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Biomedical subjects

J A Oates

Publications and source records attributed to J A Oates.

At least 109 records · Page 6Linked to original sources
PubMed1983

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects.

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1983

Hazards in operative management of patients with systemic mastocytosis.

During the past two years, six patients with systemic mastocytosis have required general or regional anesthesia for operative correction of various surgical problems. Mastocytosis constitutes an extremely difficult problem in diagnosis and management. A large experience with patients with mastocytosis in the Vanderbilt Medical Center in the last decade has enhanced awareness of this disorder and increased its early recognition. The hazardous problems of systemic mastocytosis and the difficulties of its diagnosis and management are summarized and focussed on the increased hazard of those patients with this disease who require various surgical operations. Close collaboration between anesthesiologists, surgeons, and internists in this medical center in the past two years has made it possible to carry six of these patients through anesthesia, operation, and the postoperative period safely and without fatality.

Adult↗
PubMed1983

Kinetics and imaging of indium-11-labeled autologous platelets in experimental myocardial infarction.

The kinetics of accumulation and the external imaging patterns of indium-111-labeled platelets infused in a dog model of left anterior descending coronary artery occlusion with reperfusion were studied. The effects of infarct age and regional residual myocardial blood flow upon platelet accumulation were quantified, and the capacity of indium-111 platelets to image the experimental infarction was evaluated qualitatively. The endocardial accumulation of indium-111 platelets occurred primarily in infarct zones with residual blood flow less than 0.6 times normal and was maximal (24.98 +/- 2.76 times normal) in the lowest blood flow zone (less than 0.1 times normal). Indium-111 platelet accumulation in the epicardium occurred in the regions with blood flow less than 0.6 times normal and was maximal (17.83 +/- 1.20 times normal) in the lowest blood flow zone (less than 0.1 times normal). The maximal endocardial and epicardial platelet accumulation occurred 24 hours after reperfusion and was significantly decreased at 48 hours. In vivo cardiac images revealed discrete areas of increased myocardial radioactivity uptake in the anterior wall of dogs 24 hours after reperfusion. All images 48 hours after reperfusion were negative. Thus, in the experimental setting, indium-111 platelets allow quantification of platelet accumulation after myocardial infarction at a tissue level and provide a noninvasive means of in vivo imaging of reperfused infarcted myocardium.

Animals↗
PubMed1983

Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-O-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of O-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 +/- 27 ng/ml [+/- SE] and after second maintenance dose, 230 +/- 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, O-demethyl encainide.

Action Potentials↗
PubMed1983

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.

To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.

Adenosine Diphosphate↗
PubMed1983

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 microM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 micrograms/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 alpha (PGI-M). PGI-M excretion was increased by dazoxiben; it rose a mean 2.4-fold from predosing control values at 0-6 h after administration of the highest dose studied (200 mg).

Adult↗
PubMed1983

Histamine release from a gastric carcinoid: provocation by pentagastrin and inhibition by somatostatin.

We have previously reported that flushing associated with a gastric carcinoid tumor can be provoked by pentagastrin and inhibited by either somatostatin or combined histamine H1- and H2-receptor blockade. In this report, the effects of pentagastrin and somatostatin on histamine release in a patient with a metastatic gastric carcinoid tumor were examined. Small doses of intravenous pentagastrin (0.1-0.4 micrograms) produced a dose-dependent increase in the level of circulating plasma histamine. Graded infusions of somatostatin suppressed both basal and pentagastrin-stimulated plasma histamine levels in a dose-dependent fashion. A close correlation was found between circulating plasma histamine levels and attendant changes in blood pressure and pulse rate. This study documents that pentagastrin directly evokes the release of histamine from this patient's gastric carcinoid tumor and that the release of histamine is inhibited by somatostatin. In addition, this study provides additional evidence that the primary mediator of the flushing in this patient with foregut carcinoid syndrome is histamine.

Blood Pressure↗
PubMed1983

Metabolic disposition of prostacyclin in humans.

Quantitative analysis of metabolite levels is a useful approach to investigation of the in vivo synthesis of short-lived mediators such as prostacyclin (PGI2). In order to establish the basis for metabolite assays of PGI2, we have studied the fate of radiolabeled PGI2 administered to man. Three healthy male volunteers each received i.v. 11 beta-[3H]PGI2 at 4 ng/kg/min for 24 hr. A gradual increase in plasma radioactivity was observed throughout the infusion period, followed by a biphasic decline postinfusion (T 1/2 alpha, 53 min; T 1/2 beta, 246 min) suggestive of the presence of long-lived metabolites of PGI2 in the circulation. The recovery of radioactivity averaged 82% in urine and, in contrast to other species, only 4% in feces. Direct analysis of urine by high-pressure liquid chromatography revealed the presence of at least 16 compounds and documented their relative abundance. Ten compounds were subsequently identified by gas chromatography-mass spectrometry. All identified metabolites retained the 6-keto-prostaglandin F structure characteristic of PGI2 hydrolysis and were each formed in less than 10% yield from administered PGI2. Of interest was the finding that 6-keto-prostaglandin F1 alpha accounted for 5.9% of systemically administered 11 beta-[3H]PGI2. These results identify urine as the major route of human PGI2 metabolite excretion and also illustrate the utility of direct chromotographic analysis of urine in the elucidation of prostaglandin disposition in humans.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Central and peripheral cardiovascular effects of alpha-methylepinephrine.

We compared peripheral and central cardiovascular effects of (+/-)-alpha-methylepinephrine (alpha-ME) and (+/-)-alpha-methylnorepinephrine (alpha-MNE), two putative active metabolites of alpha-methyldopa to those of (-)-epinephrine in urethane-anesthetized normotensive rats. Intravenous administration of 1 microgram doses of alpha-ME (4.3 nmol) lowered blood pressure whereas alpha-MNE (4.5 nmol) and (-)-epinephrine (3.0 nmol) raised blood pressure. Heart rate responses to each were opposite to the blood pressure response, consistent with reflex buffering. When administered into the cerebral ventricle (5-20 micrograms) (15-90 nmol) and nucleus of the solitary tract (0.3-10 nmol), each catecholamine caused marked reductions in both blood pressure and heart rate. alpha-ME was more potent than alpha-MNE and the endogenous catecholamine, (-)-epinephrine, in its central depressor effect. The greater potency of alpha-ME relative to alpha-MNE and (-)-epinephrine suggests that it could contribute to antihypertensive actions of alpha-methyldopa.

Animals↗
PubMed1983

Prostaglandin biosynthesis does not participate in hypercapnia-induced cerebral vasodilatation in the dog.

The participation of cerebral prostaglandin biosynthesis in hypercapnia-induced cerebral vasodilation was assessed in pentobarbital-anesthetized dogs using the radioactive microsphere technique. In five dogs, administration of 5% CO2 increased pCO2 from 31.0 +/- 0.8 to 53.4 +/- 2.4 mm Hg (P less than .001) and decreased total cerebral vascular resistance from 11.2 +/- 3.0 to 2.6 +/- 0.6 mm Hg . min . 100 g . ml-1 (P less than .001). The observed increases in pCO2 and the decreases in cerebral vascular resistance during 5% CO2 inhalation were unchanged 1 hr after administration of an i.v. bolus of 0.1 M Na2CO3 (vehicle). In another group of five dogs, 5% CO2 increased pCO2 from 30.4 +/- 0.58 to 55.2 +/- 4.2 mm Hg (P less than .01) and decreased total cerebral vascular resistance from 5.7 +/- 0.6 to 1.8 +/- 0.4 mm Hg . min . 100g . ml-1 (P less than .001). In these dogs, the CO2-induced decrease in cerebral vascular resistance 1 hr after a bolus dose of indomethacin (10 mg/kg i.v.) dissolved in 0.1 M Na2CO3 was also unchanged. In both groups of dogs the patterns described for total cerebral vascular resistance were also observed in the cerebrum, cerebellum and brainstem. The dose of indomethacin used in this study abolished the vasodepressor responses to i.v. arachidonic acid and suppressed the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. Furthermore, the administration of 5% CO2 did not increase the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. We conclude that cerebral prostaglandin biosynthesis does not mediate or modulate hypercapnia-induced cerebral vasodilation in the dog.

Animals↗
PubMed1983

VX2 carcinoma, pulmonary metastases, and neutrophilic leukocytosis. Possible animal model of tumor-associated granulocytosis.

In New Zealand white rabbits bearing the transplantable VX2 carcinoma intramuscularly in the hind limbs uniformly a granulocytosis syndrome developed, characterized by peripheral blood neutrophilia and marked granulocytic bone marrow hyperplasia, whereas the syndrome did not always develop in animals bearing the tumor intraabdominally. The relationship between the extent of pulmonary metastases and granulocytosis/bone marrow hyperplasia was significant (P less than 0.005). This positive correlation (correlation coefficient = 0.85) existed for both animals bearing intraabdominal tumors and animals bearing intramuscular tumors. The granulocytic syndrome occasionally occurred in rabbits with mild degrees of pulmonary metastatic involvement, but never with total absence of pulmonary metastases. Hypercalcemia occurred prior to the appearance of pulmonary metastases and was not essential to the development of granulocytosis. These data suggest that granulocytosis in VX2 carcinoma-bearing rabbits is dependent on the presence of tumor in the lungs and is not directly related to implantation site. This tumor-bearing animal model may be suitable for studies of tumor-associated granulocytosis in vivo.

Abdominal Neoplasms↗