Conformational State-dependent Effects of Halothane on Cardiac Na sup + Current

Background: The Na sup + channel is voltage gated and characterized by three distinct states: closed, open, and inactivated. To identify the effects of halothane on the cardiac Na sup + current (INa) at various membrane potentials, the effects of 1.2 mm halothane at different holding potentials (VH) on INa were examined in single, enzymatically isolated guinea pig ventricular myocytes.

Methods: The INa was recorded using the whole-cell configuration of the patch-clamp technique. Currents were generated from resting VH s of -110, -80, or -65 mV. State-dependent block was characterized by monitoring frequency dependence, tonic block, and removal of inactivation by veratridine.

Results: Halothane produced significant (P < 0.05) VH -dependent depressions of peak INa (mean +/- SEM): 24.4 +/- 4.1% (VH = -110 mV), 42.1 +/- 3.4% (VH = -80 mV), and 75.2 +/- 1.5% (VH = -65 mV). Recovery from inactivation was significantly increased when cells were held at -80 mV (control, tau = 6.0 +/- 0.3 ms; halothane, tau = 7.1 +/- 0.4 ms), but not at -110 mV. When using a VH of -80 mV, halothane exhibited a use-dependent block, with block of INa increasing from 8.6 +/- 1.4% to 30.7 +/- 3.5% at test pulse rates of 2 and 11 Hz, respectively. Use-dependent inhibition was not apparent at VH of -110 mV. When inactivation of INa was removed by exposure to 100 micro Meter veratridine, no significant difference was observed in the depressant effect of halothane at both VH s: 26.6 +/- 4.5% (VH = -80 mV) and 26.4 +/- 5.6% (VH = -110 mV).     

Loss of T-type Calcium Current in Sensory Neurons of Rats with Neuropathic Pain

Background: Pathophysiology in the primary sensory neuron may contribute to chronic neuropathic pain. Ca channels play a central role in neuronal processes, and sensory neurons are rich in low-voltage-activated calcium channels (LVACCs). However, the physiologic function of these channels is unknown. Their possible role in rebound burst firing makes them a candidate for increased excitability after neuropathic injury.

Methods: This study uses pharmacological methods to isolate LVACC in cells from the dorsal root ganglia of neuropathic and sham-operated rats, including the blockade of high-voltage-activated Ca channels with fluoride and selective toxins. LVACCs were examined with conventional whole cell patch clamp electrophysiology techniques.

Results: After chronic constriction injury of the peripheral axon, LVACC was significantly reduced compared to sham rats as shown by a 60% reduction in peak current density and an 80% reduction in total calcium influx. A depolarizing shift in the voltage dependence of activation and an increase in the rate of deactivation and inactivation appear to cause this reduction of LVACC. Either Ni2+ or mibefradil, blockers of LVACC, applied in the bath to normal dorsal root ganglion cells during current clamp significantly and reversibly increased excitability.     

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay

The antibiotic 5-nitrofurantoin (5-NF) has been used widely for the treatment of urosepsis in children during the last 20 years. Recent experimentation suggests the need for reevaluating its genotoxic potential. Because of possible differences in the metabolism and clearance of 5-NF in young and adult animals, we conducted a study to determine whether micronuclei caused by 5-NF were age-related. The in vivo micronucleus (MN) assay was performed on 3- and 8-week-old mice given single intraperitoneal injections of 5, 10, and 50 mg/kg 5-NF. Blood samples from the tail vein were taken before injection (baseline) and at 48, 96, 168, and 336 hr (2 weeks) after the treatment. One thousand reticulocytes were analyzed for micronuclei from each animal. Compared to similar baseline values for young and adult mice, 5-NF caused a significant increase in MN frequency in both age groups. The mean MN frequency in the young animals was higher than in the adult animals for each dose and sampling time. MN frequencies remained significantly elevated in young animals even 2 weeks after exposure to 5-NF. The results of the study confirm the genotoxic potential of 5-NF in young and adult animals, and indicate that young animals are more sensitive to the genotoxic effects of 5-NF than adult mice and that the response in young mice persists for a significantly longer time. These findings may be related to poorly developed mechanisms of xenobiotic detoxification and renal elimination in young animals.     

Cerebrovascular reactivity to hypercapnia is unimpaired in breath-hold divers

Hypercapnic cerebrovascular reactivity is decreased in obstructive sleep apnoea and congestive heart disease perhaps as a result of repeated apnoeas. To test the hypothesis that repeated apnoeas blunt cerebrovascular reactivity to hypercapnia, we studied breath hold divers and determined cerebrovascular reactivity by measuring changes in middle cerebral artery velocity (MCAV, cm s⁻¹) per mmHg change in end-tidal partial pressure of CO₂ (     ) in response to two hyperoxic hypercapnia rebreathing manoeuvres (modified Read protocol) in elite breath-hold divers (BHD, n = 7) and non-divers (ND, n = 7). In addition, ventilation and central (beat-to-beat stroke volume measurement with Modelflow technique) haemodynamics were determined. Ventilatory responses to hypercapnia were blunted in BHD versus ND largely due to lower breathing frequency. Cerebrovascular reactivity did not differ between groups (3.7 ± 1.4 versus 3.4 ± 1.3% mmHg⁻¹     in BHD and ND, respectively; P = 0.90) and the same was found for cerebral vascular resistance and MCAV recovery to baseline after termination of the CO₂ challenge. Cardiovascular parameters were not changed significantly during rebreathing in either group, except for a small increase in mean arterial pressure for both groups. Our findings indicate that the regulation of the cerebral circulation in response to hypercapnia is intact in elite breath-hold divers, potentially as a protective mechanism against the chronic intermittent cerebral hypoxia and/or hypercapnia that occurs during breath-hold diving. These data also suggest that factors other than repeated apnoeas contribute to the blunting of cerebrovascular reactivity in conditions like sleep apnoea.     

Should we begin with statin therapy in acute coronary syndrome?

Acute coronary syndrome (ACS) constitutes a unique syndrome with a distinct pathophysiology: rupture of the fibrous cap of unstable atherosclerotic plaques in coronary arteries resulting in subsequent platelet deposition and a thrombus formation that completely or partially occludes the artery. Remarkable therapeutic advances in the treatment of ACS have been made during the past decade with antiplatelet and antithrombotic therapy. However, these therapies alone do not appear to completely stabilize the unstable plaque. Results from several clinical trials suggest that early administration of a statin following an ACS may reduce both short-term and longterm adverse outcomes such as subsequent cardiovascular mortality, myocardial infarction and revascularization. The potential mechanisms of benefit include improvements in endothelial function and vasomotion, reduction of platelet aggregability and thrombus formation, fibrinolytic and antioxidant activity as well as reduction of inflammation within plaques, reducing matrix degradation due to reduction of macrophage metalloproteinase production and increasing collagen content. Based upon the current knowledge, it might be concluded that patients hospitalized for ACS should be given a statin and the treatment should be initiated as soon as possible.     

Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer.

PURPOSE: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO(2)) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy. EXPERIMENTAL DESIGN: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m(2)) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60-65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment. RESULTS: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO(2) = 4.7 +/- 1.2 mmHg). Five patients had well-oxygenated tumors (pO(2) = 27.6 +/- 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses. CONCLUSIONS: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.     

Free wall rupture (FWR) in patients with acute ST-elevation myocardial infarction (STEMI) receiving fibrinolytic therapy (FT): a 7-year prospective study

Previous studies have shown a paradoxical increase in early mortality in older patients (>70 years) with acute STEMI treated with fibrinolytic therapy (FT), which has been attributed to the development of free wall rupture (FWR). Our aim was to assess occurrence of FWR in STEMI patients receiving FT. In this 7-year prospective study, data from 1701 consecutive patients were obtained. We analyzed predictors of the in-hospital mortality in patients > 70 years old. The independent contribution of several variables to overall mortality and FWR development was assessed using multiple logistic regression analyses. The mortality of entire cohort was 18% (306/1701). Diabetes mellitus, anterior infarction, smoking, female gender and hypercholesterolemia were independent predictors of in-hospital mortality. FT was given to 18% of all patients (304/1701) of which 13% died (39/304). FWR was 18.4-times more often in patients who received FT. Among patients younger than 70 years who received FT there was no FWR, while in patients ≥70 years of age FWR was found in almost half of the deceased (30/68; 44%). Application of FT in STEMI patients is not associated with higher mortality, but significantly increases number of FWR, especially in patients over 70 years of age.