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Biomedical subjects

R E Goldstein

Publications and source records attributed to R E Goldstein.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1989

Mechanisms of hypotension produced by platelet-activating factor.

Platelet-activating factor (PAF) is a phospholipid mediator that induces cardiovascular collapse and release of the secondary mediator thromboxane A2 (TxA2). To clarify mechanisms involved in this collapse and, specifically, the relative contribution of left ventricular and right ventricular dysfunction, we studied 12 open-chest pigs. PAF infusion (0.04-0.28 nmol.kg-1.min-1) induced a 5- to 120-fold increase in pulmonary vascular resistance, a 75-98% fall in cardiac output, and systemic arterial hypotension. Right ventricular failure was indicated by chamber enlargement, decreased shortening, and increased right atrial pressures. In contrast, left ventricular dysfunction was accompanied by decreases in chamber dimensions and filling pressures that were unresponsive to volume expansion. U 46619 (a stable TxA2 analogue) and mechanical pulmonary artery constriction induced changes similar to PAF. In 11 additional closed-chest pigs, TxA2 blockade with indomethacin attenuated the PAF-induced rise in pulmonary vascular resistance, right ventricular dysfunction, and systemic hypotension. A specific TxA2 synthase inhibitor, OKY-046, also diminished hemodynamic effects of PAF in six other pigs. Tachyphylaxis was not observed in five pigs repeatedly given PAF. We conclude that acute right ventricular failure as the result of severe increase in pulmonary vascular resistance is the primary mechanism early in the course of PAF-induced shock in the pig. PAF-induced release of TxA2 may contribute significantly to these events.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Influence of thromboxane A2 receptor antagonism on pulmonary vasoconstrictor responses.

Thromboxane A2 (TxA2) is an arachidonic acid metabolite which causes severe pulmonary vasoconstriction (PV) and may mediate the PV produced by platelet-activating factor (PAF-acether) and leukotriene D4 (LTD4). To determine the role of TxA2 receptors on PAF-acether, LTD4, and hypoxia-induced PV, we administered PAF-acether 0.1 nmol/kg, the TxA2 analog U-46619 0.2 micrograms/kg/min, LTD4 3.0 micrograms/kg, or acute hypoxia (FiO2 = 0.12 for 3 min) before and during the infusion of the selective TxA2 receptor blocker SQ 29,548 50 micrograms/kg/min or vehicle into 27 open-chest, anesthetized newborn piglets, measuring pulmonary and systemic arterial pressures, cardiac index, and right and left ventricular pressures and dimensions. Mean pulmonary arterial pressure rose and cardiac index fell in response to PAF-acether (14 +/- 1 to 32 +/- 2 mm Hg and 91 +/- 5 to 15 +/- 5 mL/kg/min, both p less than 0.01), U-46619 (11 +/- 1 to 28 +/- 2 mm Hg and 93 +/- 10 to 36 +/- 9 mL/kg/min, both p less than 0.01), and LTD4 (13 +/- 3 to 22 +/- 2 mm Hg and 85 +/- 12 to 29 +/- 9 mL/kg/min, both p less than 0.05). Acute hypoxia increased PAP (12 +/- 1 to 26 +/- 2 mm Hg, p less than 0.01) but did not alter cardiac index. Infusion of SQ 29,548 prevented PAF-acether and U-46619-induced increases in pulmonary arterial pressure (13 +/- 1 to 14 +/- 1 mm Hg and 12 +/- 1 to 12 +/- 1 mm Hg) and decreases in cardiac index (70 +/- 4 to 70 +/- 3 mL/kg/min and 94 +/- 14 to 92 +/- 12 mL/kg/min) but failed to alter the response to LTD4 or hypoxia. Vehicle had no effect. We conclude that TxA2 receptors are not involved in LTD4 or hypoxia-induced PV but play an important role in the PV produced by PAF-acether and U-46619.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Exercise-induced fall in insulin and increase in fat metabolism during prolonged muscular work.

The role of the exercise-induced fall in insulin in fat metabolism was studied in dogs during 150 min of treadmill exercise alone (controls) or with insulin clamped at basal levels by an intraportal infusion to prevent the normal fall in insulin concentration (ICs). To counteract the suppressive effect of insulin on glucagon release, glucagon was supplemented by an intraportal infusion in ICs. In all dogs, catheters were placed in a carotid artery and in the portal and hepatic veins for sampling and in the vena cava and the splenic vein for infusion purposes. Glucose levels were clamped in ICs to recreate the glycemic response evident in controls. In controls, insulin fell by 7 +/- 1 microU/ml but was unchanged from basal levels in ICs (0 +/- 2 microU/ml). Glucagon, norepinephrine, epinephrine, and cortisol rose similarly in controls and ICs. Arterial free-fatty acid (FFA) levels rose by 644 +/- 126 mu eq/L in controls but did not increase in ICs (-12 +/- 148 mu eq/L). Arterial glycerol levels rose by 337 +/- 43 and 183 +/- 19 microM in controls and ICs. Hepatic FFA delivery and fractional extraction increased by 17 +/- 3 and 0.06 +/- 0.02 mumol.kg-1.min-1, respectively, in controls. In ICs, hepatic FFA delivery increased by only 1 +/- 2 mumol.kg-1.min-1, whereas hepatic fractional extraction fell slightly (-0.03 +/- 0.03). Consequently, net hepatic FFA uptake rose by 4.8 +/- 1.5 mumol.kg-1.min-1 in controls but decreased slightly in ICs (-0.5 +/- 1.1 mumol.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗