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Biomedical subjects

William Williams

Publications and source records attributed to William Williams.

13 recordsLinked to original sources
PubMed2006

Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis.

BACKGROUND: Intracellular proteins involved in oxidative stress and apoptosis are nitrated in diseased tissues but not in normal tissues; definitive evidence to support a causative link between a specific protein that is nitratively modified with tissue injury in a specific disease is limited, however. The aims of the present study were to determine whether thioredoxin (Trx), a novel antioxidant and antiapoptotic molecule, is susceptible to nitrative inactivation and to establish a causative link between Trx nitration and postischemic myocardial apoptosis. METHODS AND RESULTS: In vitro exposure of human Trx-1 to 3-morpholinosydnonimine resulted in significant Trx-1 nitration and almost abolished Trx-1 activity. 3-morpholinosydnonimine-induced nitrative Trx-1 inactivation was completely blocked by MnTE-2-PyP(5+) (a superoxide dismutase mimetic) and markedly attenuated by PTIO (a nitric oxide scavenger). Administration of either reduced or oxidized Trx-1 in vivo attenuated myocardial ischemia/reperfusion injury (>50% reduction in apoptosis and infarct size, P<0.01). However, administration of nitrated Trx-1 failed to exert a cardioprotective effect. In cardiac tissues obtained from ischemic/reperfused heart, significant Trx-1 nitration was detected, Trx activity was markedly inhibited, Trx-1/ASK1 (apoptosis signal-regulating kinase-1) complex formation was abolished, and apoptosis signal-regulating kinase-1 activity was increased. Treatment with either FP15 (a peroxynitrite decomposition catalyst) or MnTE-2-PyP(5+) 10 minutes before reperfusion blocked nitrative Trx inactivation, attenuated apoptosis signal-regulating kinase-1 activation, and reduced postischemic myocardial apoptosis. CONCLUSIONS: These results strongly suggest that nitrative inactivation of Trx plays a proapoptotic role under those pathological conditions in which production of reactive nitrogen species is increased and that antinitrating treatment may have therapeutic value in those diseases, such as myocardial ischemia/reperfusion, in which pathological apoptosis is increased.

Amino Acid Substitution↗
PubMed2006

Short-term effects of glipizide (an adenosine triphosphate-sensitive potassium channel inhibitor) on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep.

In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific K(ATP) channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific K(ATP) channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng.kg.(-1)min) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 +/- 3 mmHg vs. 101 +/- 2 mmHg, P < 0.05) and sheep with endotoxemia (86 +/- 3 mmHg vs. 93 +/- 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.

Adenosine Triphosphate↗
PubMed2005

Optimal timing for pulmonary valve replacement in adults after tetralogy of Fallot repair.

The timing of pulmonary valve replacement in adult patients with repaired tetralogy of Fallot remains controversial. A magnetic resonance imaging study in 17 adult patients with repaired tetralogy of Fallot reveals a statistically significant decrease in right ventricular (RV) volume (RV end-diastolic volume 163 +/- 34 to 107 +/- 26 ml/m2, p <0.001; RV end-systolic volume 109 +/- 27 to 69 +/- 22 ml/m2, p <0.001) at a mean follow-up of 21 months after pulmonary valve replacement; whereas RV systolic function remained unchanged (mean RV ejection fraction 32 +/- 7% to 34 +/- 10%, p = 0.12). In no patients with a RV end-diastolic volume >170 ml/m2 or a RV end-systolic volume >85 ml/m2 before pulmonary valve replacement were RV volumes "normalized" after surgery.

Adult↗
PubMed2003

Parenteral administration of glipizide sodium salt, an inhibitor of adenosine triphosphate-sensitive potassium channels, prolongs short-term survival after severe controlled hemorrhage in rats.

OBJECTIVE: Recent experimental evidence suggests that activation of adenosine triphosphate (ATP)-sensitive potassium channels contributes to vascular failure and early mortality after hemorrhagic shock. The present investigation evaluated the effects of the water-soluble sodium salt of glipizide, an inhibitor of ATP-sensitive potassium channels, in anesthetized and awake rats subjected to severe controlled hemorrhage. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Anesthetized rats were subjected to bleeding to reduce mean arterial pressure to either 40 or 35 mm Hg, which was maintained constant for 60 mins. In addition, awake rats underwent blood withdrawal of 4.25 mL/100 g over 20 mins. At the end of the hemorrhage period and 30 mins later, the animals received intravenous (5 and 20 mg/kg) or intramuscular (10 and 40 mg/kg) injections of glipizide sodium salt or vehicle. MEASUREMENTS AND MAIN RESULTS: In anesthetized rats subjected to pressure-controlled hemorrhage, glipizide sodium salt improved mean arterial pressure in a dose-dependent manner. Compared with the vehicle-treated animals, mean arterial pressure increased from 41.6 +/- 4.6 to 63.1 +/- 3.1 mm Hg in the 20 mg/kg intravenous group and from 33.2 +/- 4.9 to 54.0 +/- 4.7 mm Hg in the 40 mg/kg intramuscular group 60 mins after a 40-mm Hg shock. Furthermore, the drug did not affect the hemorrhage-induced changes in blood glucose concentrations. However, the higher doses of glipizide sodium salt attenuated the increments in plasma concentrations of lactate, alanine aminotransferase, creatinine, and amylase. Moreover, the higher doses markedly improved short-term survival after pressure- and volume-controlled bleeding. Overall, the intramuscular injections of the drug exerted salutary effects that were comparable to the intravenous administration. CONCLUSIONS: In rats, parenteral administration of the water-soluble glipizide sodium salt attenuates vascular and end-organ dysfunction associated with severe hemorrhagic shock and prolongs short-term survival. The intramuscular administration provides comparable benefits as obtained by the intravenous injection.

Adenosine Triphosphate↗
PubMed2003

Characterization and treatment of systemic venous to pulmonary venous collaterals seen after the Fontan operation.

OBJECTIVES: To determine the anatomical characteristics of systemic venous collaterals formed after the Fontan operation, and the efficacy of a transcatheter strategy for management. METHODS: We reviewed retrospectively the data from cardiac catherization of 50 persistently cyanotic patients after the Fontan operation. RESULTS: A total of 54 transcatheter interventions were performed, at a mean age of 6.3 +/- 3.5 years, a mean interval of 2.7 +/- 2.9 years from completion of the Fontan circulation. Of 38 patients who had fenestration of the baffle at the time of surgery, 25 had patency of the fenestration, and 24 had the fenestration occluded with a device at the time of interventional treatment for associated venous collaterals. We identified a total of 68 systemic venous collateral channels, of which 36 (53%) were supracardiac, 12 (18%) cardiac, and 20 (29%) infracardiac in origin. The most common site of origin was the brachiocephalic vein (44%), followed by the left phrenic vein (25%). A longer time from surgery, at 3.3 +/- 3.4 years, was associated with the identification of collaterals having a diameter larger than 4 mm (p < 0.01). The mean pulmonary arterial pressure was higher in those with larger compared to those with smaller collaterals (13.3 +/- 2.8 versus 11.1 +/- 2.0 mmHg, p < 0.01). Coils were used for occlusion of 61 vessels, and a Rashkind occluder for the remaining 7. After exclusion of the patients undergoing simultaneous closure of their fenestration, systemic saturation of oxygen increased from 89 +/- 6% to 95 +/- 3% (p < 0.01). CONCLUSION: Venous collateral channels are common in patients suffering progressive cyanosis in the setting of the Fontan circulation. The collaterals increase in size with time, and are associated with higher pulmonary arterial pressures. Transcatheter treatment is feasible, and results in resolution of cyanosis. Only continuing follow-up will show whether further collateralization occurs in time.

Canada↗
PubMed2002

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension.

OBJECTIVES: The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND: Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS: Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS: During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS: Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Adult↗
PubMed2002

Assessment of structural commonality between tetrahydrocannabinol and anandamide.

In order to make further structural comparisons between tetrahydrocannabinol and anandamide, substituents at C1 and C3 of the phenolic ring of tetrahydrocannnabinol were altered. In order to examine the alignment of the phenolic hydroxyl of tetrahydrocannnabinol with the hydroxyl group of anandamide, 1-fluoro-1-deoxy-tetrahydrocannnabinol analogs were prepared. These analogs had low affinity for the CB(1) cannabinoid receptor and were considerably less potent than tetrahydrocannnabinol in producing pharmacological effects in mice. These results suggest that these two oxygen moieties do not overlap. Additionally, the fact that a fluorine group can only accept hydrogen bonds suggest that the phenolic oxygen at the C1 position of tetrahydrocannnabinol donates electrons for hydrogen bonding rather than the hydrogen of the hydroxyl group interacting with the receptor. Additionally, substitution of a fluorine for the hydroxyl group at C1 led to analogs with higher affinity for CB(2) than CB(1) cannabinoid receptors, thereby underscoring a fundamental difference in the binding properties of these two receptor subtypes.

Animals↗
PubMed2002

A structure/activity relationship study on arvanil, an endocannabinoid and vanilloid hybrid.

Arvanil, a structural "hybrid" between the endogenous cannabinoid CB1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N-methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB1 receptors, activate VR1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB1 receptor. Methylation of the amide group decreased the activity at VR1, AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR1 and AMT, but not the affinity for CB1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR1 and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 microM). A water-soluble analog of arvanil, O-2142, was as active on VR1, much less active on AMT and CB1, and more potent on FAAH. All compounds induced a response in the mouse "tetrad", particularly those with EC50 <10 nM on VR1. However, the most potent compound, N-N'-di-(3-chloro-4-hydroxy)benzyl-arachidonamide (O-2093, ED50 approximately 0.04 mg/kg), did not activate VR1 or CB1 receptors. Our findings suggest that VR1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

Amidohydrolases↗
PubMed2002

Part I: pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications: studies with FP15, a novel potent peroxynitrite decomposition catalyst.

BACKGROUND: Peroxynitrite is a cytotoxic oxidant formed from nitric oxide (NO) and superoxide. Tyrosine nitration, a footprint of peroxynitrite, has been demonstrated in the pancreatic islets as well as in the cardiovascular system of diabetic subjects. Delineation of the pathogenetic role of peroxynitrite in disease conditions requires the use of potent, in vivo active peroxynitrite decomposition catalysts. The aim of the current work was to produce a potent peroxynitrite decomposition catalyst and to test its effects in rodent models of diabetes and its complications. METHODS: FP15 was synthesized and analyzed using standard chemical methods. Diabetes was triggered by the administration of streptozotocin. Tyrosine nitration was measured immunohistochemically. Cardiovascular and vascular measurements were conducted according to standard physiologic methods. RESULTS: FP15, a potent porphyrinic peroxynitrite decomposition catalyst, potently inhibited tyrosine nitration and peroxynitrite-induced cytotoxicity in vitro and in vivo. FP15 treatment (3-10 mg/kg/d) dose dependently and reduced the incidence and severity of diabetes mellitus in rats subjected to multiple low doses of streptozotocin, as well as in nonobese mice developing spontaneous autoimmune diabetes. Furthermore, treatment with FP15 protected against the development of vascular dysfunction (loss of endothelium-dependent relaxations) and the cardiac dysfunction (loss of myocardial contractility) in diabetic mice. FP15 treatment reduced tyrosine nitration in the diabetic pancreatic islets. CONCLUSIONS: The current results demonstrate the importance of endogenous peroxynitrite generation in the pathogenesis of autoimmune diabetes and diabetic cardiovascular complications. Peroxynitrite decomposition catalysts may be of therapeutic utility in diabetes and other pathophysiologic conditions.

Animals↗
PubMed1997

Synthetic Studies on the Kinamycin Family of Antibiotics: Synthesis of 2-(Diazobenzyl)-p-naphthoquinone, 1,7-Dideoxy-3-demethylprekinamycin, and 1-Deoxy-3-demethylprekinamycin.

2-(Diazobenzyl)-p-naphthoquinone was synthesized from 2-benzyl-1,4-dimethoxynaphthalene by cerric ammonium nitrate oxidation to 2-benzyl-p-naphthoquinone followed by diazo transfer with tosyl azide. 1,7-Dideoxy-3-demethylprekinamycin was prepared from 1,4-dimethoxynaphthalene by bromination, lithiation, and condensation with acetanthranil to give 2-(2'-N-acetaminobenzoyl)-1,4-dimethoxynaphthalene, which, following deacylation, was subjected to Pschorr cyclization to give 1,3,7-trihydro-O,O-dimethylkinafluorenone. This was then demethylated, subjected to hydrazinolysis, and then oxidized with Fetizon's reagent to complete the synthesis. 1-Deoxy-3-demethylprekinamycin was synthesized from 3-bromo-1,5-dimethoxy-4-naphthol by an identical route.

Journal Article↗