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Biomedical subjects

W D Watkins

Publications and source records attributed to W D Watkins.

At least 55 records · Page 3Linked to original sources
PubMed1989

Transpulmonary prostaglandin F2 alpha metabolism in sheep: an in vivo model.

We investigated transpulmonary enzymatic conversion of prostaglandin F2 alpha (PGF) to the 13,14-dihydro-15-keto metabolite (PGFM) in normal and acutely lung injured sheep. PGF was infused directly into the right ventricle. Sequential, simultaneous blood samples were drawn from the pulmonary artery (PA) and aorta (A). PGF and PGFM plasma concentrations were quantitated by double antibody radioimmunoassay (RIA). The pulmonary conversion rate of PGF in normal lung was established over a wide range of concentrations in intubated, normoxic, and hemodynamically stable sheep. Both zero and first order kinetics were present. PGF had no physiological effects on either pulmonary or systemic hemodynamics at any infusion rate studied. Acute lung injury was produced by intravenous injections of oleic acid into the PA until the resting mean pulmonary artery pressure doubled. Infusions were then repeated and fractional metabolism of PGF across the lung was assessed. PGF, at infusion rates of 2 micrograms/kg/min and 8 micrograms/kg/min, was metabolized greater than 70% respectively. Thus, there was no difference between control or experimental groups in PGF conversion. We conclude that the in vivo sheep lung has an extensive substrate-dependent capacity to metabolize PGF and this mechanism is resistant to severe acute oleic acid lung injury.

Animals↗
PubMed1989

Eicosanoids and the hemodynamic course of live Escherichia coli-induced sepsis in baboons.

Time-related changes in eicosanoid release and hemodynamic parameters were characterized in baboons during the early development of sepsis induced by intravenous (i.v.) infusion of live Escherichia coli (4 x 10(10) organisms/kg) in baboons. Plasma levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2 (TxA2), rose rapidly in arterial, venous, and pulmonary arterial blood after infusion of live E. coli, attaining maximal increases at 30 min and returning to control values by 60 min. In contrast, plasma concentrations of 6-keto-PGF1 alpha rose slowly after infusion, reaching peak concentrations at 120 min, then slowly returned to control values between 4 and 5 hr after infusion of live E. coli. Hemodynamic values remained stable during the first 2 hr after infusion, although early changes in cellular energy metabolism and incipient hemodynamic failure were inferred from pyrexia, tachycardia, and metabolic acidosis. At 3 hr, signs of further hemodynamic compromise developed, including increased venous PCO2, reduced pulmonary capillary wedge pressure, and reduced stroke volume, followed by gradual increases in systemic and pulmonary vascular resistance. These factors coincided with progressive reductions in cardiac output and deteriorating circulatory efficiency. The time course of events following infusion of live E. coli indicates that alterations in cellular energy provision occurred early (within 1 hr), whereas central hemodynamic parameters decayed much more slowly. Additionally, TxA2 and PGI2 appear related to the early events in the development of sepsis as their release preceded cardiocirculatory failure.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Effect of epidural lidocaine on spinal cord blood flow.

The effect of epidural lidocaine on spinal cord blood flow (SCBF) was measured in mongrel dogs. Spinal evoked potentials were used to measure spinal cord conduction and enabled us to time the measurement of SCBF associated with maximum reduction in latency and amplitude of spinal evoked potentials produced by instillation of 5 ml of 2% lidocaine in the epidural space. We used the radioactive microsphere technique to quantitate SCBF in the cervical, upper thoracic, lower thoracic, and lumbar regions of the spinal cord. A narcotic/relaxant technique was used to eliminate SCBF changes associated with other anesthetic agents. Other parameters known to affect SCBF were kept constant and within normal physiologic values. As compared with saline solution controls, there were significant decreases in SCBF in all the four areas of spinal cord in animals given epidural lidocaine, most marked in the lumbar area.

Anesthesia, Epidural↗
PubMed1988

Atrial natriuretic peptide plasma levels during cardiac surgery.

In this investigation, the hypothesis was tested that patients with valvular heart disease have higher atrial natriuretic peptide (ANP) plasma levels than patients with coronary artery disease during cardiac surgery. Six patients scheduled for valve replacement (group V) and seven scheduled for coronary artery bypass grafting (CABG) (group C) were studied. ANP plasma levels and hemodynamic measurements were obtained at several times during surgery. ANP levels were elevated in both groups compared to those measured in healthy volunteers; and ANP levels in valvular patients were found to be higher than in the CABG patients. In addition, isotonic fluid loading, rewarming during cardiopulmonary bypass, and weaning from cardiopulmonary bypass increased ANP from baseline in group C. Mean arterial pressure and ANP levels correlated in group C. Ejection fraction, pulmonary artery diastolic pressure, and right atrial pressure did not correlate with ANP levels in either group. In conclusion, patients with valvular heart disease have higher ANP levels during surgery compared to patients with coronary artery disease. This difference probably relates to different pressure and volume loads on atrial tissue.

Aged↗
PubMed1988

Novel compound for identifying Escherichia coli.

A new chromogenic compound, 5-bromo-4-chloro-3-indoxyl-beta-D-glucuronide, was found to be useful for the rapid, specific, differential identification of Escherichia coli in the sanitary analysis of shellfish and wastewater. Of 1,025 presumptively positive colonies (blue) and 583 presumptively negative colonies (nonblue), only 1% false-negative and 5% false-positive results were found.

Animals↗
PubMed1988

Hemodynamics and prostacyclin release in the early phases of aortic surgery: comparison of transabdominal and retroperitoneal approaches.

Although the retroperitoneal aortic approach (RP) is advocated to reduce myocardial ischemia and cardiac-related death, inadequate physiologic data exist to support this contention. As the aorta is exposed via the transabdominal approach (TA) we noted some patients have manifested reduced systemic vascular resistance (SVR) associated with tachycardia, reduced blood pressure, and facial flushing. To determine whether RP offered physiologic advantages over TA we compared cardiac dynamics and blood levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of prostacyclin, during exposure of the aorta in 52 patients (33 with TA and 19 with RP), comparable in age, cardiac history, medications, and body surface area. Serial measurements of mean arterial pressure, heart rate, wedge pressure, pulmonary artery pressure, cardiac index, and 6-keto-PGF1 alpha were obtained. Results revealed decreased mean arterial pressure and systemic vascular resistance, increased cardiac index and heart rate, and facial flush occurring 10 minutes after the bowel was explored in TA. This was not observed in RP. These hemodynamic alterations correlated in time and magnitude with a fourteen fold increase in 6-keto-PGF1 alpha. These changes in cardiac indexes can produce increased myocardial oxygen consumption with the risk for myocardial ischemia, particularly in patients with coronary artery disease. The absence of this response to bowel exploration in RP may account for some of the observed advantages in "high-risk" aortic reconstruction.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

A pertussis/cholera toxin sensitive G-protein may mediate vasopressin-induced inositol phosphate formation in smooth muscle cell.

Arg-vasopressin (AVP) stimulates the production of inositol-1,4,5-triphosphate, inositol-1,4-bisphosphate and inositol-1-phosphate in A10 smooth muscle cell line. The AVP stimulation is rapid, time and dose dependent with an ED50 value of 5 nM. Protein kinase C activator, phorbol ester blocks the AVP effect on the production of inositol phosphates, suggesting that AVP induced phospholipase C (PLC) activation is under the negative feedback regulation by diacylglycerol production. Prolonged overnight treatment with either pertussis toxin and cholera toxin resulted partial inhibition of AVP-induced production of inositol phosphates. This result suggests that a novel G-protein similar to transducin might be involved in the AVP-induced PLC activation.

Animals↗
PubMed1987

Absence of prostaglandin changes associated with protamine administration in patients with pulmonary hypertension.

In patients with pre-existing pulmonary hypertension, severe pulmonary vasoconstriction has been observed following protamine administration. Thromboxane A2, a potent vasoconstrictor, is capable of producing increases in pulmonary vascular resistance, and animal studies suggest that heparin-protamine complexes stimulate thromboxane A2 synthesis. This study assessed the effect of protamine administration on hemodynamics and on plasma thromboxane A2 and its biologic antagonist, prostacyclin, by serial measurement of the stable metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Ten adults with pulmonary artery hypertension undergoing elective mitral valve replacement were studied. After termination of cardiopulmonary bypass, baseline hemodynamic measurements were obtained and arterial blood for prostanoid analysis was sampled. Hemodynamic and prostanoid measurements were obtained 5, 10, 15, and 30 minutes after the protamine infusion began. Prostanoid levels were performed by double antibody radio-immunoassay. No significant hemodynamic changes occurred and no significant changes in prostanoid levels were observed. It is concluded that in patients with pulmonary hypertension, heparin-protamine complexes do not consistently raise circulating thromboxane levels, and the relationships among prostanoids, pulmonary hypertension, and systemic hypotension are still not clear.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors.

The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4]morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. beta-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Thromboxane release during percutaneous transluminal coronary angioplasty.

The reason for coronary artery occlusion following percutaneous transluminal angioplasty (PTCA) remains an enigma. We postulated that alterations in arachidonic acid metabolism might contribute to coronary artery occlusion, particularly if platelets are perturbed and release thromboxane because of mechanical stimuli during PTCA. We serially monitored coronary sinus and peripheral arterial plasma thromboxane (TX) and prostacyclin (by standard radioimmunoassay of the metabolites TXB2 and 6-keto-PFG1 alpha) during PTCA in 10 patients. TX and prostacyclin were unchanged from control in seven uncomplicated procedures. In one patient with vasospasm, no changes were found. In two patients with occlusion, marked increases were measured in coronary sinus plasma TX. Patient No. 1 increased from 390 to 1375 pg/ml. Patient No. 2 increased from 155 to 1425 pg/ml. Both required emergency bypass grafting. No change in 6-keto-PGF1 alpha was found. Uncomplicated PTCA does not alter arachidonic acid metabolism through cyclooxygenase. Vasospasm need not be associated with TX release, but coronary artery occlusion is. TX may play a role in coronary artery occlusion during PTCA because of (1) increased release and (2) unopposed physiologic effects because increases were not found in the physiologic antagonist prostacyclin.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin.

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

Animals↗
PubMed1986

Neuroendocrine correlates of lactate-induced anxiety and their response to chronic alprazolam therapy.

Lactate infusions are anxiogenic in patients with panic disorder or agoraphobia with panic attacks, but few neuroendocrine profiles of this effect have appeared. The authors measured the number and intensity of panic symptoms and blood hormone levels during double-blind lactate infusions in 25 patients and 10 normal subjects and during placebo infusions in another five patients. Each patient was rechallenged with an identical infusate after chronic double-blind outpatient treatment with alprazolam or placebo. The results confirm the effectiveness of lactate infusions in evoking anxiety, extend previous hormone profiles of this maneuver, and indicate that chronic alprazolam treatment minimizes the neuroendocrine response to lactate challenges in patients with panic disorder or agoraphobia with panic attacks.

Adolescent↗
PubMed1986

Interaction between highly selective mu and delta opioids in vivo at the rat spinal cord.

Possible interactions between mu- and delta-receptors in the rat spinal cord were studied using the radiant-heat-induced tail flick response and the highly selective mu- or delta-ligands: [NMePhe3,D-Pro4] morphiceptin(PL-17) and cyclic[D-Pen2,D-Pen5]enkephalin(DPDPE). Intrathecal infusions of PL-17 (0.5 microgram/hr) for 5 days caused 61- and 6-fold shifts to the right of the dose-response curves for PL-17 and DPDPE, respectively. Since PL-17 and DPDPE are highly selective agonists for mu- and delta-receptors, the partial cross-tolerance to the delta-agonist induced by PL-17 is probably not resultant from a cross-reactivity between these ligands. These data suggest that there may be an interaction between mu- and delta-receptors in the rat spinal cord.

Analgesics↗
PubMed1986

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels.

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Effect of fecal pollution on Vibrio parahaemolyticus densities in an estuarine environment.

Vibrio parahaemolyticus densities in the Narragansett Bay, R.I., estuary were found to significantly correlate with the level of fecal pollution in the water. Results of field investigations showed a definite association between the levels of this organism and those of Escherichia coli, Clostridium perfringens, and enterococci. Densities of V. parahaemolyticus were greatest in the near-surface waters of contaminated areas and decreased sharply with both the distance from the sources of fecal pollution and the depth of the water column. A positive association with the amount of particulate matter in the water and specifically with its zooplankton content also was found. No association was obtained with any of the physical or chemical parameters examined except dissolved oxygen. The results of laboratory studies on the growth of V. parahaemolyticus in collected estuarine waters were consistent with the field observations in that nutrients in sewage did not directly produce any increase in natural or inoculated levels of the organism. Of several particulates added to the water, only chitin and net zooplankters (live or dead) supported the growth of V. parahaemolyticus. The addition of sewage to the water had no measurable effect, whether or not the various particulates also were present. The data show that wastewater effluents have an effect on V. parahaemolyticus densities in this estuary and indicate that the effect is indirect, probably mediated by biostimulation of the food chain and manifested at the level of the microfauna.

Feces↗