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W D Watkins

Publications and source records attributed to W D Watkins.

At least 73 records · Page 4Linked to original sources
PubMed1985

Eicosanoids in the central nervous system.

All mammalian tissue investigated to date is capable of eicosanoid biosynthesis in response to various activating stimuli. While the importance of these metabolites as major mediators of many normal physiological processes and some pathophysiological conditions has not been proven, it is evident that these compounds are at least important modulators of many cellular and organ system functions. This review is intended to provide the reader with a brief overview of eicosanoid biology, with specific reference to the neurosciences. The increasing knowledge about the role of the eicosanoids in neurobiology may contribute to the understanding and treatment of many neurological diseases. The eicosanoids comprise several groups of biologically active unsaturated fatty acids: the "primary" prostaglandins, the cyclic endoperoxides, the prostanoids, the leukotrienes, and other acid lipids. This article includes a review of the enzymatic pathways of biosynthesis and metabolism of eicosanoids in man, and the pertinent structural nomenclature. The general basic and clinical pharmacological effects of the more important compounds on vascular perfusion, platelet function, intracellular enzyme activity, and interactions with other mediators of cellular activity are reviewed. A more detailed review of the actions of eicosanoids as mediators or modifiers of central nervous system physiology and pathophysiology is presented. Recent animal and human studies on the use and alterations of the eicosanoid metabolites is summarized, specifically where they relate to several clinical problem areas of interest to the neurosurgeon and neurobiologist. These areas include cerebrovascular circulation physiology, cerebral ischemia, cerebral vasospasm following subarachnoid hemorrhage, migraine headaches, hypothalamic function, neurotransmission, and nociception. A bibliography of 92 articles for further review is also included.

Central Nervous System↗
PubMed1985

Prostaglandin E1. A new therapy for refractory right heart failure and pulmonary hypertension after mitral valve replacement.

Patients undergoing mitral valve replacement, particularly those with severe pulmonary hypertension and/or congestive heart failure, may develop life-threatening right heart failure in the immediate postbypass period. We have observed that such patients have intense pulmonary vasoconstriction. The markedly increased pulmonary impedance may aggravate the right heart failure and prevent recovery of right ventricular function in this setting. Therefore, we studied the effects of high-dose prostaglandin E1 (30 to 150 ng/kg/min), a potent pulmonary vasodilator, in combination with massive infusion of norepinephrine (up to 1 microgram/kg/min) into the left atrium in five consecutive patients with refractory right heart failure and pulmonary hypertension after mitral valve replacement. This pharmacologic approach takes advantage of the pulmonary vasodilating effects of prostaglandin E1, while offsetting associated systemic vasodilation and resulting hypotension. All five patients had rapid pulmonary vasodilator responses followed by marked improvement in right ventricular function. All survived the operation and none had right ventricular infarction or chronic right heart failure postoperatively.

Adult↗
PubMed1984

Regional blood flow and pulmonary thromboxane release after sublethal endotoxin infusion in sheep.

Fifteen minutes after intravenous Escherichia coli endotoxin (EN) infusion the sheep lung transiently releases into the systemic circulation up to 12 micrograms of thromboxane A2 (TxA2)/min measured by radioimmunoassay as its metabolite thromboxane B2 (TxB2). To determine whether lung thromboxane release alters regional blood flow (RBF) we injected microspheres before and 20, 30, and 100 minutes after EN infusion in 13 awake sheep. In seven untreated control sheep (group 1) pulmonary vascular resistance (PVR) increased threefold at 20 and 30 minutes after EN infusion, coinciding with a large transpulmonary blood concentration gradient of TxB2. There was no measured RBF change to any systemic tissue or organ except the right ventricle at 20 minutes after EN infusion, when blood flow per gram of tissue doubled. In six sheep (group 2) treated with intravenous ibuprofen before EN infusion there was no increase in PVR, plasma TxB2, or blood flow to the right ventricle, and no difference of RBF to any other organ or tissue when compared to group 1. TxA2 is a potent local pulmonary vasoconstrictor but it rapidly hydrolyzes. Its short half-life and the circulatory delay in systemic arterial delivery prevent TxA2 from acting as a circulating vasoconstrictor.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Cardiac prostacyclin kinetics during cardiopulmonary bypass.

We have investigated the response of systemic and myocardial prostacyclin metabolism to cardiopulmonary bypass and 30 minutes of hypothermic (22 degrees C), hyperkalemic (25 mEq K+) surgical cardioplegia. Thirteen adult mongrel dogs of either sex (range 21 to 36 kg) underwent sterile cardiopulmonary bypass without donor blood. Prostacyclin levels were obtained after cannulation, 20 minutes after onset of partial bypass, and 5 seconds after the onset of cardioplegia 1 (CP-1) and cardioplegia 2 (CP-2, 30 minutes later). Samples were drawn from the thoracic aorta, the aortic root below cross-clamping, and the coronary sinus. The stable metabolite of prostacyclin, 6-keto-PGF1 alpha was measured by double-antibody radioimmunoassay (pg/ml; values +/- standard error of the mean). We found that the onset of partial bypass is associated with significant increase in the systemic production of 6-keto-PGF1 alpha (122 +/- 33 versus 518 +/- 187; p less than 0.05), which persists throughout the experiment. A small but significant positive cardiac gradient of 6-keto-PGF1 alpha is found after cannulation (aortic root 122 +/- 33, coronary sinus 202 +/- 57, p less than 0.05). This gradient is more pronounced during partial bypass (aortic root 518 +/- 187, coronary sinus 686 +/- 186 p less than 0.05), when significant cardiac lactate extraction (p less than 0.005) is observed. After cross-clamping, a significantly increased gradient of 6-keto-PGF1 alpha is found during CP-1 (aortic root 74 +/- 10, coronary sinus 264 +/- 46, p less than 0.05 versus cannulation) in the presence of significant cardiac lactate production (p less than 0.005). A further significant increase in 6-keto-PGF1 alpha production is noted during the CP-2 infusion (aortic root 73 +/- 10, coronary sinus 483 +/- 83; p less than 0.01 versus CP-1), which is inversely related to cardiac oxygen uptake and endocardial/epicardial flow ratio. Our data demonstrate significant production of prostacyclin in the systemic and cardiac circulations during cardiopulmonary bypass and surgical cardioplegia. They further indicate that both ischemic and nonischemic stimuli regulate prostacyclin metabolism during cardiopulmonary bypass.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance.

We examined the role of thromboxane in mediating the alterations in pulmonary hemodynamics and in lung fluid and protein exchange after thrombin. Studies were made in control sheep and in sheep pretreated with the thromboxane synthetase inhibitor, Dazoxiben (injection of 10 mg/kg followed by infusion of 4 mg/kg per hr). Thrombin infusion caused an increase in mixed venous and aortic concentrations of thromboxane B2, a stable degradation product of thromboxane A2, whereas the concentrations of 6-keto-PGF1 alpha, a degradation product of prostacyclin, did not change significantly. In sheep pretreated with Dazoxiben, thromboxane B2 concentrations did not increase, indicating effectiveness of the thromboxane synthetase inhibitor. The blood concentrations of 6-keto-PGF1 alpha after thrombin increased in the thromboxane synthetase-inhibited group, indicating shunting towards prostacyclin synthesis. Thrombin in untreated sheep increased pulmonary lymph flow (Qlym) and the lymph protein clearance (Qlym X lymph-to-plasma protein concentration ratio). The increases in lymph parameters were due to an increase in pulmonary vascular permeability to proteins because raising left atrial pressure further increased Qlym but did not change lymph-to-plasma ratio. Dazoxiben prevented the thrombin-induced increase in pulmonary vascular permeability because the increase in left atrial pressure resulted in an increase in Qlym and a decrease in lymph-to-plasma ratio, as was the case after left atrial hypertension in normal animals. Therefore, thrombin results in selective release of thromboxane A2 which precedes the increase in pulmonary vascular permeability. Thromboxane A2 may contribute to the increased permeability after thrombin, since inhibition of thromboxane synthesis prevents the permeability change.

Animals↗
PubMed1983

Effects of leukotrienes B4 and C4 on coronary circulation and myocardial contractility.

Arachidonic acid is metabolized to prostaglandins and thromboxane via the cyclooxygenase pathway and to leukotrienes B4, C4, D4, and E4 via the lipooxygenase pathway. A possible role played by leukotrienes in cardiogenic shock resulting from anaphylaxis prompted us to investigate the action of these compounds on coronary vessels and myocardial contractility. In this study leukotriene B4 (LTB4) and C4 (LTC4) were injected directly into the left circumflex (LCx) coronary artery of nine anesthetized Suffolk sheep. LTB4 had no effect on coronary artery blood flow or myocardial contractility, but 3 X 10(-9) mole induced profound transient circulating neutropenia, reflecting the potent chemotactic and chemokinetic properties of this compound. Injecting as little as 1.6 X 10(-11) mole of LTC4 caused a 14.5 +/- 4.3% (mean +/- SE) reduction of LCx coronary artery flow while 1.6 X 10(-10) mole caused a 26.5 +/- 3.7% decrease of LCx coronary artery flow and an 18.1 +/- 3.2% decrease in systolic shortening of the myocardial region supplied by the LCx coronary artery. Since the decrease in systolic shortening was far greater than that expected on the basis of the reduction in coronary artery flow, we postulate that LTC4 has a direct negative inotropic effect. FPL 55712, a receptor antagonist of leukotrienes C4, D4, and E4, blocked the vasoconstriction induced by LTC4 but only partially blocked the negative inotropic effects of LTC4. LTC4 is a potent vasoconstrictor and negative inotropic agent and may play an important role in anaphylactic shock.

Animals↗
PubMed1982

Thromboxane and prostacyclin (epoprostenol) during exercise in diffuse pulmonary fibrosis.

Plasma thromboxane A2, a vasoconstrictor, and plasma prostacyclin (epoprostenol), a vasodilator, were assessed by double-antibody radioimmunological assay of their respective stable circulating metabolites, thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha, in 9 patients with severe diffuse pulmonary fibrosis (DPF), who were known to become hypo-oxaemic during exercise, and in 9 healthy volunteers. In the 7 patients with the most severe DPF, mean arterial PO2 fell from 68 mm Hg at rest to 51 mm Hg at peak aerobic exercise, and mean TxB2 increased to twice the value at rest. The 9 controls remained oxygen saturated throughout exercise; their mean TxB2 did not change during aerobic exercise, but during anaerobic exercise increased to twice the value at rest, and increased further during recovery. There were no significant changes in 6-keto-prostaglandin F1 alpha in either group. The selective release of TxB2 during aerobic exercise in hypo-oxaemic patients suggests that thromboxane mediates hypoxic pulmonary vasoconstriction. Its release in normal man during anaerobic exercise may reflect a more general response to the metabolic changes of tissue hypoxia.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction.

Leukotriene D4 (2 c 10(-9) mole), injected into the left circumflex coronary artery of anesthetized sheep, produced profound coronary vasoconstriction and impaired regional ventricular wall motion. This cardiac effect was neither inhibited by prior treatment of the sheep with a cyclooxygenase inhibitor nor associated with thromboxane B2 release into the coronary sinus. Intravenous FPL 55712 completely abolished the coronary vasoconstriction of leukotriene D4, but a significant reduction of regional wall shortening persisted.

Animals↗
PubMed1982

Thromboxane and pulmonary hypertension following E. coli endotoxin infusion in sheep: effect of an imidazole derivative.

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB2 (TxA2), 6-keto-PGF1 alpha (PGI2), and PGF2 in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 microgram/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB2 concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazole treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB2 concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF1 alpha (PGI2) and PGF2 alpha were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Our study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA2.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Effect of lung thromboxane generation on regional blood flow during sheep bypass.

Acute pulmonary artery hypertension and an increased plasma concentration of thromboxane B2 (TXB2), the stable metabolite of the potent vasoconstrictor thromboxane A2, occur within minutes of the onset of venovenous (VV) partial bypass in the awake sheep. To search for systemic vasoconstriction, we assessed systemic blood flow distribution by radioactive microspheres and correlated the changes to alterations in plasma TXB2 and 6-keto-F1 alpha concentration. In 10 control sheep mean plasma TXB2 concentration increased from 0.39 ng/ml prebypass to about 1.1 ng/ml at 8 and 16 min of bypass. Despite marked pulmonary vasoconstriction with a threefold elevated resistance, the blood flow to the heart, brain, and kidney were unchanged at 8 and 16 min of bypass. However, hepatic vascular resistance increased twofold at 8 min of bypass. Indomethacin treatment (10 mg/kg) of six sheep blocked the increase of both pulmonary and hepatic vascular resistance as well as reduced TXB2 levels below 0.1 ng/ml. Thus VV bypass induces transient and selective vasoconstriction of the lung and liver mediated by vasoconstrictor eicosanoids.

Animals↗
PubMed1982

Thromboxane mediates acute pulmonary hypertension in sheep extracorporeal perfusion.

We measured serial plasma concentrations of thromboxane B2 (TXB2), the stable metabolite of the putative pulmonary vasoconstrictor thromboxane A2 (TXA2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator prostacyclin (PGI2) by double-antibody radioimmunoassay during partial venovenous bypass in 25 awake sheep. The onset of bypass caused mean pulmonary artery pressure (PAP) to increase from 16 +/- 1 to 28 +/- 2 mmHg at 12 +/- 2 min, due to an increase of pulmonary vascular resistance, followed by a return to control within 45 min. There was no systemic hypoxia. TXB2 increased simultaneously with the onset of pulmonary hypertension (PH) (236 +/- 36 to 700 +/- 120 pg/ml at 0 and 5 min) and peaked at 1,724 +/- 172 pg/ml 10 min after maximum PAP was achieved. Positive pulmonary artery-to-aortic differences of TXB2 were measured. 6-Keto-PGF1 alpha increased from 51 +/- 3 to 842 +/- 367 pg/ml at 35 min. PGF2 alpha was unchanged (130 +/- 45 pg/ml). PH, TXB2, and 6-keto-PGF1 alpha increases were blocked by pretreatment with indomethacin or ibuprofen. PH and TXB2 increases were prevented with an imidazole derivative. PH caused by a continuous infusion of an endoperoxide analog did not induce lung release of TXB2 or PGF2 alpha. We conclude that 1) transient pulmonary vasoconstriction is caused by thromboxane; 2) the lung is the primary site of thromboxane synthesis; and 3) bypass causes selective alterations in arachidonic acid metabolism rather than general activation of the cascade.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Thromboxane and prostacyclin changes during cardiopulmonary bypass with and without pulsatile flow.

Nonpulsatile cardiopulmonary bypass, in patients with coronary artery disease, produces a significant increase in thromboxane, a potent platelet aggregant and putative coronary vasoconstrictor. Pulsatile flow may decrease the incidence of perioperative infarction and the hormonal stress response to bypass. This study assessed the effect of pulsatile blood flow on plasma thromboxane and prostacyclin profiles during cardiopulmonary bypass by serial measurement of their stable metabolites, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Two groups of eight patients each were studied before, during, and after cardiopulmonary bypass. Eight patients had routine (nonpulsatile) bypass and eight had pulsatile flow. In the nonpulsatile group, the TxB2 concentration significantly increased during bypass (65 +/- 39 to 1,224 +/- 306 pg/ml, p less than 0.01) and rapidly returned to control. Prostacyclin also rose (53 +/- 20 to 613 +/- 132 pg/ml, p less than 0.01). In the pulsatile group, TxB2 rose during bypass (53 +/- 18 to 693 +/- 130 pg/ml, p less than 0.01), but peak concentration was significantly lower than in the nonpulsatile group (1,224 +/- 306 versus 693 +/- 130 pg/ml, p less than 0.05). Prostacyclin rose sharply during cardiopulmonary bypass in the pulsatile group (53 +/- 22 to 1,033 +/- 136 pg/ml, p less than 0.01) and was higher than in the nonpulsatile group (1,033 +/- 136 versus 325 +/- 33 pg/ml, p less than 0.01). There were no intragroup differences of plasma hemoglobin, hematocrit, or platelet count. These data demonstrate that pulsatile flow significantly alters prostacyclin and thromboxane profiles during cardiopulmonary bypass and favors production of the coronary vasodilator and platelet disaggregant prostacyclin. This may be an important factor in some of the clinical advantages previously reported with this modality.

6-Ketoprostaglandin F1 alpha↗