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S M Hollenberg

Publications and source records attributed to S M Hollenberg.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice.

Persistent vasodilation refractory to vasopressor agents is characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines within the vasculature is one of the primary mediators of this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure microvascular vasoconstrictive responses to topical suffusion of norepinephrine in mice made septic by cecal ligation and puncture, and contrasted the effects of topical superfusion of the nonselective NOS inhibitor N(G)-methyl-L-arginine (L-NMMA) and the selective inducible NOS (iNOS) inhibitor S-methyl-isothiourea (SMT). Mice with sepsis were less sensitive to the vasoconstrictive effects of norepinephrine than controls (EC50, the concentration that produces half-maximal response 2.0+/-0.6 x 10(-6) M vs. 7.9+/-2.2 x 10(-8) M, P=0.01). Selective inhibition of inducible iNOS with topical SMT (100 microM) markedly increased catecholamine reactivity in mice with sepsis but did not affect reactivity in controls (P=0.0007 for sepsis, P=0.24 for controls). Nonselective NOS inhibition with topical L-NMMA produced a similar increase in catecholamine reactivity in mice with sepsis but not controls (P=0.001 for sepsis, P=0.56 for controls). When excess (1 mM) L-arginine, the substrate for NOS, was added to the superfusion buffer along with both SMT and L-NMMA, arteriolar responsiveness to norepinephrine was decreased to the original values. These experiments demonstrate that iNOS inhibition is as effective as nonselective NOS inhibition in reversing decreased catecholamine reactivity in sepsis. This suggests a crucial role for microvascular activation of iNOS in the pathophysiology of hypotension and decreased vasopressor responsiveness in sepsis.

Animals↗
PubMed1999

Preoperative cardiac risk assessment.

Preoperative cardiac evaluation is aimed at evaluating the patient's current medical status, making recommendations concerning the risk of cardiac problems in the perioperative period, and providing a clinical risk profile that the patient, primary physician, consultants, anesthesiologist, and surgeon can use in making treatment decisions. Patients can be stratified on clinical grounds into low-, medium-, and high-risk categories. Use of these categories, along with consideration of the type and urgency of noncardiac surgery, allows for a reasonable approach to preoperative testing. In general, indications for cardiac testing and treatment are similar to the nonoperative setting, but their choice and timing is dependent on factors specific to the patient, the type of surgery, and the clinical situation. Use of invasive and noninvasive testing should be limited to situations in which the results of the tests will clearly affect patient management. Further research is necessary to define the most appropriate role of such testing, both in terms of efficacy and of cost-effectiveness. Cardiac intervention is rarely necessary to lower the risk of surgery, but noncardiac surgery often represents the first opportunity for a patient to receive an appropriate assessment of short- and long-term cardiac risk, and this should be taken into consideration in planning perioperative evaluation.

Heart Diseases↗
PubMed1998

Discordant epicardial and microvascular endothelial responses in heart transplant recipients early after transplantation.

BACKGROUND: Cardiac allograft vasculopathy represents the leading cause of death in heart transplant recipients who survive more than 1 year. Functional endothelial abnormalities are sensitive measures of the early development of cardiac allograft vasculopathy, but the relative importance of large and small coronary vessel abnormalities has not been evaluated. The purpose of the study was to distinguish between large and small coronary endothelial dysfunction in patients early after heart transplantation and to test the hypothesis that microvascular endothelial responses can be preserved in the presence of epicardial endothelial dysfunction. METHODS: Changes in epicardial lumen area and coronary artery blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously by use of an intravascular ultrasound catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed distinction between large and small coronary vascular responses. In 19 patients studied early after transplantation, adenosine (16 and 32 microg), acetylcholine (5.4 and 54 microg), and nitroglycerin (200 microg) were infused, with continuous intravascular ultrasound imaging and Doppler velocity measurements. RESULTS: Acetylcholine induced paradoxical epicardial vasoconstriction in 12 of 19 patients (73% +/- 6% of baseline); vasodilation occurred in 7 (108% +/- 3%). In spite of this constriction, coronary artery flow increased in all 19 patients, to the same extent in patients with constriction and those with dilation (239 +/- 26 vs 193 +/- 20, p = 0.38). Adenosine and nitroglycerin increased area (107% +/- 1% and 112% +/- 3%) and flow (258% +/- 17% and 197% +/- 11%) in all patients. None of the area or flow responses correlated with the degree of intimal thickening. CONCLUSIONS: Acetylcholine increased coronary artery flow early after transplantation, indicating preserved microvascular responses in spite of epicardial vasoconstriction. Simultaneous measurement of area and velocity responses, by permitting evaluation of the relative contribution of epicardial and microvascular vessels, may offer unique insights into coronary endothelial function.

Acetylcholine↗
PubMed1997

Effect of coronary angioplasty on QT dispersion.

Increased QT dispersion (QTmax-QTmin [QTd]) reflects inhomogeneous ventricular repolarization that may provide a substrate for serious arrhythmias and is associated with adverse clinical outcomes in patients with heart disease. Effective treatment of acute myocardial infarction or ventricular arrhythmias may reduce QTd, but the effect of coronary revascularization on QTd in patients without these conditions is unknown. In this study, QTd was measured before and 4 and 24 hours after successful angioplasty in 94 patients without ongoing symptomatic myocardial ischemia or malignant arrhythmias. QTd decreased from 434 +/- 17 msec before angioplasty to 354 +/- 15 msec 4 hours (p < 0.05) and 33 +/- 14 msec 24 hours after angioplasty (p < 0.05). QTd was improved in 64% of patients, worse in 28%, and unchanged in 8%. Thus angioplasty significantly improves QTd. This may reflect increased myocardial perfusion and may be inherently beneficial by reducing the propensity for arrhythmias.

Aged↗
PubMed1997

Impaired microvascular vasoconstrictive responses to vasopressin in septic rats.

OBJECTIVE: To evaluate mechanisms of vasodilation in sepsis by comparing responses of resistance arterioles to vasopressin in rat cremaster muscle of septic and control rats. DESIGN: Prospective, experimental study. SETTING: Experimental animal laboratory. SUBJECTS: Twenty male rats, anesthetized with ketamine and acepromazine. INTERVENTIONS: Topical superfusion of vasoactive compounds on skeletal muscle resistance arterioles. MEASUREMENTS AND MAIN RESULTS: The effect of sepsis on responses to local application of vasopressin was investigated using in vivo videomicroscopy. Vasopressin was superfused topically on the cremaster muscle resistance arterioles (15 to 25 microns) of rats made septic by cecal ligation and puncture, and the responses were compared with the responses of controls that underwent sham ligation. Responses to topically suffused vasopressin were also assessed in septic and control rats, before and after superfusion of the muscle with the nitric oxide synthase inhibitor NG-methyl-L-arginine (NMA). Sepsis produced a decrease in the vasoconstrictive effects of vasopressin; the maximal response was lower, and the concentration-response curve was shifted to the right in septic rats (p < .05). Contractions at vasopressin concentrations of 0.01, 1, and 10 nM were 39%, 36%, and 40%, respectively, of sham controls. Superfusion of the muscle with NMA partially restored arteriolar responsiveness in the septic rats, significantly increasing the arteriolar constriction of the septic rats in response to vasopressin. This effect was reversed with superfusion of excess L-arginine (1 mM). CONCLUSIONS: This study illustrates the reduced responsiveness of the resistance arterioles of septic rats in response to vasopressin in vivo, and the partial restoration of responsiveness by concurrent application of NMA. In previous studies using this model, we have shown similar results using norepinephrine and endothelin-1, as well as angiotensin II. These findings, and the findings of this study, suggest a generalized abnormality in responsiveness of resistance arterioles to endogenous vasoconstrictors in sepsis. Partial reversal of this abnormality with NMA supports an important role for nitric oxide in mediating abnormal vasopressor responsiveness in sepsis.

Animals↗
PubMed1997

Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to endothelin-1 in septic rats.

Persistent vasodilation refractory to vasopressor agents is the hemodynamic abnormality characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines has been hypothesized to play a pathogenetic role in this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure responses of resistance arterioles (15-20 microm) to topical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), in rat cremaster muscle. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats before and after superfusion of the muscle with the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induced vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentrations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sham controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing arteriolar constriction at 1 and 10 nM. This effect was reversed with superfusion of excess L-arginine (1 mM). This study demonstrates that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition. Taken together with previous studies showing sepsis-induced impairment of vasoconstriction with norepinephrine, a vasopressor with a mechanism of action different from ET-1, these findings suggest a generalized abnormality in the responsiveness of resistance arterioles in sepsis. Reversal of hyporesponsiveness to both of these vasopressor agents by NOS inhibition suggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.

Animals↗
PubMed1997

Pulmonary artery catheters in cardiovascular disease.

OBJECTIVE: To review the literature addressing the use of the pulmonary artery catheter (PAC) in patients with cardiovascular disease. DATA SOURCE: All pertinent English language articles dealing with pulmonary artery catheterization in patients with cardiovascular disease were retrieved from 1976 through 1996. STUDY SELECTION: Articles were chosen for review if the use of pulmonary artery catheterization in patients with cardiovascular disease was studied or reviewed. DATA EXTRACTION: From the articles selected, information was obtained about changes in therapy and changes in outcome associated with PAC use in patients with cardiovascular disease. DATA SYNTHESIS: Whether enhanced understanding of patient hemodynamics translates into definable benefits for those patients has recently come into question. Although there are a number of conventional clinical indications for pulmonary artery catheterization, and several studies have shown that catheterization prompts changes in therapy in many patients, most data regarding outcomes are retrospective; prospective randomized trials are lacking. Nonetheless, we believe, based on the available evidence and the preponderance of expert opinion, that management with the PAC improves outcome in several patient populations. These populations include: a) patients with acute myocardial infarction either complicated by cardiogenic shock or progressive hypotension, or associated with mechanical complications; b) patients with congestive heart failure refractory to empiric therapy; c) patients with pulmonary hypertension; and d) patients with shock or hemodynamic instability. CONCLUSION: Pulmonary artery catheterization is often used to optimize patient management, although this may not be demonstrable in terms of prospective trials using mortality or other "hard" outcome measures. Nonetheless, more rapid diagnosis and achievement of therapeutic endpoints guided by PAC use can decrease morbidity and intensive care days.

Cardiovascular Diseases↗
PubMed1996

A positive genetic selection for disrupting protein-protein interactions: identification of CREB mutations that prevent association with the coactivator CBP.

The Escherichia coli tet-repressor (TetR) operator system was used to develop a variation of the yeast two-hybrid assay in which disruptions of protein-protein interactions can be identified by a positive selection. This assay, designated the "split-hybrid system," contains a two-component reporter. The first component contains LexA binding sites upstream of the TetR gene and the second contains TetR operator binding sites upstream of HIS3. Interaction of one protein fused to the LexA DNA binding domain with a second protein fused to the VP16 activation domain results in TetR expression. TetR subsequently binds to the tet operators, blocking the expression of HIS3 and preventing yeast growth in media lacking histidine. The utility of the split-hybrid system was analyzed by examining the phosphorylation-dependent interaction of CREB and its coactivator CREB binding protein (CBP). CREB and CBP associate through an interaction that depends upon CREB phosphorylation at Ser-133. Mutation of this phosphorylation site prevents yeast growth in the standard two-hybrid assay but allows growth in the split-hybrid strains. The split-hybrid system was used to identify other CREB mutations that disrupt its association with CBP. These mutations localized around the site of CREB phosphorylation, indicating that only a small portion of the CREB activation domain is required for CBP interaction. The yeast split-hybrid system should be useful in identifying mutations, proteins, peptides, and drugs that disrupt protein-protein interactions.

Amino Acid Sequence↗
PubMed1996

Cardiac endothelin release and infarct size, myocardial blood flow, and ventricular function in canine infarction and reperfusion.

BACKGROUND: The potent vasoconstrictor endothelin-1 (ET) may play an important pathophysiologic role in acute myocardial infarction, but its precise effects are incompletely understood. The purpose of this study was to evaluate the interrelationships between cardiac ET-1 release and infarct size, myocardial blood flow, and ventricular function. METHODS: Fifteen closed chest dogs underwent 3 hours of coronary artery occlusion followed by 3 hours of reperfusion. Coronary sinus and aortic ET-1 levels during occlusion and after reperfusion were determined by radioimmunoassay. Left ventricular function and regional myocardial blood flow were measured by echocardiography and colored microspheres, respectively. Myocardial infarct size was determined by postmortem staining with blue dye and triphenyl tetrazolium chloride. RESULTS: Coronary occlusion and reperfusion produced significant elevations of coronary sinus ET-1 (p < 0.05) and cardiac ET-1 release (p < 0.05), and a trend toward an increase in aortic ET-1 (p = 0.08). A trend toward more ET-1 release was observed in dogs with larger infarcts (p = 0.06), and in dogs with substantial no-reflow in the reperfused territory (p = 0.05). Endothelin-1 release also was associated with increased contractility in nonischemic myocardial segments (p = 0.002), and ET-1 correlated with increased global left ventricular function (p < 0.02). CONCLUSIONS: In this canine model of coronary occlusion and reperfusion, greater increases in cardiac ET-1 release were observed in dogs with larger infarcts, and increased ET-1 release was associated with the no-reflow phenomenon in the reperfused territory. These data suggest that ET-1 release may have adverse consequences in acute myocardial infarction, including a reduction of myocardial blood flow in the reperfused zone after reperfusion and increased contractility in nonischemic myocardium.

Animals↗
PubMed1995

Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein.

Basic helix-loop-helix (bHLH) proteins are instrumental in determining cell type during development. A bHLH protein, termed NeuroD, for neurogenic differentiation, has now been identified as a differentiation factor for neurogenesis because (i) it is expressed transiently in a subset of neurons in the central and peripheral nervous systems at the time of their terminal differentiation into mature neurons and (ii) ectopic expression of neuroD in Xenopus embryos causes premature differentiation of neuronal precursors. Furthermore, neuroD can convert presumptive epidermal cells into neurons and also act as a neuronal determination gene. However, unlike another previously identified proneural gene (XASH-3), neuroD seems competent to bypass the normal inhibitory influences that usually prevent neurogenesis in ventral and lateral ectoderm and is capable of converting most of the embryonic ectoderm into neurons. The data suggest that neuroD may participate in the terminal differentiation step during vertebrate neuronal development.

Amino Acid Sequence↗
PubMed1995

Ras-Raf interaction: two-hybrid analysis.

The identification of proteins mediating Ras effects, such as the serine/threonine kinases of the Raf family, has advanced our understanding of how signals are transmitted from the extracellular milieu to the nucleus. The modified two-hybrid system has proved to be a powerful tool for identifying specific protein interactions, such as those between Ras and Raf. We hope that the insight gained from the Ras screen, as well as insights from other two hybrid screens, will prove valuable in the application of this system to other enigmatic questions in biology.

Amino Acid Sequence↗
PubMed1995

Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system.

With modified two-hybrid technology, we have isolated a member of a new family of basic helix-loop-helix (bHLH) transcription factors. Thing1 (Th1) was identified in a screen of a mouse embryo cDNA library as a partner for the Drosophila E protein daughterless. RNA in situ hybridization and reverse transcriptase-PCR demonstrate a stage- and tissue-specific distribution for the expression of Th1. Although tissue specific, the expression pattern of Th1 is fairly complex. During development, Th1 mRNA is widely expressed in extraembryonic tissues, portions of the heart, autonomic ganglia, the gut, and pharyngeal arches. At embryonic day 7.5 (E7.5), extraembryonic derivatives show robust Th1 expression. By E8.5, expression in the embryonic heart becomes detectable. During the next 2 days of development, the signal also includes gut and pharyngeal arches. Predominant expression at E13.5 is in neural crest derivatives, especially the autonomic nervous system and adrenal medulla. Expression of Th1 persists in the adult, in which it is localized to the smooth muscle cells of the gut. In vitro, Th1 protein recognizes a set of DNA sites that are more degenerate than has been determined for other bHLH factors, indicating a reduced binding specificity. Transient transfection of NIH 3T3 cells with GAL4-Th1 fusions reveals a repression activity mediated by the Th1 bHLH domain. In combination, these properties define Th1 as a new bHLH protein with a unique set of properties.

Amino Acid Sequence↗
PubMed1994

Endothelial and vascular smooth muscle function in sepsis.

The vascular abnormalities that arise during sepsis imply disturbances in the delicately tuned homeostatic mechanisms of vascular endothelium and smooth muscle. In the microvasculature, smooth muscle tone represents a complex equilibrium among metabolic stimuli, hemodynamic forces, and neurohumoral influences. Local tissue perfusion also is modulated by vasoactive mediators that can be produced locally, through endothelium-dependent adhesion and activation of inflammatory cells, or at a distance. In sepsis, derangement of normal autoregulation of perfusion, together with toxic effects of mediators, may be severe enough to result in organ dysfunction. Recent advances in vascular biology have illuminated a variety of targets, such as adhesion molecules, platelet activating factor, and inducible nitric oxide synthase for potential therapeutic intervention in sepsis.

Endothelium, Vascular↗
PubMed1994

Eicosanoid production by human aortic endothelial cells in response to endothelin.

Endothelial cells actively regulate their environment by secreting humoral substances, including endothelin-1 and a variety of eicosanoids, that have local actions. To elucidate interactions among these local mediators, we measured release of cyclooxygenase and lipoxygenase pathway products of arachidonate metabolism by human aortic endothelial cells after incubation with endothelin-1. Supernatants were collected, extracted, and fractionated using high-performance liquid chromatography. Radioimmunoassays for eicosanoids were performed on the appropriate fractions. After endothelin stimulation, production of the prostacyclin metabolite 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the thromboxane (Tx) metabolite TxB2, and prostaglandin E2 (PGE2) were increased (307 +/- 48, 320 +/- 91, and 315 +/- 74% of control, P < 0.05). Leukotriene B4 (LTB4) release was modestly increased (195 +/- 19% of control, P < 0.05). The release of 5-hydroxyeicosatetraenoic acid (5-HETE) was increased (300 +/- 57% of control, P < 0.05); production of 12-HETE and 15-HETE was unchanged. Production of eicosanoids peaked between 30 and 120 min. Preincubation with pertussis toxin prevented increased production of PGE2, LTB4, and 5-HETE after endothelin-1 stimulation; pretreatment with sphingosine had no effect. Interactions between endothelin and eicosanoids may be important components of the complex network that regulates vascular tone, coagulation, and inflammation at the local level.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗