Effect of nozzle selection on deposition of thiamethoxam in Actara® spray drift and implications for off-field risk assessment.

Off-target drift during pesticide spray applications represents a potential pathway for the introduction of active ingredient into field-adjacent water, soils, and/or vegetation. This study investigated the extent of downwind spray drift deposition of thiamethoxam (as a model insecticide) from an application of Actara® 25WG using standard nozzles (TeeJet XR11003, DG11004, and AIXR11002) onto a fallow field test site in the Midwestern USA. Single broadcast applications at a target rate of 96 g a.i./ha were made uniformly via tractor boom to a mowed stubble plot at a spray volume of 93.5 L/ha. Sampling devices (stainless steel disks, filter paper, and stainless steel rods) were located upwind of the spray swath (as negative control samples), within the spray swath (filter paper only), and downwind (all samplers), perpendicular to the spray swath from 12.5 to 400 ft. (3.8 to 122 m) from the edge of the treated field. Comparison of measured residues from the three types of samplers indicated that filter paper generally had greater variability in results than metal disks. When nozzles were compared, the AIXR11002 air induction nozzle produced less off-field deposition than other nozzles tested. Measured downwind concentrations of thiamethoxam from disk samplers were used to predict distances for mitigating potential effects to honey bees. Based on field-derived models, downwind distances from the spray swath required to reduce exposure levels below levels of concern for honey bees varied from <1 ft. to 148 ft. (0.3 to 45 m) depending on the hazard endpoint and nozzle used. These distances were considerably lower than those predicted using the AgDRIFT model, particularly for distances further downwind. At 400 ft. (122 m), AgDRIFT over-predicted the calculated concentrations by up to a factor of 4.8, 7.2, and 10 for DG11004, XR11003, and AIXR11002, respectively. These data suggest that the AgDRIFT model is less reliable for predicting spray deposition at further downwind distances, with implications for risk assessment.

Effects of rolipram and zaprinast on learning and memory in the Morris water maze and radial arm maze tests in naive mice.

Inhibition of phosphodiesterase 5 (PDE) improved recognition memory and counteracted spatial learning impairment induced by nitric oxide synthase (NOS) inhibition in recent studies. Aim of this study was to investigate effects of rolipram, a PDE4 inhibitor and zaprinast, a PDE5 inhibitor, on learning and memory in Morris water maze (MWM) and radial arm maze (RAM) tests in naive mice. Male Balb-c mice were treated subchronically with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) for 6 days in the MWM test and acutely before the retention trial of radial arm maze test. Rolipram (0.05 and 0.1 mg/kg) significantly decreased escape latency between 2(nd) and 5(th) sessions, while zaprinast (10 mg/kg) significantly decreased escape latency only in 2(nd) session. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly increased time spent in escape platform's quadrant in probe trial of MWM test; only rolipram decreased mean distance to platform, while zaprinast had no effect on mean distance to platform. Zaprinast (3 and 10 mg/kg) significantly decreased number of errors compared to control group, while rolipram (0.05 and 0.1mg/kg) had no effect on number of errors in retention trial of RAM test. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly decreased time spent to complete retention trial (latency) compared to control group. Our study revealed that both zaprinast and rolipram enhanced spatial memory in MWM, while zaprinast seems to have more memory enhancing effects compared to rolipram in radial arm maze test.

Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats.

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examined. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 weeks) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body weight/day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body weights of rats. Impaired nitric oxide-mediated relaxation to insulin (10⁻9 to 3×10⁻6 M), and enhanced contraction to endothelin-1 (10⁻¹¹ to 10⁻8 M) were associated with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS production. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviors of unpredictable chronic mild stress-exposed mice.

BACKGROUND: Strong evidence indicates that impaired cognition is a core element of depression, and antidepressant treatment may ameliorate cognitive impairments experienced by depressive patients. Present study was performed to investigate effects of chronic tianeptine (5 mg/kg) or olanzapine (2.5 mg/kg) administration on cognitive behaviors of unpredictable chronic mild stress (UCMS)-exposed mice and to compare these effects to those induced by widely used SSRI antidepressant fluoxetine (15 mg/kg) in mice. METHODS: To investigate effects of these drugs, the Morris water maze test (MWM), elevated plus maze test (EPM) and radial arm maze test (RAM) were used. The effects of stress and drugs on gene expression in the hippocampus was determined by quantitative Real Time-PCR. RESULTS: In MWM test, fluoxetine significantly increased escape latency of non-stressed mice in acquisition sessions and decreased time spent in escape platform quadrant in probe trial; tianeptine and olanzapine decreased enhancement in escape latency, and only olanzapine significantly enhanced attenuation in time spent in the escape platform quadrant in UCMS-exposed mice. In EPM test, all drugs significantly decreased enhancement in transfer latency in UCMS-exposed mice. In RAM test, fluoxetine significantly increased number of errors made by both non-stressed and UCMS-exposed mice. CONCLUSION: Quantitative real-time PCR revealed that CREB and BDNF gene expression levels were significantly decreased in UCMS-exposed group, and this effect was significantly reversed by each of drugs tested. Our results seem to be test dependent and should be further investigated using different learning and memory tasks.

Effects of olanzapine and clozapine on radial maze performance in naive and MK-801-treated mice.

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25 mg/kg, i.p.) and clozapine (0.5 and 1 mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2 mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.

Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure.

Pathophysiological remodeling of cardiac function occurs at multiple levels, spanning the spectrum from molecular and sub-cellular changes to those occurring at the organ-system levels. Of key importance to arrhythmias are changes in the electrophysiological substrate at the tissue level. In this manuscript, we provide an overview of mechanisms by which heterogeneous remodeling of ion channels, calcium handling proteins, gap junctions, and stretch-activated pathways produce functionally significant repolarization gradients across regions (anterior vs lateral) and muscle layers (epicardial vs midmyocardial vs endocardial) of the left ventricule. These repolarization gradients form an electrophysiological substrate that predisposes to arrhythmias and sudden cardiac death in heart failure.

From mitochondrial dynamics to arrhythmias.

The reactive oxygen species (ROS)-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell-wide collapse of the mitochondrial membrane potential, Delta psi(m), visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in Delta psi(m), NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of Delta psi(m) under criticality leads to: (i) energetic failure, (ii) temporal and regional alterations in action potential (AP), (iii) development of zones of impaired conduction in the myocardium, and, ultimately, (iv) a fatal ventricular arrhythmia.

The effect of long-term resveratrol treatment on relaxation to estrogen in aortae from male and female rats: role of nitric oxide and superoxide.

Resveratrol, which is found in several foods, has vasorelaxing and estrogen-like activities. The aim of the present study was to determine whether the relaxation to estrogen is differently modified between male and female genders after long-term resveratrol treatment. To test this, we compared endothelium-dependent and -independent relaxations to estrogen in the aortae of control and resveratrol-treated male and female rats. Nitric oxide and superoxide levels were also evaluated to explain the mechanism of action of resveratrol. Concentration-response curves to estrogen (10(-10)-10(-4) M) were obtained in aortic rings with and without endothelium from control or long-term resveratrol-treated (50 mg/l in drinking water for 21 days) male and female rats. Estrogen produced mainly endothelium-dependent relaxation in aortic rings of rats, with a higher potency in females than males. Resveratrol treatment increased both endothelium-dependent and -independent relaxations to estrogen especially in aortae from males. The relaxations to estrogen in the aortae of resveratrol-treated rats were inhibited, almost to the same extent as those of control, by pretreatment with ICI 182,780 (10(-6) M), an estrogen receptor antagonist. In both genders, resveratrol treatment increased basal nitric oxide and nitrite/nitrate productions and decreased both basal and NAD(P)H-induced superoxide productions in the aortae. In addition, plasma estrogen levels were found decreased in long-term resveratrol-treated animals of both genders. The improvement in the relaxations to estrogen observed in resveratrol-treated animals could be related to elevated nitric oxide and/or decreased superoxide productions and possibly mediated by classical estrogen receptors. The modulating effect of resveratrol on estrogen responsiveness may differ between male and female.

Collaborative therapy with nebivalol and L-NAME for spinal cord ischemia/reperfusion injury.

Postoperative neurologic deficit is the most devastating complication after thoracoabdominal aortic aneurysm repair. Our aim was to investigate whether nebivolol has protective effects during ischemia or reperfusion and the most effective mechanism of protection via inhibiting nitric oxide (NO) release with an NO synthase inhibitor in an experimental model of spinal cord ischemia/reperfusion injury. Spinal cord ischemia was induced by occlusion of the infrarenal aorta for 30 min. Thirty-one rabbits were divided into five groups according to the administration period of nebivolol and/or N(G)-nitro-L-arginine methyl ester (L-NAME): control group; group NI, nebivolol during ischemic period; group NR, nebivolol during reperfusion period; group NILR, nebivolol during ischemic period and L-NAME during reperfusion period; and group LINR, L-NAME during ischemic period and nebivolol during reperfusion period. Blood samples were taken at both ischemia and reperfusion periods to obtain nitrite/nitrate levels. After neurologic evaluation at 24 hr of reperfusion, malondialdehyde (MDA) levels were measured. Neurologic impairment was significantly lower in group LINR (Tarlov score 3.4 +/- 0.6, p < 0.05). MDA levels were lower in nebivolol-treated animals, but the lowest value was achieved in the NR group, 35.6 +/- 2.7 nmol/g (p < 0.001). Nitrite levels were decreased significantly in all nebivolol-treated animals in the reperfusion period, but the lowest value was measured in the LINR group (455 +/- 137 vs. 1,760 +/- 522 nmol/mL, p < 0.001). Prophylactic use of nebivolol reduced neurologic injury, and combining with L-NAME provided the best clinical improvement by attenuating the inflammatory mileu in this experimental model. Combination of nebivolol and L-NAME appears to be an effective option for spinal cord protection against ischemia/reperfusion injury.

Circulatory arrest to protect transplant kidney in a patient with chronic type III dissection.

With broader indications for renal transplantation and improved allograft survival, it is anticipated that the problem of aortic disease in the post-transplant patient will be encountered with increasing frequency. We report a technique of protecting the transplant kidney from ischemic damage during distal aortic surgery. A 30-year-old renal transplant patient who had undergone an operation for ruptured chronic type III dissection 3 years previously underwent abdominal aortic aneurysm repair under hypothermic circulatory arrest. The patient recovered uneventfully and is presently doing well 1 year after the operation. Hypothermic circulatory arrest could be used in selected cases as a useful alternative for transplant kidney protection.

Contractile regulation of the Na(+)-K(+)-2Cl(-) cotransporter in vascular smooth muscle.

Vasoconstrictors activate the Na(+)-K(+)-2Cl(-) cotransporter NKCC1 in rat aortic smooth muscle, but the mechanism is unknown. Efflux of (86)Rb(+) from rat aorta in response to phenylephrine (PE) was measured in the absence and presence of bumetanide, a specific inhibitor of NKCC1. Removal of extracellular Ca(2+) completely abolished the activation of NKCC1 by PE. This was not due to inhibition of Ca(2+)-dependent K(+) channels since blocking these channels with Ba(2+) in Ca(2+)-replete solution did not prevent activation of NKCC1 by PE. Stimulation of NKCC1 by PE was inhibited 70% by 75 microM ML-9, 97% by 2 microM wortmannin, and 70% by 2 mM 2,3-butanedione monoxime, each of which inhibited isometric force generation in aortic rings. Bumetanide-insensitive Rb(+) efflux, an indication of Ca(2+)-dependent K(+) channel activity, was reduced by ML-9 but not by the other inhibitors. Stretching of aortic rings on tubing to increase lumen diameter to 120% of normal almost completely blocked the stimulation of NKCC1 by PE without inhibiting the stimulation by hypertonic shrinkage. We conclude that activation of the Na(+)-K(+)-2Cl(-) cotransporter by PE is the direct result of smooth muscle contraction through Ca(2+)-dependent activation of myosin light chain kinase. This indicates that the Na(+)-K(+)-2Cl(-) cotransporter is regulated by the contractile state of vascular smooth muscle.

Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation.

Electrical coupling between myocytes plays a critical role in propagation, repolarization, and arrhythmias. On the basis of predictions from cable theory, we hypothesized that the cardiac space constant (lambda) measured from the decay of subthreshold transmembrane potential (ST-Vm) in space would provide an index of regional cell-to-cell coupling in the intact heart. With the use of voltage-sensitive dyes, the distribution of ST-Vm was measured from hundreds of sites in close proximity to the site of subthreshold stimulation. lambda was calculated from the exponential decay of ST-Vm in space. Consistent with known directional differences in axial resistance, the spatial distribution of ST-Vm was strongly dependent on fiber orientation, because lambda was significantly (P < 0.001) longer along (1.5 +/- 0.1 mm) compared with across (0.8 +/- 0.1 mm) fibers. There was a close linear relationship (P < 0.001) between conduction velocity (CV) and lambda along all fiber angles tested. Reducing gap junctional conductance by heptanol reversibly decreased CV and lambda in parallel by approximately 50%. In contrast, sodium channel blockade by flecainide slowed CV by 40% but had no effect on lambda, reaffirming that lambda was an index of passive but not active membrane properties. These data establish the feasibility of measuring lambda as an index of cell-to-cell coupling in the intact heart, and indicate strong dependency of lambda on fiber orientation and pharmacological alterations of gap junction conductance.

Endothelial reactivity to the immediate hypersensitivity reaction of guinea pig pulmonary artery.

Ovalbumin at low doses (0.1 microg/ml) caused pronounced relaxations in the precontracted pulmonary arteries of sensitized guinea pigs but, at high doses, (1-100 microg/ml) the relaxations were blunted by the contractions. The relaxations in response to ovalbumin challenge were related to histamine, which is released during the immediate hypersensitivity reaction, because they were almost blocked by mepyramine (10(-5) M) plus cimetidine (10(-4) M) pretreatment and never observed in unsensitized animal arteries. Additionally, the inhibition of relaxations by endothelium removal or N(G)-nitro-L-arginine (L-NOARG, 10(-4) M) treatment implies that the phenomenon requires endothelial nitric oxide synthesis. However, the contractions appear to depend on leukotriene production since they were markedly blocked in the presence of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SKF 104353, 10(-5) M), a leukotriene receptor antagonist. These results indicate that ovalbumin-induced nitric oxide and histamine H(2) receptor dependent relaxations in pulmonary artery may have an important role in the recovery of the increased pulmonary vascular resistance during the hypersensitivity reaction.

Cellular basis for dispersion of repolarization underlying reentrant arrhythmias.

Substantial heterogeneity in ion channel density and expression exists in cells isolated from various regions of the heart. Cell-to-cell coupling in the intact heart, however, is expected to attenuate the functional expression of the ion channel heterogeneities. Due to limitations of conventional electrophysiological recording techniques, the extent to which cellular electrical heterogeneities are functionally present in intact myocardium remains unknown. High-resolution optical mapping with voltage-sensitive dyes was used to measure transepicardial and transmural repolarization gradients in the Langendorff perfused guinea pig ventricle and the canine wedge preperation, respectively. Diversity of repolarization kinetics in the transepicardial direction modulated dispersion of repolarization in a biphasic fashion as premature coupling interval was shortened. Moreover, modulation of repolarization paralleled arrhythmia vulnerability in a predictable fashion. Transmural optical mapping revealed significant gradients of repolarization across the ventricular wall that were markedly increased in a surrogate model of LQTS. Transmural gradients of repolarization in LQTS were associated with an enhanced susceptibility to TdP. Therefore, despite strong cell-to-cell coupling in the normal heart, heterogeneities in the ionic make-up of cells across the epicardial and transmural surfaces result in functional heterogeneities of repolarization leading to arrhythmias.

Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury.

We investigated the influences of the K+ channel opening drugs cromakalim and diazoxide and their blocker, glibenclamide, in indomethacin-induced gastric injury in rats. Cromakalim (0.1 and 0.3 mg/kg) and diazoxide (10 and 30 mg/kg) produced dose-dependent gastroprotection at doses that were also effective on the cardiovascular system. Glibenclamide reversed their gastroprotective effects and aggravated indomethacin-induced gastric damage by its own. Cromakalim (10(-9)-10(-5) M) and diazoxide (10(-9)-10(-4) M) relaxed noradrenaline pre-contracted gastric arteries (94.59+/-1.58% and 93.86+/-2.99%, respectively). Their relaxant effects were inhibited by glibenclamide (10(-5) M) but not by indomethacin (10(-5) M) and LG-nitro-L-arginine (10(-4) M). Cromakalim (0.1 and 0.3 mg/kg) did not change gastric mucosal blood flow but increased the gastric mucosal vascular conductance in anaesthetized rats as measured by the hydrogen gas clearance technique. Indomethacin increased myeloperoxidase activity in the gastric mucosa, an effect which was reversed by cromakalim and diazoxide. Glibenclamide abolished their effects on myeloperoxidase activity and, alone, increased this parameter. Additionally, indomethacin caused infiltration of neutrophils which was reduced by cromakalim and diazoxide in a glibenclamide sensitive manner. The effects of cromakalim and diazoxide on mucosal myeloperoxidase activity, neutrophil infiltration and gastric injury correlated with each other. The effects of diazoxide (30 mg/kg) and glibenclamide (10 mg/kg) on blood glucose level were not correlated with their effects on gastric injury. Taken together, K+ channel opening drugs show misoprostol-like protective effects in indomethacin-induced gastric injury which seems to be related to modulation of neutrophil function.

Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl- cotransporter in rat aorta.

Little is known about the function and regulation of the Na+-K+-2Cl- cotransporter NKCC1 in vascular smooth muscle. The activity of NKCC1 was measured as the bumetanide-sensitive efflux of 86Rb+ from intact smooth muscle of the rat aorta. Hypertonic shrinkage (440 mosmol/kgH2O) rapidly doubled cotransporter activity, consistent with its volume-regulatory function. NKCC1 was also acutely activated by the vasoconstrictors ANG II (52%), phenylephrine (50%), endothelin (53%), and 30 mM KCl (54%). Both nitric oxide and nitroprusside inhibited basal NKCC1 activity (39 and 34%, respectively), and nitroprusside completely reversed the stimulation by phenylephrine. The phosphorylation of NKCC1 was increased by hypertonic shrinkage, phenylephrine, and KCl and was reduced by nitroprusside. The inhibition of NKCC1 significantly reduced the contraction of rat aorta induced by phenylephrine (63% at 10 nM, 26% at 30 nM) but not by KCl. We conclude that the Na+-K+-2Cl- cotransporter in vascular smooth muscle is reciprocally regulated by vasoconstrictors and nitrovasodilators and contributes to smooth muscle contraction, indicating that alterations in NKCC1 could influence vascular smooth muscle tone in vivo.

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation.

BACKGROUND: Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. METHODS AND RESULTS: -T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209+/-46 bpm) that was significantly lower (by 57+/-36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. CONCLUSIONS: Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.

Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart.

BACKGROUND: Previously, we have shown that a premature stimulus can significantly modulate spatial gradients of ventricular repolarization (ie, modulated dispersion), which result from heterogeneous electrophysiological properties between cells. The role modulated dispersion may play in determining electrical instability in the heart is unknown. METHODS AND RESULTS: To determine if premature stimulus-induced changes in repolarization are a mechanism that governs susceptibility to cardiac arrhythmias, optical action potentials were recorded simultaneously from 128 ventricular sites (1 cm2) in 8 Langendorff-perfused guinea pig hearts. After baseline pacing (S1), a single premature stimulus (S2) was introduced over a range of S1S2 coupling intervals. Arrhythmia vulnerability after each premature stimulus was determined by measurement of a modified ventricular fibrillation threshold (VFT) during the T wave of each S2 beat (ie, S2-VFT). As the S1S2 interval was shortened to an intermediate value, spatial gradients of repolarization and vulnerability to fibrillation decreased by 51+/-9% (mean+/-SEM) and 73+/-45%, respectively, compared with baseline levels. As the S1S2 interval was further shortened, repolarization gradients increased above baseline levels by 54+/-30%, which was paralleled by a corresponding increase (37+/-8%) in vulnerability. CONCLUSIONS: These data demonstrate that modulation of repolarization gradients by a single premature stimulus significantly influences vulnerability to ventricular fibrillation. This may represent a novel mechanism for the formation of arrhythmogenic substrates during premature stimulation of the heart.

The comparison of the responsiveness of human isolated internal mammary and gastroepiploic arteries to levcromakalim: an alternative approach to the management of graft spasm.

AIMS: We studied the effectiveness of levcromakalim, a potassium channel opener (KCO), in the prevention and reversal of spasm in arterial grafts used in coronary artery bypass operations, namely, internal mammary artery (IMA) and gastroepiploic artery (GEA). METHODS: Spasm was mimicked in vitro in arterial rings from 109 patients by increasing the vascular tension with noradrenaline, the thromboxane analogue U46619, endothelin-1 and K+. RESULTS: GEA displayed considerably higher contractile force to these agents than IMA. Pretreatment with levcromakalim depressed significantly the maximal contractile responses (either absolute or relative) to noradrenaline and U46619 but did not affect those of endothelin-1 and K+ in both of the arteries. Sensitivities (to all agents, except to endothelin-1) decreased significantly after levcromakalim. In experiments evaluating the antispasmodic activity of levcromakalim, a higher relaxant capacity was observed in GEA than IMA (for K+ contraction; IMA: 31.32 +/- 3.83%, n= 13 vs GEA: 98.01 +/- 0.71%, n=7, P<0.05). This different activity of levcromakalim between two arterial grafts was apparent even when GEA rings were contracted to higher force (g) than that of IMA (for K+ contraction; GEA: 72.56 +/- 4.96%, n = 7). Responses to levcromakalim were similar in IMA and GEA when endothelin-1 was used as the spasmogenic agent (IMA: 80.98 +/- 4.85%, n=10 vs GEA: 91.93 +/- 3.17%, n=7, P>0.05). CONCLUSIONS: Our results provide evidence that levcromakalim may have a therapeutic value in the treatment of spasm of coronary artery bypass grafts, especially GEA.

The comparison of vascular reactivities of arterial and venous grafts to vasodilators: management of graft spasm.

Graft spasm in the perioperative or postoperative period increases the risk of morbidity and mortality after coronary revascularization and hence necessitates urgent treatment. We have studied the effects of various vasodilators against noradrenaline- and endothelin-1-induced spasms in saphenous vein, internal mammary artery and gastroepiploic artery. In internal mammary and gastroepiploic arteries, the nitrovasodilators, sodium nitroprusside and glyceryl trinitrate, effectively reversed the spasms induced either with noradrenaline (for sodium nitroprusside; internal mammary artery: 101.07% +/- 1.63%; gastroepiploic artery: 94.10% +/- 2.07%) or endothelin-1 (for sodium nitroprusside; internal mammary artery: 97.67% +/- 4.94%; gastroepiploic artery: 90.69% +/- 2.61%). However, in saphenous vein contracted with endothelin-1, the responsiveness to nitrovasodilators was significantly blunted (for sodium nitroprusside: 52.33% +/- 5.19%) than that of rings contracted with noradrenaline (for sodium nitroprusside: 95.04% +/- 1.94%). Both arterial and venous grafts exhibited moderate beta-receptor function in response to isoproterenol. Isoproterenol was less effective in inhibiting the contractions of endothelin-1 in saphenous vein and gastroepiploic artery but not in internal mammary artery. On the other hand, nifedipine and papaverine were fully effective in reversing all the spasms in three of the graft materials. From these results, it can be deduced that saphenous vein is refractory against cyclic guanidine monophosphate (cGMP)-dependent and beta-receptor mediated relaxations when endothelin-1 was used as the spasmogenic agent. Internal mammary artery is the most responsive graft material to the vasodilators regardless of the nature of spasmogenic stimulus. Gastroepiploic artery exhibits functional similarity with internal mammary artery, with the exception of beta-receptor responsiveness.