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Biomedical subjects

R E Goldstein

Publications and source records attributed to R E Goldstein.

At least 19 recordsLinked to original sources
PubMed1992

The effects of acute elevations in plasma cortisol levels on alanine metabolism in the conscious dog.

The present study was undertaken to determine whether an acute physiological increase in plasma cortisol level had significant effects on alanine metabolism and gluconeogenesis within 3 hours in conscious, overnight-fasted dogs. Each experiment consisted of an 80-minute tracer and dye equilibration period, a 40-minute basal period, and a 3-hour experimental period. A primed, continuous infusion of [3-3H]glucose and continuous infusions of [U-14C]alanine and indocyanine green dye were initiated at the start of the equilibration period and continued throughout the experiment. Dogs were studied with (1) a hydrocortisone infusion ([CORT] 3.0 micrograms.kg-1.min-1, n = 5), (2) hydrocortisone infused as in CORT, but with pancreatic hormones clamped using somatostatin and basal intraportal replacement of insulin and glucagon (CLAMP+CORT, n = 5), or (3) saline infusion during a pancreatic clamp (CLAMP, n = 5). Glucose production and gluconeogenesis were determined using tracer and arteriovenous difference techniques. During CLAMP, all parameters were stable except for a modest 67% +/- 6% increase in gluconeogenic conversion of alanine to glucose and a 53% +/- 26% increase in gluconeogenic efficiency. When plasma cortisol levels were increased fourfold during CLAMP+CORT, there was no change in the concentration, production, or clearance of glucose. Gluconeogenic conversion of alanine to glucose increased 10% +/- 34% and gluconeogenic efficiency increased 65% +/- 43%, while net hepatic alanine uptake (NHAU) increased 60% +/- 19% and hepatic fractional extraction of alanine increased 38% +/- 12%. Cortisol did not cause an increase in the arterial glycerol level or net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1992

Patient maintenance of esthetic restorations.

There are probably as many ways to maintain esthetic restorations as there are restorations. After esthetic treatment is completed, schedule a mandatory postoperative appointment to make certain that whatever technique the patient uses is effective. At the postoperative visit, it should be apparent that the patient's tissue is healthy. If the tissue has not healed, some change in home care or additional periodontal or restorative treatment may be necessary. There are virtually hundreds, perhaps even thousands of home plaque removal devices. The ones mentioned here have worked for us and are therefore discussed. It isn't the type of device that is critical, however, but patient compliance. The described regimens have worked effectively for us in overcoming this obstacle of compliance. Appropriate recall visits with the hygienist should be made at one- to six-month intervals. In the final analysis, your success with esthetic restorations may well depend on your patients' success with esthetic maintenance.

Dental Devices, Home Care↗
PubMed1991

Cardiovascular effects of platelet-activating factor.

Sudden release of platelet-activating factor (PAF) into the circulation can cause hypotension, tachycardia, and circulatory collapse. To further examine this response, we performed detailed studies of cardiovascular function after PAF administration to young domestic pigs and newborn piglets. Our results indicate that circulatory dysfunction after PAF reflects severe constriction of pulmonary resistance vessels and consequent acute right ventricular failure. Although PAF-induced coronary artery constriction and contractile depression may be complicating problems, left ventricular underperfusion and dysfunction after PAF are mainly the result of systemic arterial hypotension and diminished left ventricular filling. The adverse hemodynamic effects of PAF are accompanied by substantial release of thromboxane A2 (TxA2). These effects are mimicked by the TxA2 agonist U-46619 and partially blocked by specific and nonspecific inhibitors of TxA2 synthesis (OKY-046 and indomethacin). Even more potent blockade of PAF action is exerted by the TxA2 receptor blocker, SQ 29,548. Taken together, these findings indicate that severe pulmonary vascular constriction and hemodynamic collapse soon after intravenous PAF are at least partially mediated by PAF-induced TxA2 release. Tachyphylaxis to PAF influence has been observed in studies of leukocyte and platelet function. We hypothesized that tachyphylaxis to PAF might also occur in our studies of constrictor responses in pulmonary vessels. Recently, we have examined the capacity of PAF to produce sustained pulmonary vasoconstriction in open-chested, anesthetized newborn piglets. Infusions sufficient to produce 100% increase in mean pulmonary artery pressure after 3 min showed no loss of efficacy when sustained for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

In vivo enhancement of platelet activating factor-induced prostacyclin production by OKY-046, a selective inhibitor of thromboxane A2 synthase.

Platelet-activating factor (PAF), a likely mediator of endotoxin action, causes thromboxane A2 (TXA2) release and pulmonary hypertension in pigs. We examined the effect of selective TXA2 synthase inhibition with OKY-046 on cyclooxygenase metabolites during PAF-induced pulmonary hypertension. Six closed-chest pigs received PAF in escalating doses (0.1, 0.3, 1.0, and 3.0 nmol intravenously, i.v.) before and after (E)-3[4-(1-imidazolyl methyl) phenyl]-Z-propenoic acid hydrochloride monohydrate OKY-046, 10-mg/kg i.v. bolus plus 20-mg/kg/h infusion. Plasma samples at peak PAF effect had radioimmunoassay (RIA) for the stable metabolites of TXA2 (TXB2) and prostacyclin (6-keto-PGF1 alpha). Tachyphylaxis was not noted in 5 control pigs given sequential repeats of the PAF dosing series. Pulmonary vascular resistance (PVR) was 240 +/- 30 (SE) dyne s cm-5 at baseline and increased to 3,100 +/- 1,300 after 1.0 nmol PAF (p less than 0.05). When the same amount of PAF was given after OKY-046, PVR increased only to 820 +/- 280 dynes/s/cm-5. TXB2 was 34 +/- 7 pg/0.1 ml at baseline and increased to 70 +/- 4 pg/0.1 ml with PAF 1.0 nmol (p less than 0.001). TXB2 levels were unchanged from 34 +/- 4 pg/0.1 ml when PAF 1.0 nmol was administered after OKY-046 (NS vs. pre-OKY-046). In contrast, 6-keto-PGF1 alpha, 6 +/- 2 pg/0.1 ml at baseline, increased to 24 +/- 4 pg/0.1 ml after PAF 1.0 nmol and increased further to 50 +/- 8 pg/0.1 ml when PAF 1.0 nmol was given after OKY-046 (p less than 0.05 vs. pre-OKY-046).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group.

The Multicenter Diltiazem Postinfarction Trial (MDPIT) reported no consistent diltiazem effect on new or worsened congestive heart failure (CHF) during 12-52 months' follow-up after acute myocardial infarction. This was puzzling in light of the observation that patients with findings suggesting left ventricular dysfunction (LVD) at baseline on diltiazem had more cardiac events (cardiac mortality or recurrent nonfatal infarction) than such patients on placebo. We hypothesized that diltiazem increased the frequency of late CHF as well as of cardiac events, but only in patients predisposed by LVD. Using the same characterizing variables as the primary MDPIT analysis, we found that patients with pulmonary congestion, anterolateral Q wave infarction, or reduced ejection fraction (EF) at baseline were more likely to have CHF during follow-up than those without these markers of LVD. CHF was particularly frequent in the patients with LVD who were randomized to diltiazem. Among those with a baseline EF of less than 0.40, late CHF appeared in 12% (39/326) receiving placebo and 21% (61/297) receiving diltiazem (p = 0.004). Life table analysis in patients with an EF of less than 0.40 confirmed more frequent late CHF in those taking diltiazem (p = 0.0017). In addition, the diltiazem-associated rise in the frequency of late CHF was progressively greater with increasingly severe decrements in baseline EF. This diltiazem effect was absent in patients with pulmonary congestion at baseline but an EF of 0.40 or more, suggesting a unique association between diltiazem-related late CHF and systolic LVD.(ABSTRACT TRUNCATED AT 250 WORDS)

Diltiazem↗
PubMed1991

Sustained effects of platelet-activating factor infusion in piglets.

Acute exposure to platelet-activating factor (PAF) causes severe pulmonary vasoconstriction (PV), but its action may be markedly limited by tachyphylaxis. To determine the effects of PAF exposure per se and the effects compared with the hypoxemic state (33 +/- 1 mm Hg), PAF infusions (0.05-0.15 nmol/kg/min x 30-180 min) were administered to 15 open-chested, anesthetized, neonatal piglets before and during administration of selective receptor blockers to PAF (SRI 63,441, 5 mg/kg i.v. or WEB 2086, 10 mg/kg i.v.) or vehicle. Measurements included mean pulmonary (PAP) and systemic arterial pressures, cardiac index, right and left ventricular pressures and dimensions, and coronary blood flow. Mean PAP and pulmonary vascular resistance index rose in response to 30 min PAF infusion (14 +/- 1 to 30 +/- 1 mm Hg and 4500 +/- 700 to 16,400 +/- 1900 dynes s cm-5.kg, both p less than 0.01, n = 10). Similar changes occurred when PAF was infused for 180 min (n = 5). Other parameters were unaffected. Acute hypoxia also increased in PAP and pulmonary vascular resistance index (17 +/- 1 to 32 +/- 2 mm Hg and 6400 +/- 900 to 17,100 +/- 1800 dynes s cm-5.kg, both p less than 0.01) and did not alter other measured variables. Treatment with SRI 63,441 prevented PAF-induced increases in PAP (14 +/- 1 to 14 +/- 1 mm Hg, p less than 0.05) and pulmonary vascular resistance index (5300 +/- 900 to 5500 +/- 800 dynes s cm-5.kg, p less than 0.05) but failed to alter the response to hypoxia. SRI 63,441 and WEB 2086, administered during PAF infusion, rapidly reversed PAF action. Vehicle had no effect. We conclude that PAF can produce severe and sustained PV in vivo and that PAF receptor blockade may be useful in treatment of neonatal disease featuring PAF-mediated PV. PAF receptors may not be involved in PV induced by hypoxia.

Animals↗
PubMed1990

Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group.

A total of 1,975 plasma diltiazem concentrations were obtained from 1,067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population, we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose, (2) drug dose taken, (3) patient height (an index of lean body weight), and (4) patient age were important determinants of plasma concentration. For an equivalent dose, plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure, they were not altered by renal dysfunction, hepatic disease or beta blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p less than 10(-9), but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations, but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration greater than 150 ng/ml (7.4 and 1.9%, respectively) than among patients with lower concentrations (2.6% for atrioventricular block, 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related, and that the consideration of patient size, age, and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.

Adult↗
PubMed1990

Involvement of leucocytes and leukotrienes in ischaemic dysfunction of the coronary microcirculation.

Recent evidence suggests that leucocytes may exert an important influence on microvessel flow during pathophysiologic conditions. This is particularly true in the case of coronary occlusive disorders. Diminution of coronary perfusion pressure favours trapping of the large, stiff leucocytes in capillaries. Perhaps more importantly, ischaemic changes in the endothelial lining of microvessels promote early sequestration of leucocytes within capillaries of ischaemic regions during underperfusion and, to a much greater degree, during reperfusion. If these trapped leucocytes are activated by the ischaemic environment, the mechanical plugging of microvessels can be significantly complicated by leucocyte release of a variety of materials affecting the function of blood vessels and myocytes. Leukotrienes are a potent group of inflammatory mediators released by activated leucocytes. A subgroup, the peptidoleukotrienes (C4, D4, and E4), has a profound vasoconstrictor influence on coronary microvessels. Members of this group can also cause platelet aggregation. Agents that block peptidoleukotriene synthesis, such as nafazatrom, have been reported to diminish the adverse effects of myocardial ischaemia. However, these agents often have non-specific actions that blur the interpretation of their anti-ischaemic efficacy. Our laboratory has made a number of observations that cast doubt--or at least stimulate further inquiry--on the role of peptidoleukotrienes on promotion of sustained microvessel constriction in ischaemic coronary beds. Most importantly, we found that continuous intracoronary administration of leukotriene C4 or D4 led initially to marked diminution of coronary flow and myocardial contractility. However, this was soon followed by a complete, dose-independent escape from these effects even though leukotrienes continued to be infused at a constant rate. The cause of this escape is unclear, but it may involve a specific product released when leukotrienes interact with platelets. In a second series of experiments, we found that the coronary constrictor efficacy of bolus leukotrienes (and also the stable thromboxane A2 analogue, U46619) was markedly reduced by concomitant myocardial ischaemia. Constrictor responses were rapidly restored with reperfusion, suggesting a transient metabolic blockade of constrictor responsiveness during myocardial ischaemia. Nevertheless, these data indicate that leukotrienes may not act simply as agents that exaggerate underperfusion due to proximal coronary occlusion. Finally, we have measured the leukotriene immunoreactivity in coronary venous blood exiting from beds made ischaemic (and dysfunctional) by partial occlusion of epicardial arteries. Although the occlusion was sufficient to cause release of lactate and other metabolic markers of ischaemia, we were unable to find measurable rises in release of any of the leukotrienes after occlusions lasting 3 h and reperfusions lasting up to 1 h.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Circulatory effects of endothelin in newborn piglets.

Endothelin, a recently described endothelial cell-derived peptide, produces pulmonary and coronary vasoconstriction in mature animals. We investigated the acute hemodynamic effects of porcine endothelin in 14 anesthetized open-chest new-born piglets during normoxia (Pao2 = 102 +/- 5 mmHg) and hypoxia (fractional inspired O2 concentration = 0.12 X 15 min, Pao2 = 31 +/- 1 mmHg). Six of these animals were pretreated with indomethacin, a cyclooxygenase inhibitor. Low-dose (100 pmol/kg) intravenous bolus injection of endothelin decreased pulmonary vascular resistance index (PVRI) (42 +/- 6 to 16 +/- 4 mmHg.l-1.min.kg, P less than 0.01) and increased coronary blood flow (CBF) (17 +/- 2%, P less than 0.01); cardiac index (CI) and coronary vascular resistance were unaffected. The pulmonary and coronary responses to endothelin were preserved during hypoxia: PVRI fell (160 +/- 22 to 83 +/- 13 mmHg.l-1.min.kg, P less than 0.05) and CBF rose (35 +/- 11%, P less than 0.05). Low-dose endothelin moderately increased mean arterial pressure (61 +/- 3 to 75 +/- 6 mmHg, P less than 0.05) and systemic vascular resistance index (SVRI) (375 +/- 23 to 491 +/- 41 mmHg.l-1.min.kg, P less than 0.01). High-dose (1,000 pmol/kg) endothelin mildly decreased PVRI (51 +/- 7 to 35 +/- 12, NS), moderately increased SVRI (375 +/- 45 to 594 +/- 95 mmHg.l-1.min.kg, P less than 0.05), and markedly diminished CBF (-54 +/- 6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Exercise-induced fall in insulin and hepatic carbohydrate metabolism during muscular work.

To examine the role of the exercise-induced fall in insulin, dogs were studied during 150 min of treadmill exercise alone (C) or with insulin clamped at basal levels by an intraportal infusion so as to prevent the normal fall in its concentration (IC). To counteract the suppressive effect of insulin on glucagon release, glucagon was replaced intraportally in a separate group of dogs in which insulin levels were clamped (IC + G). In all dogs, catheters were placed in an artery and in the portal and hepatic veins for sampling and in the vena cava and the portal vein for infusion purposes. Glucose production (Ra) and gluconeogenesis were assessed with isotope and arteriovenous difference techniques. In C, insulin fell 5 +/- 2 microU/ml by the end of exercise and was unchanged in IC (delta 0 +/- 2 microU/ml) and IC + G (delta 0 +/- 1 microU/ml). Glucagon rose 54 +/- 11 pg/ml with exercise in C and was unchanged in IC (delta - 4 +/- 11 pg/ml), and normal increments were restored in IC + G (delta 55 +/- 10 pg/ml). Catecholamines and cortisol rose similarly in all groups. Ra increased by an average of 4.0 +/- 0.4, 0.9 +/- 0.3, and 1.8 +/- 0.4 mg.kg-1.min-1 during exercise in C, IC, and IC + G, respectively. Gluconeogenesis from alanine rose by 212 +/- 34, 91 +/- 39, and 184 +/- 47% with exercise in C, IC, and IC + G.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1989

Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work.

The effects of the exercise-induced rise in glucagon were studied during 2.5 h of treadmill exercise in 18-h fasted dogs. Five dogs were studied during paired experiments in which pancreatic hormones were clamped at basal levels during a control period (using somatostatin and intraportal hormone replacement), then altered during exercise to stimulate the normal exercise-induced fall in insulin, while glucagon was 1) increased to mimic its normal exercise-induced rise (SG) and 2) maintained at a basal level (BG). Six additional dogs were studied as described with saline infusion alone (C). Gluconeogenesis (GNG) and glucose production (Ra) were measured using tracers [( 3-3H]glucose and [U-14C]alanine) and arteriovenous differences. Glucose fell slightly during exercise in C and was infused in SG and BG so as to mimic the response in C. Glucagon rose from 60 +/- 3 and 74 +/- 5 pg/ml to 118 +/- 14 and 122 +/- 17 pg/ml with exercise in C and SG and was unchanged from basal in BG (67 +/- 6 pg/ml). In C, SG, and BG, insulin fell during exercise by 5 +/- 1, 6 +/- 1, and 6 +/- 1 microU/ml. Ra rose from 3.3 +/- 0.2 and 3.0 +/- 0.2 mg.kg-1.min-1 to 8.6 +/- 0.8 and 9.5 +/- 1.5 mg.kg-1.min-1 with exercise in C and SG, but from only 3.0 +/- 0.2 to 5.5 +/- 0.8 mg.kg-1.min-1 in BG. GNG increased by 248 +/- 38 and 183 +/- 75% with exercise in C and SG but by only 56 +/- 21% in BG. Intrahepatic gluconeogenic efficiency was also enhanced by the rise in glucagon increasing by 338 +/- 55 and 198 +/- 52% in C and SG but by only 54 +/- 46% in BG. The rise in hepatic fractional alanine extraction was 0.38 +/- 0.04 and 0.33 +/- 0.04 during exercise in C and SG and only 0.08 +/- 0.06 in BG. Ra was increased beyond that which could be explained by effects on GNG alone, hence hepatic glycogenolysis must have also been enhanced by the rise in glucagon. In conclusion, in the dog, the exercise-induced rise in glucagon 1) controls approximately 65% of the increase in Ra, 2) increases hepatic glycogenolysis and GNG, and 3) enhances GNG by stimulating precursor extraction by the liver and precursor conversion to glucose within the liver.

Alanine↗
PubMed1989

Circulatory effects of PAF-acether in newborn piglets.

Platelet-activating factor (PAF-acether) is a lipid mediator that can exhibit potent vasoconstrictor influence in the pulmonary vessels. Therefore, the release of PAF-acether during inflammatory conditions in newborns might cause deleterious increases in pulmonary vascular tone. Thirty-four anesthetized open-chest newborn piglets were given 0.01-1 nmol PAF-acether iv. In separate experiments, animals were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), SQ 29548 (a thromboxane receptor blocker), or LY 171883 (a leukotriene receptor blocker). The primary hemodynamic change was a 67 to 1,537% increase in the pulmonary vascular resistance index (PVRI) (P less than 0.01): mean pulmonary artery pressure (PAP) rose significantly at all doses tested, whereas only the largest dose consistently decreased cardiac index. Treatment with indomethacin or SQ 29548 prevented the decrease in cardiac index and attenuated the PAF-acether-induced rises in PAP and PVRI. Vehicle and LY 171883 had no effect. The inhibitory influence of indomethacin and SQ 29548 suggests that an important component of PAF-acether's pulmonary vasoconstrictor action is mediated (at least in the newborn piglet) by cyclooxygenase products, most likely thromboxane.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Lethal ischemia due to intracoronary endothelin in pigs.

Endothelin is a recently discovered endothelium-derived peptide with potent coronary constrictor properties in vitro. To evaluate endothelin's cardiac actions in vivo, we measured coronary flow and regional myocardial shortening when intracoronary porcine endothelin was given to anesthetized open-chested pigs. Bolus adminstration into the left anterior descending (LAD) coronary artery of six pigs caused dose-related rapidly reversing depression of LAD flow and local shortening. Marked reductions in flow [-71 +/- 8 (SE) %] and shortening (-83 +/- 2%) after 30 pmol/kg demonstrated endothelin's potency in cardiac tissues. Systemic hemodynamic values were unaltered except for transient rises in left ventricular end-diastolic pressure. Endothelin-induced decrement in LAD flow was accompanied by electrocardiographic signs of myocardial ischemia and net release of local myocardial lactate. Intracoronary infusion of endothelin, 15 pmol.kg-1.min-1, caused progressive decline in LAD flow and local shortening followed by severe persistent hypotension and terminal ventricular fibrillation in four of five pigs. Unlike intracoronary delivery of other potent coronary constrictors, intracoronary administration of endothelin did not lead to rapid escape from the peptide's deleterious influence. Coronary exposure to endothelin under pathophysiological circumstances could result in uniquely persistent decrements in myocardial perfusion and contractile function.

Animals↗