were compared with eight age-matched healthy volunteers. Four milligrams of oral DEX was administered at 0900h (time 0 min) and plasma samples for GH were taken at +60, +180, +240 and +300 min. Baseline samples for GH and cortisol were taken at −15 min and 0 min. Patients had higher basal cortisol levels (391.6 ± 89.4 nmol/l) as opposed to controls (138.0 ± 13.2 nmol/l) (paired t-test, t=4.68, DF=6, p < .0004). The mean ( ± SD) ΔGH (calculated as the maximum GH level relative to baseline) in the manic patients was 0.7 ± 0.8 ng/ml and in the healthy controls was 9.2 ± 4.3 ng/ml (paired t-test, t=−0.589, DF=6, p < .0001). In conclusion, patients with bipolar mania had lower DEX-induced GH responses in comparison to controls.     

Relationships between fibrinogen, plasminogen activator inhibitor-1, and their gene polymorphisms in current smokers with essential hypertension

Background: To elucidate the role of some haemostatic gene polymorphisms and environmental factors, we studied fibrinogen (Fb), plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (t-PA) levels with respect to Fb G455A and PAI-1 4G/5G gene polymorphisms in smokers and nonsmokers with essential hypertension. Material and methods: The study was done in 90 patients (including 30 smokers) with essential hypertension (HT) and 40 controls (including 8 smokers). Fb and PAI-1 genotypes were PCR identified. The groups did not differ significantly as to genotype frequencies. Results: When allele A455 carriers were compared, HT patients had significantly higher Fb (p=0.015) and t-PA levels (p=0.013). Comparison of 4G allele carriers (4G/4G homozygotes) revealed significantly higher Fb (p=0.045), PAI-1 (p=0.009), and t-PA levels (p=0.007) in HT patients than controls. Interactions of Fb and PAI-1 gene polymorphisms with smoking were disclosed in HT patients only. Allele A455-carrying HT smokers compared with nonsmokers had significantly higher t-PA (12.1±5.8 vs. 7.4±3.1 ng/ml; p=0.002) and tendency to higher Fb (3.36±0.74 vs. 2.95±0.70 g/l; p=0.075) levels. Higher Fb levels were disclosed in 4G/4G smokers than nonsmokers (3.31±0.81 vs. 2.84±0.85 g/l; p=0.064). Finally, in smokers, significantly higher levels of PAI-1 were found in 4G/4G (42.1±29.4 ng/ml) as compared with 4G/5G (18.6±13.7 ng/ml; p=0.025) and 5G/5G (14.4±10.8 ng/ml; p=0.044) genotypes. Conclusions: Smoking potentiates the prothrombotic effect of allele A455 and PAI-1 4G/4G genotype in untreated essential hypertension, reflected by increased levels of haemostatic risk factors and accelerated progression of cardiovascular diseases.     

Daytime sleepiness after long-term continuous positive airway pressure (CPAP) treatment in obstructive sleep apnea syndrome

A modified maintenance of wakefulness test was performed in 58 patients with obstructive sleep apnea (OSA) syndrome before treatment and after long-term (554 ± 28 days) home therapy with nasal continuous positive airway pressure (CPAP). Before treatment the patients had a shorter mean sleep latency than controls (16 ± 1 vs. 27 ± 1 in, mean ± SEM, P < 0.001) After treatment, the mean sleep latency increased to 20 ± 1 min P < 0.002 as compared to baseline), but was still shorter than in controls (P < 0.001). The incomplete normalization of the mean latency contrasted with the patient's claim that they no longer felt sleepy. The improvement in daytime alertness was significantly correlated with the reduction in sleep fragmentation after CPAP treatment and with the baseline mean sleep latency. These results support the hypothesis that sleep disruption related to respiratory events plays a role in the pathogenesis of daytime sleepiness.     

Suboptimal anticoagulation with pre-hospital heparin in ST-elevation myocardial infarction

This is a prospective, observational study performed in all consecutive ST-elevation myocardial infarction (STEMI) patients who had activated clotting time (ACT) measurement on arrival in the cathlab before coronary angiography. We studied the therapeutic effects of a pre-hospital fixed heparin bolus dose in consecutive patients with STEMI. A total of 1,533 patients received pre-hospital administration of aspirin, high dose clopidogrel (600 mg) and a fixed bolus dose of 5,000 IU unfractionated heparin (UFH), according to the national ambulance protocols. Some patients were also treated with glycoprotein IIb/IIIa inhibitors (GPI) in the ambulance. A therapeutic ACT range was defined according to the ESC guidelines as 200-250 seconds when patients had GPI pre-treatment and 250-350 seconds when no GPI pre-treatment. Of the 1,533 patients, 216 patients (14.1%) had an ACT within the therapeutic range, 82.3% of the patients had a too low ACT, whereas 3.5% of the patients had a too high ACT. After multivariable analysis, the only independent predictor of a too low ACT was increasing weight (odds ratio 1.02/kg, 95% confidence interval 1.01-1.03, p=0.001). Patients with a too low ACT had less often an open infarct related vessel (initial TIMI flow 2,3) as compared to patients with an ACT in range (36.5% vs. 45.9%, p=0.013). In only a minority of patients with STEMI, pre-hospital treatment with a fixed bolus dose UFH is within the therapeutic ACT range. Increased weight is an independent determinant of a too low ACT. We strongly recommend weight adjusted administration of UFH in the ambulance.     

A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy

The pharmacokinetics of midazolam, a water soluble 1,4-benzodiazepine, has been studied in 12 patients (11 male, 1 female; age range 19–57 years) with epilepsy. All patients were taking hepatic enzyme inducing antiepileptic drugs (AEDs) on a regular basis. Midazolam (5 mg) was administered intravenously and 1 week later midazolam was administered intramuscularly, the dose used being dependent on the sedative response to the intravenous dose (10 mg, N = 2; 7 mg, N = 8; 5 mg, N = 2). Serial blood samples were collected at timed intervals for 5–7 h. After intravenous administration initial distribution was rapid with a mean half-life (t¹/2) of 0.06 ± 0.03 h followed by a terminal half-life (t¹/2β or γ) of 1.5 ± 0.3 h. Volume of distribution was 0.62 ± 0.27 1/kg. After intramuscular administration midazolam was rapidly absorbed with peak serum concentrations achieved at 25 ± 23 min. Two patients showed delayed absorption. Mean terminal half-life was 2.8 ± 1.7 h. The absolute bioavailability of intramuscular midazolam was calculated in 11 patients as 87 ± 18%. Sedation was rapid (< 1–2 min) but transient (7–75 min) after intravenous and slower (2–30 min) and for a longer period (20–120 min) after intramuscular administration. Since intravenous administration of AEDs including diazepam is not always feasible in status epilepticus there are obvious advantages in having an effective intramuscular formulation. Our data suggest that midazolam may be such a drug.     

Fluctuations in tremor at rest and saccadic eye movements in subjects with Parkinsons disease

This study investigates the possible relationships between fluctuations in finger tremor amplitude and the performance of visual saccades. Saccadic eye movements were analyzed in five subjects with Parkinson's disease (PD) and five age-matched controls. Tremor was recorded by using a position laser system, and eye movements were recorded with an infrared reflectometry technique (Ober2). Tremor amplitude (root mean square) was significantly larger in the group of subjects with PD (2.87 ± 4.37 mm) than in the control group (0.017 ± 0.005 mm, U = 0, p < 0.01). In addition, subjects with PD showed more fluctuations in their tremor at rest (0.52 ± 0.98 mm versus 0.003 ± 0.006 mm, U = 1, p < 0.05). Latency, saccade error and percentage of predictive saccades were not significantly different between subjects with PD and control subjects. Average saccade amplitude was smaller in the group of subjects with PD (16.1 ± 2.31°) than in the control group (18.49 ± 3.62°, U = 1, p < 0.05). Spearman's rank correlation coefficient showed no direct relationship between saccade amplitude and changes in tremor amplitude at the time of each saccade but, in general, subjects with PD who had more fluctuations in their tremor at rest had also more fluctuations in their saccade error (Rho = 0.9). These results suggest that the mechanisms causing short-term fluctuations in tremor at rest do not directly influence the visual saccadic system.     

Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration

INTRODUCTION: A thrombin inhibitor management (TIM) point-of-care test based upon the ecarin clotting time (ECT) has been developed. The ECT has been suggested to more accurately reflect the anti-coagulant effect of direct thrombin inhibitors compared with the activated clotting time (ACT). We sought to examine the correlation of the TIM-ECT test with bivalirudin concentration in patients undergoing percutaneous coronary intervention (PCI), and to compare the performance of this test with the current standard (i.e., ACT). MATERIALS AND METHODS: In a multicenter study, blood samples were obtained at six pre-defined time-points in 170 consecutive patients undergoing PCI using bivalirudin. For each sample, the TIM-ECT (citrated and non-citrated), ACT, and bivalirudin concentration was determined. RESULTS: Considering samples from all time-points (n=784), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were 0.96, 0.93, and 0.90, respectively. For samples collected at therapeutic levels of bivalirudin (n=353), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were lower, and showed a greater disparity between methods, with correlation coefficients of 0.75, 0.59, and 0.37, respectively. Prediction models based on the measured bivalirudin concentration were developed for TIM-ECT and ACT, and the coefficients of determination (r(2)) of actual versus predicted TIM-ECT and ACT were 0.91 and 0.81, respectively. CONCLUSIONS: In this PCI population, the TIM-ECT point-of-care test and ACT demonstrated a strong correlation with bivalirudin concentration. The TIM-ECT test had a higher correlation with bivalirudin concentration at therapeutic levels of the drug, and for individual samples appears to more consistently reflect the bivalirudin concentration compared with the ACT.     

Reduction of GH response to the GABA-B agonist baclofen in patients with major depression

In order to establish whether alterations in the GABAergic control of GH secretion occur in male patients with major depression, the GH response to the GABAergic-B agonist baclofen (10 mg at 0830h) or to placebo was tested in 9 depressed men and in 10 age- and weight-matched male normal controls.

The basal concentrations of GH were significantly lower in the depressed patients (0.87± 0.69 ng/ml) than in the normal controls (1.57±0.33 ng/ml) (p=0.011) and were not modified by the administration of placebo. The administration of baclofen induced a striking, significant increase in GH concentrations in the normal controls (mean peak at 90 MIN=6.4±1.5 ng/ml). In contrast, a slight, nonsignificant GH increase occurred in the depressed patients after baclofen (mean peak at 90 MIN=1.57±1.45 ng/ml). The GH response was significantly lower in the depressed than in the control subjects (p<0.001). These data indicate the presence of reduced GABAergic control of GH secretion in male depressed patients.     

Homocysteine and hemostatic disorder as a risk factor for myocardial infarction at a young age

Introduction: Hyperhomocysteinemia is a coronary risk factor, but its pathophysiologic mechanism remains unclear. Materials and methods: The importance of hyperhomocysteinemia in the pathogenesis of early myocardial infarction, was determined in case-control study of 127 men with a first early myocardial infarction ≤45 years and 150 age-matched male controls. We measured plasma concentrations of homocysteine, fibrinogen, antithrombin, tissue factor, tissue factor pathway inhibitor, tissue plasminogen activator, plasminogen activator inhibitor-I, plasminogen, ₂-antiplasmin, lipoprotein(a), protein C, protein S, factor VII, and activated factor VII. Results: Homocysteine concentrations were higher in patients with early myocardial infarction than in controls (11.2±5.3 and 8.3±5.0 μmol/l, respectively, P<0.001). Hyperhomocysteinemia was associated with early myocardial infarction (odds RATIO=2.22, P<0.001) by multivariate logistic regression analysis. Tissue factor, antithrombin, plasminogen, tissue plasminogen activator, plasminogen activator inhibitor-I, lipoprotein(a), diabetes, and smoking also had associations. In a stepwise logistic regression analysis, hyperhomocysteinemia was the strongest predictor of early myocardial infarction (R²=0.19, P<0.001). Hyperhomocysteinemia also had positive correlations with tissue factor (ρ=0.26, P=0.009), tissue factor pathway inhibitor (ρ=0.23, P=0.020), and tissue plasminogen activator (ρ=0.25, P=0.011) in patients with early myocardial infarction, but not in controls. Conclusions: Hyperhomocysteinemia is an independent risk factor for early myocardial infarction, and is associated with a hypercoagulable state mediated by the extrinsic coagulation cascade.     

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.     

A comparison of hypotensive and non-hypotensive hemorrhage on Fos expression in spinally projecting neurons of the paraventricular nucleus and rostral ventrolateral medulla

The protein, Fos, detected immunohistochemically, was used to identify neurons in the brain that were activated after hemorrhage in the conscious rat. Spinally projecting neurons in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) were identified by the presence of rhodamine-labeled latex beads which had been previously injected into the upper thoracic spinal cord. On the experimental day, conscious rats underwent either (1) withdrawal of 4 ml of blood from a carotid cannula (n = 8) which reduced mean arterial pressure from 96.6 ± 2.7 to 42.7 ± 7.1mmHg, (2) withdrayl of 2 ml of blood (n = 4) which did not affect mean arterial pressure. Animals that were not hemorrhaged were used as controls (n = 6). After the 4 ml hemorrhage, dense concentrations of Fos-positive cells nuclei were found in the lamina terminalis, supraoptic nuclei (SON), PVN and in the medulla. In contrast, the density of Fos-positive cells in 2 ml-hemorrhaged rats was not different from controls except in the SON and in the medial PVN in 2 of 4 rats. After the 4 ml hemorrhage 14.4 ± 1.2% of the spinally projecting neurons in the PVN and 22.7 ± 6.1% in the RVLM expressed Fos (P < 0.001 compared to control). After the 2 ml hemorrhage the proportion was 12.2 ± 3.1% in the PVN (P < 0.001 compared control) but only 5.4 ± 2.2% in the RVLM (P > 0.05 compared to control) . The results suggest that spinally projecting neurons in the PVN and RVLM participate in the reflex responses to hemorrhage. PVN-spinal neurons may respond to changes in blood volume even when arterial pressure does not alter.     

Microinjection of orexin into the rat nucleus tractus solitarius causes increases in blood pressure

Orexin A (OX-A) and orexin B (OX-B), also known as hypocretin-1 and hypocretin-2, have been suggested to play a role cardiovascular control. The nucleus tractus solitarius (NTS), located in the dorsal medulla plays an essential role in neural control of the cardiovascular system. Orexin-immunoreactive axons have been demonstrated within this nucleus suggesting that NTS may be a site through which OX acts to influence cardiovascular control. We report here that microinjection of OX-A into the NTS of urethane anesthetized rats causes increases in blood pressure (10⁻⁹ M, mean AUC=607.1±65.65 mmHg s, n=5) and heart rate (10⁻⁹ M, mean AUC=16.15±3.3 beats, n=5) which returns to baseline within 90 s. We show that these effects are dose related and site specific. Microinjection of OX-B into NTS elicited similar increases in BP (mean AUC=680.8±128.5 mmHg s, n=4) to that of OX-A suggesting specific actions at the OX₂R receptor. These observations support the conclusion that orexins act as chemical messengers in the NTS likely influencing the excitability of cardiovascular neurons in this region and thus regulating global cardiovascular function.     

Relationship Between Fibrinogen Protein and Fibrinogen Function in Postmyocardial Infarction Patients

The present study investigates the association between increases in the concentration and function of plasma fibrinogen in two groups of patients with chronic ischemic heart disease (11 with recurrent ischemic events and 19 free of these episodes) and in 34 healthy controls. The fibrinogen function index (fibrinogen function per unit of fibrinogen protein) (FgFI) was used as a measure of the fibrinogen clotting potential. The prothrombin fragment 1+2 (F1+2) and thrombin–antithrombin (TAT) were used as procoagulant markers. Plasma sialic acid (SA) was also evaluated as an inflammatory marker. No differences were found between FgFI (1.06±0.13 vs. 1.02±0.13), F1+2 (1.2±0.5 vs. 1.1±0.4 nmol/l) and TAT (2.5±1.3 vs. 2.5±0.7 μg/ml) in postinfarction patients without recurrent coronary ischemic events and the control group. However, postinfarction patients who suffered recurrent coronary ischemic events had significantly higher FgFI than patients without these symptoms (1.19±0.09 vs. 1.06±0.13), P<.01) and than the control group (1.19±0.09 vs. 1.02±0.13, P<.001). Moreover, the F1+2 (1.4±0.5 vs. 1.1±0.4 nmol/l, P<.05) and TAT (3.6±3.3 vs. 2.5±0.7 μg/ml, P<.05) were significantly higher in patients who suffered recurrent coronary ischemic events than in the control group. However, F1+2 and TAT were not different between patients with and without these symptoms. The fibrinogen protein (Fg-protein) concentration and high molecular weight fibrinogen (HMW-Fg) levels were significantly higher in both postinfarction patient groups than in the control group and in postinfarction patients with recurrent coronary ischemic events than in postinfarction patients without these symptoms. The plasma SA levels were significantly increased in postinfarction patients with and without recurrent coronary ischemia as compared with the control group. A positive correlation was found between fibrinogen and SA levels (r=.5, P<.01). In conclusion, our study indicates that the procoagulant factors, among which we include fibrinogen, F1+2 and TAT play a very active role in recurrent ischemic events in postmyocardial infarction patients. High plasma concentrations of both fibrinogen and SA suggests that fibrinogen becomes elevated as a consequence of inflammatory processes. The FgFI as an indicator of clotting potential of fibrinogen appears to be associated with ischemic events in chronic coronary artery disease.     

Response to cyanide of two types of glomoid cells in mature rat carotid body

Cells belonging to glomoids of mature rat carotid bodies were studied using the whole-cell patch clamp technique following acute dissociation. The recorded population encompassed two subtypes: one type (n=202), termed G(out), was characterized by a small voltage-dependent inward current (43±9pA, mean ±S.E.M.), large outward current (671±31 pA@⁺40 mV), high membrane resistance (1910 ± 110M Ω) and low capacitance (5.1 ± 0.1pF). A second subtype (n=56), termed G(in), had significantly lower membrane resistance (177 ± 35 MΩ), membrane capacitance (15.0 ± 1.0 pF) and little voltage-dependent current. Neither subtype supported generation of multiple action potentials during depolarization in the current clamp mode. Intracellular staining of the recorded cells by Lucifer yellow showed co-localization of both subtypes to clusters of cells which stained positively for catecholamines. Somal diameter was slightly, but significantly, larger for G(in) cells 8.7 ± 0.4 μM, n=7) compared to G(out) cells (7.8±0.2 μM, n=31) and all cells had fine cytoplasmic process s extending around neighboring cells. During recordings using the perforated patch technique, histotoxic hypoxia significantly decreased a voltage-dependent outward current in G(out) cells by 113±60pA (n=13), and decreased the holding current by 10±4pA (n=13) from a control value of −32±6pA. In G(in) cells, cyanide significant decreased membrane resistance and decreased holding current by 55±28pA from a control value of +120±42pA (n=7), but caused no significant change in outward current. These results show that glomoids of mature rat carotid bodies contain at least two types of cells which differ in their morphologic and electrophysiologic characteristics. The subtypes rapidly respond to histotoxic hypoxia and thus may mediate separate roles in the organ response to chemostimuli.     

A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83±10%, n=5, P<0.01, compared with controls of 160±11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63±1% at 100 ng/ml, n=5 and 66±1% at 200 ng/ml, n=4, compared to controls of 56±6%, n=6). Manumycin A (2μM) had no effect on LTP (162±2%, n=5, compared to controls of 167±13%, n=5), but significantly attenuated LTD (88±6%, n=5, P<0.01, compared to controls of 63±9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240±40%, n=5, P<0.01, compared with controls of 100±4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92±2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP.