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Biomedical subjects

A S Wechsler

Publications and source records attributed to A S Wechsler.

At least 19 recordsLinked to original sources
PubMed1996

Salbutamol changes the molecular and mechanical properties of canine skeletal muscle.

1. Salbutamol, a beta 2-agonist, increased the weight of the canine latissimus dorsi muscle. It also increased fusion frequency, and decreased time-to-peak tension, half-relaxation time, and total contraction time. These changes in twitch times and fusion frequency were associated with changes in the levels of proteins expressed in slow- and fast-twitch fibres. Salbutamol decreased the levels of the slow-twitch cardiac isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban proteins, and increased the level of the fast-twitch isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA1a). 2. Changes in the levels of SERCA proteins, particularly SERCA1a, could account for most of the increases in calcium uptake rate observed in homogenates of muscles from the salbutamol-treated animals and could partially account for the changes in half-relaxation rates and other twitch times. 3. Changes in the levels of SERCA1a, SERCA2a and phospholamban protein did not always follow changes in the levels of their corresponding mRNAs. Divergence depended upon the SERCA isoform and muscle. The muscles studied were latissimus dorsi and vastus intermedius. 4. Salbutamol did not change the level of myosin heavy chain (HC)-I isoforms in either muscle, suggesting that it did not increase the proportion of slow-twitch fibres in these muscles. It did increase the level of HC-IIx and decrease the level of HC-IIa isoforms in the latissimus dorsi. Salbutamol did not produce these effects in the vastus intermedius. It is of particular interest that salbutamol changed the relative levels of SERCA proteins in the latissimus dorsi muscle without producing significant change in the level of HC-I isoform.

Adrenergic beta-2 Receptor Agonists↗
PubMed1996

Salbutamol and chronic low-frequency stimulation of canine skeletal muscle.

1. The effect of simultaneous application of chronic muscle stimulation and salbutamol on the expression of mRNAs and proteins normally expressed by fast- or slow-twitch fibres was followed and the effects of changes in protein expression on mechanical performance were evaluated. Chronic low-frequency stimulation increased the myosin heavy chain (HC)-I level in the canine latissimus dorsi muscle and simultaneous administration of salbutamol partially blocked this change. Associated with the increase in HC-I level was a decrease in the velocity of shortening at zero load, VMAX. The change in VMAX was partially blocked by salbutamol. 2. Chronic low-frequency stimulation increased the levels of slow-twitch cardiac isoform sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban mRNA, and SERCA2a and phospholamban protein expression. These changes were associated with an increase in time-to-peak tension and a decrease in fusion frequency. Simultaneous administration of salbutamol blocked these changes in protein expression and muscle mechanics. Chronic stimulation of latissimus dorsi decreased the levels of the fast-twitch isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA1a) and increased SERCA2a protein expression and decreased calcium uptake rate by muscle homogenates. These changes were blocked by salbutamol. 3. The loss of latissimus dorsi muscle weight by chronic stimulation was partially blocked by salbutamol.

Adrenergic beta-Agonists↗
PubMed1996

Pulmonary artery endothelial cell function in swine pseudomonas sepsis.

A substantial increase in pulmonary vascular resistance is associated with sepsis and its sequelae (sepsis syndrome and septic shock). It is postulated that increased resistance may result from sepsis-induced endothelial cell injury or altered vasoreactivity secondary to pulmonary hypertension. We, therefore, tested the hypothesis that sepsis causes endothelial cell injury and that increased pulmonary pressure alters vascular reactivity. Young swine (15-25 kg) were anesthetized and ventilated. Septic animals received a 1-hr infusion of live Pseudomonas aeruginosa (n = 11), and the control cohort received 0.9% NaCl (n = 7). All animals were studied for 300 min following the infusion. Postmortem branches of peripheral pulmonary arteries were prepared and tested in a vessel myograph. Ring segments were set to 90% of the circumference the vessels would have at pressures of 20, 30, 40, or 50 mmHg (L90), corresponding to varying pulmonary pressures observed in sepsis. A high dose of potassium was used to obtain maximum possible contraction. Prostaglandin was used to precontract the vessels before testing endothelial cell responses to acetylcholine or bradykinin. Sodium nitroprusside was added at the end of each experiment to obtain maximum possible smooth muscle relaxation. No differences in contraction or relaxation were observed when vessels were set to different pressures (i.e., 20 vs 50 mmHg). Maximum possible contraction to KCl was significantly decreased after 300 min of sepsis compared to control. No differences between groups were found in contractility to prostaglandin. Bradykinin-induced EDRF/NO production, mediated by BK2 receptors, was not altered in Pseudomonas sepsis (97-98% of total relaxation control and 91-95% septic cohort). Response to acetylcholine was significantly decreased after sepsis (89-95% of total relaxation control and 51-61% of septic cohort relaxation). Decreased response to acetylcholine could not be attributed to decreased smooth muscle sensitivity to nitric oxide because the response to bradykinin plus sodium nitroprusside was not altered following sepsis. Vessel reactivity was not altered by increasing pressure settings reflective of changing pulmonary pressure in vivo. These results strongly suggest a sepsis-induced alteration in pulmonary artery endothelial cell receptor sensitivity to acetylcholine, independent of changing pulmonary arterial pressures. This is the first time this decrease has been shown in pseudomonas sepsis.

Animals↗
PubMed1996

Neonatal myocardial oxygen consumption during ventricular fibrillation, hypothermia, and potassium arrest.

BACKGROUND: Many investigators have examined oxygen consumption in adult heats under conditions that simulate those encountered during cardiac operations and those that approximate basal metabolism. Few studies, however, have addressed this issue in neonatal myocardium. METHODS: Hearts from 3- to 9-day-old piglets were studied in a blood-perfused isolated heart preparation in working, empty beating, fibrillating, potassium chloride-arrested (at 37 degree C and 15 degree C), and hypothermic (15 degree C) states. RESULTS: Oxygen consumption (expressed in milliliters of O2 per 100 g of ventricular tissue per minute; mean +/- standard deviation) was 6.69 +/- 1.91 for working hearts and fell to 3.19 +/- 1.08 for empty-beating hearts, 3.72 +/- 0.84 for fibrillating hearts, 1.30 +/- 0.34 for potassium-arrested hearts at 37 degree C, 0.37 +/- 0.18 for hypothermic (15 degree C) hearts, and 0.32 +/- 0.10 for potassium-arrested hearts at 15 degree C. All values were significantly different except the two obtained at 15 degree C. CONCLUSIONS: Vented fibrillating hearts used more oxygen than empty beating hearts. The addition of an arresting concentration of KCl did not lower oxygen consumption below that observed with hypothermia alone at 15 degree C. If potassium-based cardioplegia is incrementally beneficial in neonatal myocardial protection over that afforded by hypothermia alone, its effects cannot be explained by reduction in oxygen demand.

Animals↗
PubMed1996

Reactivity to alpha agonists is heightened in immature porcine pulmonary arteries.

BACKGROUND: Pulmonary hypertension after cardiopulmonary bypass is a common problem in pediatric cardiac operations. This study tested the hypothesis that there is a difference between adult and immature pulmonary artery constrictor and dilator responses. METHODS: Reactivity of pulmonary artery ring segments from 22 mature (15 to 19 weeks) and 15 immature pigs (4 to 5 weeks) was tested in a vessel myograph. Potassium as a receptor-independent vasoconstrictor and phenylephrine as an alpha-receptor-mediated vasoconstrictor were used to assess smooth-muscle vasoconstriction. To assess endothelial cell function (nitric oxide production and secretion), we used increasing concentrations of bradykinin or acetylcholine. Sodium nitroprusside was used to produce maximum smooth-muscle relaxation at the end of each experiment. RESULTS: The data demonstrated maturation-independent endothelium and smooth-muscle-mediated vasodilation. Pulmonary artery ring segments from immature pigs had significantly less KCl constriction compared with mature pigs (p < 0.05). In contrast, pulmonary ring segments from immature pigs demonstrated enhanced alpha-receptor-mediated constriction compared with mature pigs. CONCLUSIONS: These data may explain perioperative pulmonary vasoconstriction in pediatric patients.

Adrenergic alpha-Agonists↗
PubMed1995

Transcriptional regulation of phospholamban gene and translational regulation of SERCA2 gene produces coordinate expression of these two sarcoplasmic reticulum proteins during skeletal muscle phenotype switching.

Chronic 1 Hz stimulation of the canine latissimus dorsi muscle produced a time-dependent switch from the fast-twitch to the slow-twitch phenotype. This included changes in the proteins of the sarcoplasmic reticulum. After 3 days of muscle stimulation, there was down-regulation of fast-twitch Ca-ATPase (SERCA1a) mRNA and induction of slow-twitch Ca-ATPase (SERCA2a) mRNA; most changes in both mRNAs were nearly complete after 14 days of stimulation. Although the induction of phospholamban mRNA began after 3 days of muscle stimulation, its up-regulation was not completed until the muscle had been stimulated for 42 days. The time course of expression of SERCA2a protein was very different from that of SERCA2a mRNA, suggesting that SERCA2 gene expression is regulated at the translational as well as the transcriptional level. The time course of expression of phospholamban protein closely followed that of phospholamban mRNA, suggesting that this gene is under transcriptional control. Thus coordinated expression of SERCA2a and phospholamban proteins is achieved via translational control of the SERCA2 gene and transcriptional control of the phospholamban gene.

Adenosine Triphosphatases↗
PubMed1995

Clinical experience with nonthoracotomy cardioverter defibrillators.

A new generation of defibrillators has been introduced that do not require a thoracotomy. The purpose of this report was to examine 100 consecutive nonthoracotomy implantations at our institution and compare them with a series of 102 patients undergoing thoracotomy implantations by the same surgeon over a 4-year period between August 1989 and September 1994. The two groups were comparable for age, sex, comorbidity, cardiac disease status, ejection fraction, and electrophysiologic presentation. Nonthoracotomy systems were implanted successfully in 94% of patients. Patients undergoing a nonthoracotomy implantation had significantly shorter intensive care unit (1.7 +/- 1.7 versus 3.3 +/- 3.9 days; p < 0.005) and postoperative stays (5.0 +/- 2.8 versus 9.5 +/- 5.6 days; p < 0.001) than patients undergoing a thoracotomy approach. This was due to a significant decrease in the incidence of postoperative complications from 29% in the thoracotomy group to 11% in the nonthoracotomy group (p < 0.001). There was no significant difference in overall mortality rates. Nonthoracotomy systems are implantable in the majority of patients and are associated with less morbidity and shorter hospital stays than traditional thoracotomy approaches.

Cardiac Pacing, Artificial↗
PubMed1995

Is there an alternative to potassium arrest?

BACKGROUND: Mounting clinical and experimental evidence suggests that postoperative myocardial dysfunction is a frequent consequence of surgical global ischemia and reperfusion, despite our modern techniques of myocardial protection. The ubiquitous use of hyperkalemic depolarizing solutions in all forms of cardioplegia may be partly responsible for this phenomenon because of the known ongoing metabolic processes and damaging transmembrane ionic fluxes that occur at depolarized membrane potentials. Cardiac arrest at hyperpolarized potentials, the natural resting state of the heart, may avoid the shortcomings of depolarized arrest and provide an alternative means of myocardial protection. METHODS: An adenosine triphosphate-sensitive potassium channel opener, aprikalim, was used to induce hyperpolarized arrest. Aprikalim was able to produce sustained and reproducible electromechanical arrest that was reversible by reperfusion. RESULTS: In isolated heart models, when compared with depolarized hyperkalemic arrest, hyperpolarized arrest afforded better protection from global normothermic ischemia and resulted in better postischemic recovery of function upon reperfusion. Preliminary studies in a porcine cardiopulmonary bypass model also have revealed that hyperpolarized arrest can be achieved in a model more closely approximating the clinical setting, and can effectively protect the heart during normothermic surgical global ischemia. CONCLUSIONS: Hyperpolarized cardiac arrest may offer an effective alternative to traditional potassium arrest.

Animals↗
PubMed1995

Hyperpolarized cardiac arrest with a potassium-channel opener, aprikalim.

Cardioplegic solutions that arrest the heart at or near the resting membrane potential may provide better myocardial protection than standard depolarizing hyperkalemic cardioplegia by reducing both metabolic demand and harmful transmembrane ion fluxes. This hypothesis was investigated in an isolated, blood-perfused, rabbit heart Langendorff model during 30 minutes of normothermic global ischemia. Hyperpolarized cardiac arrest induced by aprikalim, an opener of adenosine triphosphate-dependent potassium channels, was compared with hyperkalemic depolarized arrest and with unprotected global ischemia. Left ventricular pressure was recorded over a wide range of balloon volumes before ischemia and 30 minutes after reperfusion. End-diastolic pressure versus balloon volume data were fitted to a two-coefficient exponential relationship. Changes in the diastolic compliance of the left ventricle were assessed by comparison of preischemic and postischemic coefficients within each cardioplegia group. Postischemic recovery of developed pressure was used to assess changes in left ventricular systolic function. The tissue water content of each heart was also determined. Myocardial protection with aprikalim resulted in better postischemic recovery of developed pressure (90% +/- 9%) than either protection with hyperkalemic cardioplegia (73% +/- 11%) or no protection (62% +/- 9%). Myocardial tissue water content in hearts protected with hyperkalemic cardioplegia (77.4% +/- 1.4%) was less than the tissue water content of either unprotected hearts (79.4% +/- 1.2%) or hearts protected with aprikalim (78.7% +/- 0.9%). Despite these differences, neither hyperkalemic cardioplegia (p = 0.15) nor aprikalim cardioplegia (p = 0.30) was associated with a significant postischemic decrease in ventricular compliance. By contrast, unprotected global ischemia was associated with a significant decrease in ventricular compliance (p < 0.001).

Adenosine Triphosphate↗
PubMed1995

Intermittent aortic crossclamping prevents cumulative adenosine triphosphate depletion, ventricular fibrillation, and dysfunction (stunning): is it preconditioning?

This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocardium becomes preconditioned after the first episode of ischemia in canine models in vivo. The role of adenosine triphosphate catabolism and subsequent release of purines on reperfusion-mediated postischemic ventricular dysfunction and arrhythmias was assessed with the use of selective inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBMPR), and a specific adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA). Thirty-two anesthetized dogs were instrumented to monitor left ventricular contractility, off bypass, by sonomicrometry. During cardiopulmonary bypass dogs were treated before ischemia with either saline solution (control group, n = 8) or EHNA (100 mumol/L) and NBMPR (25 mumol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of reperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of adenosine triphosphate and induced reperfusion-mediated ventricular fibrillation and severe left ventricular dysfunction in the control group. EHNA/NBMPR treatment augmented myocardial adenosine trapping during ischemia, attenuated ventricular fibrillation, and enhanced left ventricular functional recovery, despite similar depletion of adenosine triphosphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant adenosine triphosphate depletion, ventricular fibrillation, and left ventricular stunning in both control and drug-treated groups. The prevalence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0.05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group (p < 0.05 versus control). Subsequent episodes of ischemia prevented ventricular fibrillation and did not cause cumulative left ventricular stunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adenosine triphosphate, limited purine release, and prevented ventricular fibrillation and cumulative stunning. These results suggest that intermittent ischemia and reperfusion augmented the endogenous protective mechanism or mechanisms of "preconditioning." Nucleoside trapping improved functional recovery after sustained or repetitive ischemia. It is concluded that adenosine triphosphate preservation or blockade of nucleoside transport may play an important role in the activation of endogenous myocardial protective mechanisms that "precondition" against subsequent ischemic stress.

Adenine↗
PubMed1995

Microvascular dysfunction after myocardial ischemia.

Endothelium-mediated relaxation and smooth muscle function in large coronary arteries are resistant to prolonged global ischemia. We used a small-vessel myograph to test the hypothesis that small intramyocardial artery endothelium and smooth muscle function have greater sensitivity to ischemic injury than large artery endothelium and smooth muscle. Normothermic global ischemia was induced in 15 porcine hearts. Intramyocardial arterial ring segments were assessed at 0, 30, 60, 90, and 120 minutes of ischemia in vitro with a small-vessel myograph. Potassium determined smooth muscle contraction, bradykinin endothelium-mediated relaxation, and sodium nitroprusside direct smooth muscle relaxation. Endothelium-mediated relaxation after 30 minutes of ischemia was similar to control (56% versus 66%) but was impaired at 60, 90, and 120 minutes of ischemia (32%, 11%, and 6%). Smooth muscle contraction was unchanged at 30 and 60 minutes compared with control (56 and 53 versus 63 mm Hg) but was significantly decreased at 90 and 120 minutes (33 and 13 mm Hg). Direct smooth muscle relaxation was significantly decreased at 120 minutes of ischemia compared with control (58% versus 95%). In a previous study, epicardial coronary artery endothelium-mediated smooth muscle vasodilation and direct smooth muscle vasodilation were preserved until 160 minutes of ischemia. After 160 minutes of ischemia, endothelium-mediated relaxation was lost and only direct smooth muscle vasodilation was preserved. In contrast to vasodilation, vasoconstriction was significantly reduced at 140 minutes of ischemia. These data indicate a greater and earlier adverse effect of ischemia on intramyocardial arterial endothelium-mediated relaxation than smooth muscle contraction or relaxation. These data support the hypothesis that there is an early functional endothelial cell injury associated with global ischemia. Relaxation that is endothelium-dependent in intramyocardial arteries is more sensitive to ischemic injury than in epicardial arteries. Unique to this study was the evaluation of small intramyocardial arteries (281 +/- 29 microns) that are the primary sites of coronary vascular resistance. Microvascular endothelial dysfunction after ischemia, therefore, may contribute to the "no-reflow phenomenon" seen during reperfusion injury.

Animals↗
PubMed1995

Myocardial preconditioning: a model or a phenomenon?

A brief ischemic episode (ischemic preconditioning) limits myocardial necrosis produced by a prolonged period of coronary artery occlusion and reperfusion. In absence of infarction, lack of cumulative ATP depletion, and ventricular arrhythmias and dysfunction "stunning" in models of intermittent ischemia and reperfusion also could be a component of an adaptive response to brief ischemia (preconditioning). Nonischemic stimuli also precondition the myocardium against ventricular arrhythmias and infarction by activating endogenous mechanism(s) of protection similar to that induced by ischemic preconditioning. Preservation of myocardial ATP, abolishing purine release, attenuation of free radical production, activation of adenosine receptors and KATP channels, and induction of heat shock proteins are common responses to ischemic and nonischemic stimuli of preconditioning. Although a significant reduction in myocardial infarction is critical to myocardial salvage and patient survival, it is equally important to have a functioning heart that can sustain systemic pressure without inotropic support or assist devices. It is scientifically challenging and clinically important to elucidate the mechanisms of myocardial preconditioning. However, it is necessary to expand the definition of myocardial preconditioning to include nonischemic stimuli of preconditioning and other important monitors of myocardial protection such as ventricular function and electrophysiological stability in addition to that of infarction.

Adenosine Triphosphate↗
PubMed1994

Induction of IL-8 expression in T cells uses the CD28 costimulatory pathway.

IL-8, a potent chemotactic factor for neutrophil granulocytes and lymphocytes, is a proinflammatory cytokine secreted by a variety of cell types, including T cells. Stimulation of the CD28 cell surface molecule delivers costimulatory signals essential for lymphokine production in activated T cells via a conserved sequence element found in the promoter of several lymphokine genes. Anti-CD28-stimulated T cells produced significant amounts of IL-8; additionally, costimulation with anti-CD3 and anti-CD28 Abs resulted in a synergistic induction of IL-8 secretion. Sequence homology, single nucleotide mutations, and anti-CD28 Ab stimulation studies established that the NF-kappa B-like sequence in the promoter of the IL-8 gene functioned as a CD28 response element. Furthermore, cyclosporin A, but not rapamycin, blocked the synergistic induction of IL-8 expression achieved with anti-CD3 and anti-CD28 costimulation. The involvement of a CD28 response element in the induction of IL-8 expression in activated T cells may provide new insights into the pathogenesis and persistence of immune disorders characterized by increased levels of IL-8, such as psoriasis and rheumatoid arthritis.

Base Sequence↗
PubMed1994

Early gene changes in myocardial ischemia.

After certain periods of myocardial ischemia and reperfusion, cardiac dysfunction exists in the absence of myonecrosis. In a blood-perfused isolated rat heart model, we have demonstrated early gene changes that are associated with global myocardial "stunning." Early gene changes included elevations in the expression of messenger RNAs for HSP70, c-myc and c-fos. Increased expression of messenger RNAs for protooncogenes is an important observation because of the role of protooncogenes as nuclear transcription factors. From these study findings, it would appear that the stunning state is associated with early gene changes that may signal the induction of a hypertrophic process. Subsequent studies are required to demonstrate the exact events which take place in the course of stunning that directly initiate an alteration in gene expression.

Animals↗
PubMed1994

Effect of triiodothyronine on postischemic myocardial function in the isolated heart.

Thyroid dysfunction has been shown to have a significant impact on hemodynamic status and cardiac function. The purpose of this study was to determine the influence of triiodothyronine (T3) on cardiac functional recovery after ischemia in a dose-dependent manner. Postischemic functional recovery was assessed in isolated rabbit hearts mounted in a modified Langendorff preparation. Left ventricular systolic, diastolic, and peak developed pressures were measured before and after ischemia, and calculated as a percentage of preischemic function. Two cohorts of hearts were studied: the first was exposed to warm ischemia until a myocardial contracture of 4 mmHg was produced; the second cohort was exposed to warm ischemia until a contracture of 15 mm Hg was observed. In each cohort, T3 was added to the perfusion solution after ischemia in a physiologic concentration (2.5 x 10(-9) g/mL; 1 x T3), as well as ten times (2.5 x 10(-8) g/mL; 10 x T3) and a hundred times (2.5 x 10(-7) g/mL; 100 x T3) the physiologic concentration. One group, given the carrier only but without T3, served as the control. Rabbit hearts exposed to a short period of ischemia (4-mmHg diastolic contracture) showed increased recovery with 1 x T3 and 10 x T3. 100 x T3 did not bring about improved left ventricular recovery versus that in the control group. Rabbit hearts in the 15 mm Hg-diastolic contracture cohort showed increased recovery with 10 x T3 but not with 1 x T3. 100 x T3 led to decreased recovery in this cohort versus that in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗