Biomedical subjects

C R Benedict

Publications and source records attributed to C R Benedict.

At least 73 records · Page 4Linked to original sources

PubMed1993

Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. The SOLVD Investigators.

OBJECTIVES: The aim of this study was to determine the differences in neurohumoral responses between patients with pulmonary congestion with and without impaired left ventricular ejection fraction. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to the impairment in systolic contractility. METHODS: The 898 patients recruited into the Studies of Left Ventricular Dysfunction (SOLVD) Registry substudy were examined to identify those patients with pulmonary congestion on chest X-ray film who had either impaired (< or = 45%, group I) or preserved (> 45%, group II) left ventricular ejection fraction. Plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were measured in these two groups of patients and compared with values in matched control subjects. RESULTS: Distribution of the New York Heart Association symptom classification was the same in the two groups of patients. Compared with control subjects, patients in group II with pulmonary congestion and preserved ejection fraction had no activation of the neurohumoral mechanisms, except for a small but statistically significant increase in arginine vasopressin and plasma renin activity. Compared with patients in group II, those in group I with pulmonary congestion and impaired ejection fraction had significant increases in plasma norepinephrine (p < 0.002), plasma renin activity (p < 0.02) and atrial natriuretic peptide levels (p < 0.0007). When we controlled for baseline differences between groups I and II, the between-group differences in plasma norepinephrine (p < 0.02) and atrial natriuretic peptide (p < 0.002) remained significant. However, plasma renin activity was not significantly different between groups I and II. When the effects of diuretic agents and angiotensin-converting enzyme inhibitors were adjusted, patients with lower ejection fraction were found to have significantly higher plasma norepinephrine and atrial natriuretic peptide levels. CONCLUSIONS: The results point to the importance of the decrease in left ventricular ejection fraction as one of the mechanisms for activation of neurohormones in patients with heart failure.

Adult↗

PubMed1993

Restenosis after coronary angioplasty.

Coronary angioplasty is used to treat coronary atherosclerotic disease in many patients. One problem with coronary angioplasty is the phenomenon of restenosis. Restenosis appears to be a universal response to arterial wall injury. The biological events that underlie restenosis are characterized by: platelet adhesion and aggregation at sites of damaged endothelium, and within dissections into the medial layers, release of platelet derived growth-promoting substances, inflammation of the injured medial zone, transformation, migration, and proliferation of smooth muscle cells of the media following their activation by growth-promoting substances, secretion of copious amounts of extracellular matrix material, and finally, termination of the growth process following regrowth of endothelium over the damaged area. More than a decade of research work has helped identify clinical correlates of restenosis after coronary angioplasty. Patient-related correlates include male gender, unstable angina, diabetes, and continued smoking after angioplasty. Lesion-related correlates include multilesion and multivessel procedures, higher post-angioplasty residual stenosis, proximal vessel location, location in the left anterior descending coronary artery, location in a vein graft, long lesions, and total occlusions. However, for the purposes of individual patient care, clinical correlates are not particularly helpful. No group of variables has predicted complete freedom from restenosis, and conversely no group of variables has reliably indicated its presence. All patients undergoing angioplasty will require some form of follow-up evaluation. Symptom status by itself has not been found to be useful for predicting restenosis. However, when symptom status is combined with exercise thallium-201 scintigraphy, performed 4-6 months after angioplasty, it is less than ideal, but has a negative predictive value of over 90%. This means that over 90% of patients who are asymptomatic and have no evidence of ischemia by thallium-201 scintigraphy, will not have angiographic restenosis. Numerous clinical trials have been performed in order to reduce or prevent restenosis. Almost all have been disappointing, while a few have been encouraging. Studies of antiplatelet agents such as aspirin, dipyridamole (Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA), and Ticlopidine (Syntex, Humgcao, Puerto Rico) have not shown efficacy, yet studies of an inhibitor of platelet-derived growth factor have been provocatively encouraging. No reduction in restenosis rates was found with the anticoagulants Coumadin (Du Pont Pharmaceuticals, Wilmington, DE, USA) and Heparin (Wyeth-Ayerst, Philadelphia, PA, USA). Fish oils (omega fatty acids) have been found in several clinical trials to provide modest, but encouraging, reductions in restenosis, but await further confirmation.(ABSTRACT TRUNCATED AT 400 WORDS)

Angioplasty, Balloon, Coronary↗

PubMed1992

Thrombolytic therapy: a state of the art review.

The plasminogen-plasmin enzyme system and its therapeutic manipulation provide the substrate for an assessment of the clinical use of thrombolytic agents. Proven effective in acute MI and its complications, such agents have other potential applications--e.g., in stroke or pulmonary embolism--and are being investigated in those contexts.

Cardiovascular Diseases↗

PubMed1992

Influence of dietary fish oil on mitochondrial function and response to ischemia.

Dietary supplementation with marine oils may reduce the incidence of thromboembolism and decrease cardiac arrhythmias during myocardial ischemia. However, function of subcellular organelles isolated from hearts of these animals is impaired. In contrast to studies where marine oil was the sole source of dietary lipid in rats, menhaden oil was used to supplement standard canine laboratory chow. In mitochondria isolated from hearts of dogs fed this diet for 60 wk, the phospholipid content of arachidonic acid was replaced by the n-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Mitochondrial levels of linoleic and linolenic acids were not altered. The mitochondrial membrane phospholipid from the menhaden oil-fed dogs demonstrated increased cardiolipin. The respiratory function of heart mitochondria from the menhaden oil-supplemented dogs was not decreased from that of dogs on standard chow only. Increased succinate-supported respiration paralleled increased cytochrome oxidase in mitochondria from menhaden oil-fed dogs. The activity of the cardiolipin-dependent carnitine acylcarnitine translocase was unaffected. Myocardial ischemia decreased mitochondrial respiration in menhaden-fed dogs. Decreased palmitoylcarnitine-carnitine exchange following ischemia resulted from decreased matrix carnitine rather than decreased translocase activity. Normal levels of the essential fatty acids in the n-3-enriched mitochondrial membrane phospholipids appear to eliminate the mitochondrial dysfunction observed in essential fatty acid-deficient membranes.

Animals↗

PubMed1992

ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries.

The goal of this study was to test the hypotheses that endogenous ADP plays an important role in vivo in mediating platelet aggregation and cyclic coronary artery blood flow variations (CFVs) in stenosed and endothelium-injured coronary arteries in an experimental canine model. Anesthetized animals were studied and coronary blood flow velocities monitored by a pulsed Doppler flow probe positioned around the left anterior descending coronary artery. CFVs were established by an external constrictor positioned at sites with injured endothelium. Apyrase, an ADP-removing enzyme, was infused into the left anterior descending coronary artery (0.3-1.8 units/min) 30 minutes or 2 hours after the establishment of CFVs. Complete abolition of CFVs was achieved in 81% (13/16) of dogs with 30-minute CFVs and in 83% (five of six) of dogs with 2-hour CFVs. In other dogs, a potent inhibitor of ADP-induced platelet aggregation, clopidogrel, was administered as a 10 mg/kg i.v. bolus and a 2.5 mg/kg/hr infusion 30 minutes and 3 hours after the establishment of CFVs. This treatment resulted in complete abolition of CFVs in 14 dogs (100%) with either 30-minute or 3-hour CFVs. Epinephrine was infused into some dogs after CFVs had ceased as a result of either apyrase or clopidogrel administration and into some dogs in whom SQ29548, a thromboxane A2 receptor antagonist, had been given when apyrase failed to abolish CFVs. Epinephrine restored CFVs in all dogs treated with apyrase alone, 67% (four of six) of dogs treated with the combination of apyrase and SQ29548, and 29% (two of seven) of dogs treated with clopidogrel. The plasma epinephrine levels required for CFV restoration were 20 times higher than baseline values in dogs receiving apyrase alone, 100 times higher when a combination of apyrase and SQ29548 had been given, and more than 5,000 times higher in dogs receiving clopidogrel. In vitro studies showed that apyrase only inhibited ADP-induced platelet aggregation, whereas clopidogrel not only inhibited ADP-induced platelet aggregation, but also reduced platelet aggregation induced by the thromboxane mimetic U46619 and serotonin. These data suggest that 1) ADP is an important mediator of platelet aggregation and CFVs in vivo and 2) combined inhibition of thromboxane A2 and ADP's effects provides marked protection against CFVs in experimentally stenosed and endothelium-injured canine coronary arteries. These data and our previous observations are consistent with the possibility that specific antagonists of thromboxane A2, serotonin, and ADP, alone and together, may provide substantial protection against platelet aggregation leading to CFVs at sites of endothelial injury and coronary artery stenosis.

Adenosine Diphosphate↗

PubMed1992

Arterial norepinephrine changes in patients with septic shock.

Arterial, mixed venous (pulmonary arterial), and peripheral venous norepinephrine and epinephrine levels; hemodynamics; and blood lactate levels were measured in 28 patients with septic shock (16 men and 12 women). During hospital follow-up, 18 patients (64%) died of circulatory failure. There were no significant differences in hemodynamic parameters or initial blood lactate levels between survivors and nonsurvivors. Initial arterial, mixed venous, and peripheral venous norepinephrine levels were elevated above normal in both survivors and nonsurvivors. However, norepinephrine levels at all three sampling sites were significantly higher in nonsurvivors than in survivors. Arterial or mixed venous norepinephrine level was better than peripheral venous norepinephrine level in distinguishing survivors from nonsurvivors. In contrast, the differences in plasma epinephrine levels between survivors and nonsurvivors became significantly different only after 48 hr of follow-up. During 60 degrees head-up tilt, the increase in plasma norepinephrine level was significantly higher in survivors compared to non-survivors, suggesting a differential response in the sympathetic nervous system in the two groups of patients. These data suggest that measurement of arterial or mixed venous plasma norepinephrine levels may be a useful guide for assessing the clinical course of patients in septic shock. Moreover, the differences in the sympathetic nervous system response to a 60 degree tilt may predict a poor outcome in these patients.

Acidosis, Lactic↗

PubMed1991

Frequency and severity of cyclic flow alternations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury.

The role of recurrent platelet aggregation in the development of neointimal proliferation of coronary arteries was explored in this study, and the hypothesis was evaluated that recurrent platelet aggregation and the consequent frequency and severity of cyclic coronary blood flow variations are important pathophysiologic factors in the subsequent development of neointimal proliferation. In 24 chronically instrumented dogs, variable degrees of coronary artery neointimal proliferation were observed 3 weeks after mechanical injury of the arterial endothelium and the placement of an external coronary artery constrictor. The severity of neointimal proliferation at 21 days was closely related to the frequency and severity of cyclic coronary blood flow variations during the initial 7 days after instrumentation of the animals, itself a manifestation of recurrent platelet aggregation and dislodgement. Pharmacological therapy with a dual thromboxane A2 synthetase inhibitor and receptor antagonist and with a serotonin S2 receptor antagonist frequently was successful in abolishing cyclic blood flow variations and in retarding neointimal proliferation.

Animals↗

PubMed1991

Quantitation of adenosine, inosine and hypoxanthine in biological samples by microbore-column isocratic high-performance liquid chromatography.

This paper describes a simple and sensitive high-performance liquid chromatographic method for measuring adenosine, inosine and hypoxanthine in cell suspensions. The method involves direct injection of the filtered sample on a microbore C18 reversed-phase column with UV detection at 259 nm. The mobile phase consisted of 125 mM potassium dihydrogenphosphate, 1.0 mM tetrabutylammonium hydrogen-sulfate, 1.5% acetonitrile and 20 mM triethylamine, pH 6.5. The minimum detectable amounts (signal-to-noise ratio of 3:1) were 2.0 pmol of adenosine, 2.5 pmol inosine and 3.5 pmol of hypoxanthine. The limits of quantitation were 2.9 +/- 0.2 pmol for adenosine, 4.2 +/- 0.3 pmol for inosine and 4.9 +/- 0.4 pmol for hypoxanthine. This method was used to quantitate adenosine release by dispersed rat renal outer medullary cells (tubules) under conditions of normoxia and hypoxia.

Adenosine↗

PubMed1991

Effect of aspirin on local prostaglandin production and serotonin accumulation in a canine model with coronary cyclic flow variations or thrombosis.

We have reported that thromboxane A2 and serotonin are two important mediators of coronary cyclic flow variations (CFVs) caused by recurrent platelet aggregation and dislodgement on a stenosed coronary arterial wall with endothelial injury. To test the hypothesis that blocking the synthesis of thromboxane A2 would not prevent serotonin release, 1.1, 4.6, and 9.2 mg/kg of aspirin were administered through the left atrium to 27 dogs with CFVs. The CFV elimination rate was 70% in the aspirin-treated dogs. Thromboxane B2 and serotonin concentrations were measured in different coronary arterial segments. There were significantly lower thromboxane B2 and 6-keto-PFG1a levels in the stenosed left arterior descending (LAD) segments with increasing dosage of aspirin-208 +/- 36, 24 +/- 31, 50 +/- 6 ng/g (P less than 0.0001) and 125 +/- 27, 58 +/- 38, 25 +/- 5 ng/g (P less than 0.0001), respectively. Serotonin levels were significantly higher in stenosed LAD (265.7 +/- 131.2 ng/g) than in LAD segments proximal or distal to the stenosis and in corresponding circumflex coronary artery segments, 17.1 +/- 3.7, 18.6 +/- 3.7, and 19.2 +/- 5.1 ng/g, respectively (P less than 0.05) following the highest dose of aspirin. In 41 additional dogs, electrical injury was used to initiate thrombosis in the circumflex artery and in those receiving aspirin (15 mg/kg) (n = 5), occlusive thrombus formation was inhibited. However, the local accumulation of serotonin was not significantly different between the control (194 +/- 27 ng/g) (n = 36) and the aspirin-treated group (167 +/- 19 ng/g) (n = 5). In vitro platelet aggregation induced by arachidonic acid was inhibited by the in vivo administration of 1.1 mg/kg of aspirin and abolished by 4.6 + 1.1 and 9.2 + 4.6 + 1.1 mg/kg of aspirin. However, serotonin-induced platelet aggregation was not affected following all doses of aspirin. Thus, aspirin eliminates CFVs in 70% of dogs, and markedly diminishes thromboxane A2 and prostacyclin concentrations in stenosed canine coronary arteries, but it does not prevent local serotonin accumulation. Similarly, aspirin prevents occlusive coronary thrombosis in dogs with electrically-induced endothelial injury, but it did not prevent local assumulation of serotonin. These experimental findings suggest that cyclo-oxygenese inhibition does not prevent serotonin accumulation at sites of coronary artery endothelial injury, and they thereby help provide a potential explanation of the lack of complete protection provided by aspirin in eliminating CFVs in this experimental model.

6-Ketoprostaglandin F1 alpha↗

PubMed1991

Effects of graded oxygen tension on adenosine release by renal medullary and thick ascending limb suspensions.

Adenosine is released from renal cells, and extracellular adenosine may influence the effects of ischemia on medullary tubule segments by altering ion transport or renal hemodynamics. While adenosine release and excretion are enhanced during renal ischemia, the specific sites of renal adenosine production have not been completely elucidated. In the present study, extracellular adenosine concentrations in suspensions of renal outer medulla and thick ascending limb segments were quantitated by reversed-phase high performance liquid chromatography. Media from other medullary (OM) suspensions incubated for 8 and 15 minutes at 0% oxygen contained significantly greater amounts of adenosine (1.404 +/- 0.21 and 2.034 +/- 0.27 ng/micrograms protein, respectively), when compared to values obtained from media of suspensions incubated for equivalent periods under non-hypoxic conditions (8, 20, and 95% oxygen), 0.78 +/- 0.05 (8 min) and 1.37 +/- 0.21 ng/micrograms protein (15 min). Similarly, adenosine release was greater in medullary thick ascending limb (mTAL) suspensions incubated for 8 minutes at 0% versus 8% oxygen (0.81 +/- 0.17 vs. 0.20 +/- 0.12 ng/micrograms protein, respectively). Moreover, the observed increase in adenosine release by thick ascending limbs at 0% oxygen could be inhibited completely by either furosemide or ouabain. These studies demonstrate that: 1) the renal medulla and medullary thick ascending limb are sites of adenosine release; 2) adenosine release by the mTAL is enhanced significantly during hypoxic conditions; and 3) the increased release of adenosine during hypoxia appears to be related to ion transport and oxidative metabolism, as the increased release was prevented by two disparate inhibitors of transport in this segment.

Adenosine↗

PubMed1991

In vitro and in vivo effects of R023-6152 on heart mitochondrial calcium and energy metabolism.

Previous studies have shown that Ca2+ channel antagonists in all chemical classes can inhibit Na(+)-induced CA2+ release from mitochondria. The effects of R023-6152, a new thiazepinone Ca2+ channel antagonist, on isolated rabbit heart mitochondrial Ca2+ transport and respiratory activity were compared with those of diltiazem. Heart mitochondria were also isolated and assayed from dogs treated in vivo with either R023-6152 or diltiazem. The results indicate that R023-6152 produces half-maximal inhibition of Na(+)-induced Ca2+ release from isolated mitochondria at relatively the same concentrations (10-30 microM) as diltiazem but also produces inhibition of mitochondrial Ca2+ uptake and state 3 respiration at concentrations (25-100 microM), at which diltiazem has no effect. The greater lipophilicity of R023-6152 in gaining access to and inhibiting the phosphate transporter in the mitochondrial membrane as compared with that of diltiazem may explain these results. Heart mitochondria isolated from dogs treated with diltiazem and R023-6152 exhibited lower rates of state 3 respiration as compared with controls. We suggest that this may result from a reduction in transsarcolemmal Ca2+ flux causing a down-regulation in mitochondrial dehydrogenase activity and not from any direct intracellular effects of the two drugs.

Animals↗

PubMed1991

In vivo inhibition of platelet aggregation and occlusive coronary thrombus formation by a new calcium antagonist (R023-6152).

Reports have shown that all three major classes of calcium antagonists can inhibit platelet aggregation in vitro. In this study, we compared the platelet antiaggregatory effects of R023-6152, a thiazepinone-type calcium antagonist, with diltiazem in an in vivo canine model of spontaneous coronary thrombosis. Plasma serotonin (5-HT) levels measured in the coronary sinus were used as an index of in vivo platelet aggregation and coronary flow measured by a Doppler flow probe. Untreated controls developed total coronary occlusion in 62 +/- 18 min after the current used to initiate thrombus formation was discontinued. Control 5-HT levels peaked at 213 +/- 63 ng/ml just before occlusion. Dogs receiving intravenous (i.v.) R023-6152 (200 micrograms/kg) or diltiazem (50 micrograms/kg) immediately after the current was discontinued exhibited no significant elevations in 5-HT values (12.3 +/- 1.4 and 1.84 +/- 0.42 ng/ml for R023-6152 and diltiazem, respectively) or development of coronary occlusions in the next 3 h. Small, transient decreases in arterial pressure (8-10 mm Hg) and changes in contractility occurred during infusion of both drugs. Gravimetric determinations of thrombus weights showed significantly smaller thrombi in the drug-treated animals as compared with controls. The results indicate that both R023-6152 and diltiazem are effective in suppressing in vivo platelet aggregation associated with occlusive coronary thrombus formation.

Animals↗

PubMed1991

ATP-sensitive Na(+)-H+ antiport in type II alveolar epithelial cells.

Type II alveolar epithelial cells in suspension have been previously shown to possess a Na(+)-H+ antiporter that modulates recovery from an intracellular acid load in the nominal absence of HCO-3 [E. Nord, S. Brown, and E. Crandall. Am. J. Physiol. 252 (Cell Physiol. 21): C490-C498, 1987]. Such a Na(+)-dependent mechanism has also been demonstrated in cultured type II cell monolayers (K. Sano et al. Biochim. Biophys. Acta 939: 449-458, 1988). It has recently been suggested that cultured type II cells possess a H(+)-ATPase that contributes to recovery from an intracellular acid load [R. Lubman, S. Danto, and E. Crandall. Am. J. Physiol. 257 (Lung Cell. Mol. Physiol. 1): L438-L445, 1989]. The present study was undertaken to investigate and characterize the mechanisms by which cultured type II cells recover from an intracellular acid load in the nominal absence of HCO-3. Cultured type II cell monolayers were loaded with the pH-sensitive probe 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, and the characteristics of recovery from an imposed intracellular acid load were studied. Recovery of intracellular pH (pHi) was found to be strictly Na(+)-dependent and inhibited greater than or equal to 95% by 1 mM amiloride. Initial rate of recovery was highly sensitive to pHi, with recovery rates varying inversely with increasing pHi. An acidic extracellular pH (6.5) abolished pHi recovery. Treatment of type II cells with either the sulfhydryl reagent N-ethylmaleimide, a nonspecific sulfhydryl reagent, or 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, a specific vacuolar H(+)-ATPase inhibitor at the concentration tested, resulted in marginal but not statistically significant decrements in pHi recovery. Intracellular ATP depletion, using KCN or replacement of glucose by a nonmetabolizable glucose analogue, reduced pHi recovery by 70-75% relative to control values. Sensitivity to ATP was apparent even under conditions that preserved the transmembrane Na+ gradient. Taken together, these data are most consistent with a single mechanism for pHi recovery in the absence of HCO3-. We interpret this mechanism to be an ATP-sensitive Na(+)-H+ antiporter that acts to reestablish pHi in type II alveolar epithelial cells.

Adenosine Triphosphate↗

PubMed1991

Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.

To assess the contribution of Factor IX/IXa, to intravascular thrombosis, a canine coronary thrombosis model was studied. Thrombus formation was initiated by applying current to a needle in the circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycyl-arginyl-Factor IXa (IXai), a competitive inhibitor of Factor IXa assembly into the intrinsic Factor X activation complex, bovine Factor IX, or heparin. Animals receiving saline or Factor IX developed coronary occlusion due to a fibrin/platelet thrombus in 70 +/- 11 min. In contrast, infusion of IXai prevented thrombus formation completely (greater than 180 min) at doses of 460 and 300 micrograms/kg, and partially blocked thrombus formation at 150 micrograms/kg. IXai attenuated the accumulation of 125I-fibrinogen/fibrin at the site of the thrombus by approximately 67% (P less than 0.001) and resulted in approximately 26% decrease in serotonin release from platelets in coronary sinus (P less than 0.05). Hemostatic variables in animals receiving IXai, remained within normal limits. Animals given heparin in a concentration sufficient to prevent occlusive thrombosis had markedly increased bleeding, whereas heparin levels that maintained extravascular hemostasis did not prevent intracoronary thrombosis. This suggests that Factor IX/IXa can contribute to thrombus formation, and that inhibition of IXa participation in the clotting mechanism blocks intravascular thrombosis without impairing extravascular hemostasis.

Animals↗

PubMed1990

The Enzymatic Synthesis of Rubber Polymer in Parthenium argentatum Gray.

Washed rubber particles isolated from stem homogenates of Parthenium argentatum Gray by ultracentrifugation and gel filtration on columns of LKB Ultrogel AcA34 contain rubber transferase which catalyzes the polymerization of isopentenyl pyrophosphate into rubber polymer. The polymerization reaction requires Mg(2+) isopentenyl pyrophosphate, and an allylic pyrophosphate. The K(m) values for Mg(2+), isopentenyl pyrophosphate, and dimethylallyl pyrophosphate were 5.2 x 10(-4) molar, 8.3 x 10(-5) molar, and 9.6 x 10(-5) molar, respectively. The molecular characteristics of the rubber polymer synthesized from [(14)C]isopentenyl pyrophosphate were examined by gel permeation chromatography on three linear columns of 1 x 10(6) to 500 Angstroms Ultrastyragel in a Waters 150C Gel Permeation Chromatograph. The peak molecular weight of the radioactive polymer increased from 70,000 in 15 minutes to 750,000 in 3 hours. The weight average molecular weight of the polymer synthesized over a 3 hour period was 1.17 x 10(6) compared to 1.49 x 10(6) for the natural rubber polymer extracted from the rubber particles. Over 90% of the in vitro formation of the rubber polymer was de novo from dimethylallyl pyrophosphate and isopentenyl pyrophosphate. Treatment of the washed rubber particles with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate solubilized the rubber transferase. The solubilized enzyme(s) catalyzed the polymerization of isopentenyl pyrophosphate into rubber polymer with a peak molecular weight of 1 x 10(5) after 3 hours of incubation with Mg(2+) and dimethylallyl pyrophosphate. The data support the conclusion that the soluble preparation of rubber transferase is capable of catalyzing the formation of a high molecular weight rubber polymer from an allylic pyrophosphate initiator and isopentenyl pyrophosphate monomer.

Journal Article↗

PubMed1990

Effects of benazeprilat on left ventricular systolic and diastolic function and neurohumoral status in patients with ischemic heart disease.

The effects of the intravenous administration of the angiotensin converting enzyme inhibitor benazeprilat on left ventricular function were examined in 18 patients with ischemic heart disease. Twenty minutes after drug infusion (0.3-10 mg), heart rate (78 +/- 17 to 71 +/- 16 beats/min, p less than 0.0003), left ventricular systolic pressure (-9 mm Hg, p less than 0.0004), and plasma norepinephrine concentration all decreased significantly. The isovolumic indexes of inotropic state also decreased slightly (-10% in dP/dtmax, p less than 0.001), whereas the ejection fraction (39 +/- 16% to 41 +/- 16%, p less than 0.08) and the end-systolic volume (-6%, p less than 0.04) tended to improve, probably because of the afterload reduction (-13% in mean systolic wall stress, p less than 0.05). After benazeprilat administration, the left ventricular end-diastolic pressure was unchanged at the group level, but there was a consistent downward shift of the diastolic pressure-volume relation during rapid filling, and the mean diastolic wall stress decreased from 99 +/- 73 to 69 +/- 42 kdyne/cm2 (p less than 0.007). These data indicate that the acute administration of benazeprilat has a dual action on left ventricular pump function, which is that the negative inotropic effect of bradycardia and reduced sympathetic drive are compensated by afterload reduction. The drug also improved left ventricular diastolic distensibility and significantly reduced wall stress during diastole. The beneficial effects on diastolic function were noted both in patients with mild left ventricular dysfunction and in patients with heart failure.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

Stimulation of Isopentenyl Pyrophosphate Incorporation into Polyisoprene in Extracts from Guayule Plants (Parthenium argentatum Gray) by Low Temperature and 2-(3,4-Dichlorophenoxy) Triethylamine.

Rubber particles isolated from guayule (Parthenium argentatum Gray) stem homogenates contain a polyprenyl transferase which catalyzes the polymerization of isopentenyl pyrophosphate into polyisoprene. The polymerization reaction is stimulated with the addition of an allylic pyrophosphate initiator and forms a polymer of polyisoprene with a molecular weight distribution from 10(3) to 10(7). The polymerization reaction in crude stem homogenates is not affected by the addition of an initiator probably due to the high activity of isopentenyl pyrophosphate isomerase furnishing saturating levels of dimethylallyl pyrophosphate. Polyisoprene formation in stems of guayule plants exposed to cold winter temperatures increased from 15.4 milligrams per gram dry weight in October to 24.5 milligrams per gram dry weight in January and increased from 16.2 to 38.1 milligrams per gram dry weight in the same period by additionally treating the plants with 5000 ppm of 2-(3,4-dichlorophenoxy)triethylamine. The rate of polymerization of isopentenyl pyrophosphate into polyisoprene in stem homogenates of the cold treated plants increased from 12.1 nanomoles per hour per gram fresh weight in October to 144.3 nanomoles per hour per gram fresh weight in January and increased from 17.7 to 446.8 nanomoles per hour per gram fresh weight in the same period by additionally treating the plants with 5000 ppm of 2-(3,4-dichlorophenoxy)triethylamine. These results show that the increase in polyprenyl transferase activity partially accounts for the increase in polyisoprene synthesis in guayule plants exposed to low temperature and treated with 2-(3,4-dichlorophenoxy)triethylamine.

Journal Article↗

PubMed1989

Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology.

Serotonin is released by activated platelets and may act as a mediator to initiate or sustain certain unstable syndromes of ischemic heart disease in humans. To determine whether or not serotonin concentration increases across the coronary bed in patients with severe, limiting angina, we measured central aortic and coronary sinus serotonin concentrations by a sensitive radioenzymatic assay in 39 patients with coronary artery disease and 13 patients with minimal or no coronary artery lesions as detected by arteriography. Although no difference existed in the mean aortic or coronary sinus serotonin concentrations between these two groups, elevated coronary sinus serotonin concentrations were detected in 23% of those with coronary artery disease. The coronary sinus and aortic serotonin concentration difference was greater in patients with significant coronary artery disease (0.6 +/- 6.62 ng/ml) compared with patients without significant coronary artery disease (-5.6 +/- 10.32 ng/ml) (mean +/- SD) (p less than 0.05). Further analysis revealed that patients with eccentric, irregular coronary artery lesions or intraluminal filling defects had a significantly elevated coronary sinus and aortic serotonin difference (3.1 +/- 5.54 ng/ml) compared with those with smooth concentric lesions (-1.9 +/- 6.61 ng/ml) (p less than 0.02). These data suggest that serotonin is released into the coronary circulation of some patients with coronary artery disease, especially those with frequent angina and complex coronary lesions. Although serotonin may be released in some patients with coronary artery disease, the specific pathophysiologic role of serotonin in the development or perpetuation of certain coronary syndromes in humans remains to be determined.

Aged↗