PubMed Health⌕ Search

Biomedical subjects

D T Engelman

Publications and source records attributed to D T Engelman.

At least 19 recordsLinked to original sources
PubMed2000

Preconditioning of swine heart with monophosphoryl lipid A improves myocardial preservation.

BACKGROUND: Ischemic preconditioning has been proven to be a powerful tool for myocardial protection in the setting of ischemia and reperfusion. A new drug to provide pharmacologic preconditioning, monophosphoryl lipid A (MLA), was administered 24 hours before an acute coronary occlusion in pigs to determine the effect on pharmacologic preconditioning. METHODS: Two studies were completed. In the first, swine were distributed into five groups: group I, control; group II,. aminoguanidine (AMG) (30 mg/kg), a selective inducible nitric oxide synthase (iNOS) blocker; group III, MLA (10 microg/kg); group IV, MLA (35 microg/kg); and group V, MLA and AMG (35 microg/kg and 30 mg/kg, respectively). Twenty-four hours after administration of the MLA, AMG, or both, regional left anterior descending coronary artery ischemia was induced for 15 minutes followed by one hour of global normothermic cardioplegic arrest and three hour reperfusion. Left ventricular function, tissue injury, and percentage of myocardial infarction were measured. Left ventricular myocardium in the left anterior descending coronary artery region was sampled for iNOS messenger RNA (mRNA) during ischemia and reperfusion. In the second study, pigs were sacrificed 0, 4, 6, 8, and 24 hrs after MLA/AMG administration for iNOS mRNA determination in nonischemic myocardium. RESULTS: Use of MLA significantly improved postischemic ventricular function, and reduced creatinine kinase release and percentage of infarction. Monophosphoryl lipid A induced expression of iNOS mRNA in nonischemic myocardium within four hours of administration which returned to base line by 24 hours. Normothermic regional ischemia then induced expression of iNOS mRNA, which returned to base line during reperfusion. Aminoguanidine completely abolished both MLA-induced and ischemia-induced iNOS mRNA and blocked the beneficial effects of MLA. CONCLUSIONS: Use of MLA can provide myocardial preservation through enhanced expression of iNOS mRNA.

Animals↗
PubMed1999

Impact of body mass index and albumin on morbidity and mortality after cardiac surgery.

OBJECTIVE: Extremely thin and overly obese patients may not tolerate cardiac surgery as well as other patients. A retrospective study was conducted to determine whether the extremes of body mass index (weight/height(2) [kg/m(2)]) and/or cachexia increased the morbidity and mortality associated with cardiac operations. METHODS: Body mass index was used to objectively measure "thinness" (body mass index < 20) and "heaviness" (body mass index > 30); preoperative serum albumin was used to quantify nutritional status and underlying disease. Data were gathered between 1993 and 1997 from 5168 consecutive patients undergoing coronary artery bypass or valve operations, or both. RESULTS: No significant correlations were observed between body mass index and preoperative albumin levels. Low body mass index (<20) and low albumin level (<2.5 g/dL) were each independently associated with increased mortality after cardiopulmonary bypass (P </=.0005). Operative mortality was highest among those with both low body mass index and low albumin level. Multivariable logistic regression, adjusting for potentially confounding variables, demonstrated that an albumin level of less than 2.5 g/dL was independently associated with increased risk of reoperation for bleeding, postoperative renal failure, and prolonged ventilatory support, intensive care unit stay, and total length of stay. A body mass index of more than 30 was associated with increased sternal wound infection and saphenous vein harvest site infection. CONCLUSIONS: Hypoalbuminemia and low body mass index each independently predict increased morbidity and mortality after cardiac operations. Preoperative risk stratification with the use of body mass index and serum albumin may help to identify subgroups of patients at high risk for adverse outcomes after cardiac operations.

Aged↗
PubMed1999

Incidence and predictors of tias and strokes following coronary artery bypass grafting: report and collective review.

BACKGROUND: Neurologic complications account for some of the most devastating problems following coronary artery bypass surgery. In this study we determined the incidence and predictors of perioperative transient ischemic attacks (TIAs) and strokes in patients undergoing coronary artery bypass grafting at our institution. METHODS: Data was prospectively collected from 4,518 consecutive patients undergoing isolated coronary artery bypass grafting at Brigham & Women's Hospital between 1993 and 1997. RESULTS: One hundred and twenty of the 4,518 patients sustained either a TIA (30 patients, 0.7%) or a stroke (90 patients, 2.0%), for an overall incidence of 2.7%. Significant univariate predictors of TIA/stroke included a history of: 1) cerebral vascular disease, 2) peripheral vascular disease, 3) diabetes, 4) renal failure, 5) preoperative myocardial infarction, 6) hypertension, and 7) age > 70 years. Multivariate logistic regression analysis revealed the following significant associations (incidence of TIA/stroke, odds ratio): 1) cerebral vascular disease (6.4%, OR 2.5); 2) peripheral vascular disease (5.3%, OR 1.6); 3) renal failure (5.6%, OR 1.6); 4) myocardial infarction (3.2%, OR 1.5); 5) diabetes (3.7%, OR 1.5); 6) age > 70 (3.5%, OR 1.5). Perioperative TIA/stroke was significantly associated with postoperative low cardiac output and atrial fibrillation. Patients with TIA/stroke had a significantly longer ICU stay (4 vs. 2 median days), length of hospitalization (14 vs. 7 median days), and higher mortality rate (22% vs. 2.6%). CONCLUSIONS: Perioperative TIA/stroke occurred in less than 3% of patients following coronary artery bypass grafting but was associated with significant mortality. The strongest predictors were cerebral and peripheral vascular disease.

Aged↗
PubMed1996

Nitric oxide/carbon monoxide. A molecular switch for myocardial preservation during ischemia.

BACKGROUND: In heart, NO is produced from L-arginine catalyzed by NO synthase, and CO is formed during the conversion of bilirubin from heme by the action of heme oxygenase. NO, which exerts its biological actions through cGMP and heme, has recently been implicated in myocardial protection during ischemia and reperfusion. We hypothesized that the intracellular signaling by NO may be modulated by heme oxygenase. METHODS AND RESULTS: To test this hypothesis, isolated rat hearts were perfused for 10 minutes with one of the following: (1) buffer alone; (2) 3 mmol/L L-arginine, a precursor for NO; (3) 650 mumol/L zinc protoporphyrin, a heme oxygenase inhibitor; (4) 3 mmol/L L-arginine plus 650 mumol/L zinc protoporphyrin; (5) 15 mumol/L methylene blue, a cGMP inhibitor; or (6) 3 mmol/L L-arginine plus 15 mumol/L methylene blue. Hearts were then made ischemic for 30 minutes, followed by 30 minutes of reperfusion. L-Arginine afforded significant myocardial protection, as evidenced by increased developed pressure (DP) (53.3 +/- 4.3 versus 35.4 +/- 1.8 for control), dP/dtmax (2405 +/- 125 versus 1758 +/- 117 for control), aortic flow (23 +/- 1.5 versus 9.4 +/- 1.6 for control), and coronary flow (CF) (23.0 +/- 0.8 versus 19.0 +/- 1.6 for control) at the end of reperfusion. Protoporphyrin tended to reduce these values compared with L-arginine alone (DP, 27.5 +/- 1.4; dP/dtmax, 1400 +/- 78; CF, 17 +/- 0.5), suggesting a contribution of heme oxygenase in addition to NO for myocardial preservation. Increased mRNAs for the heme oxygenase were noticed in the ischemic reperfused myocardium. Contents of cGMP, the second messenger for NO signaling, increased in the L-arginine group (1.6 +/- 0.1 versus 1.1 +/- 0.1 for control) and were reduced by protoporphyrin. cGMP was completely inhibited by methylene blue, which also retarded postischemic myocardial functional recovery. Malonaldehyde formation, a presumptive marker for free radical generation, was decreased in the L-arginine group (0.053 +/- 0.003) compared with control (0.089 +/- 0.005) but was increased in the protoporphyrin group (0.09 +/- 0.003) compared with the L-arginine group. In vitro studies demonstrated that NO was able to reduce the reactive oxygen species produced by myoglobin, especially oxoferrylmyoglobin, which either are present in heart or are formed in high concentrations during the reperfusion of ischemic myocardium. CONCLUSIONS: The results suggest that NO contributes to myocardial preservation by both cGMP-dependent and cGMP-independent mechanisms, the former being modulated by CO signaling and the latter by virtue of its antioxidant action.

Animals↗
PubMed1996

Critical timing of nitric oxide supplementation in cardioplegic arrest and reperfusion.

BACKGROUND: It has been shown that increased nitric oxide (NO) generation is associated with improved myocardial preservation during ischemia/reperfusion. This study sought to determine the optimal timing for NO supplementation in the setting of cardioplegic arrest, regional ischemia, and reperfusion. METHODS AND RESULTS: Isolated working rat hearts were arrested with normothermic oxygenated potassium cardioplegia for 5 minutes, followed by 60 minutes of normothermic continuous cardioplegic administration with left anterior descending coronary artery (LAD) occlusion. The hearts were divided into four groups. Hearts in group 1 were ischemic/reperfused controls without L-arginine treatment. Hearts in group 2 were perfused with 3 mmol/L L-arginine for 5 minutes before cardioplegic arrest. Hearts in group 3 were perfused with 3 mmol/L L-arginine in the cardioplegia solution. Hearts in group 4 were perfused with 3 mmol/L L-arginine for 5 minutes only during initial reperfusion. Myocardial contractile function after 30 minutes of reperfusion was significantly better in group 2 compared with the other groups and was significantly lower in group 4 than group 1. Coronary flow, although decreased from base line in all groups at 30 minutes of reperfusion, was highest in group 2. The tissue accumulation of cGMP in groups 2 and 3 increased significantly after L-arginine infusion compared with the control group (group 1). In contrast, the LAD regional cGMP after reperfusion in group 4 was comparable to group 1 and significantly lower than groups 2 and 3, whereas the circumflex region cGMP in group 4 was significantly increased over group 1, comparable to groups 2 and 3. LDH release in groups 2 and 3 was significantly lower compared with groups 1 and 4. CONCLUSIONS: As assessed by myocardial function and LDH release, L-arginine is most beneficial when given before cardioplegic arrest, effective during cardioplegic arrest, and detrimental during reperfusion. This suggests that L-arginine given during reperfusion is deleterious to optimal recovery of myocardial function in this ischemic model and that the effect of NO generation in the ischemic/reperfused myocardium may be dependent on the condition of the endothelium.

Animals↗
PubMed1996

Transgenic mice overexpressing glutathione peroxidase are resistant to myocardial ischemia reperfusion injury.

To test the authors' hypothesis that cellular antioxidant enzymes constitute a cellular defense against acute stress, myocardial ischemia reperfusion injury in transgenic mice overexpressing the cellular glutathione peroxidase (GSHPx-1) was studied. Transgenic mice were generated using the entire mouse GSHPx-1 gene including approximately 2.0 kb 5'flanking sequence. A 400% increase of GSHPx activity was found in the hearts of transgenic mice compared with non-transgenic controls. Isolated perfused hearts were prepared from two groups of mice: transgenic overexpressed; non-transgenic controls. Hearts were perfused by Langendorff mode, and after 10 min of stabilization subjected to 30 min of ischemia followed by 20 min of reperfusion. In addition, a group of hearts were perfused for 50 min without subjecting them to ischemia and reperfusion to demonstrate the stability of heart preparation. Transgenic mouse hearts demonstrated significantly improved recovery of contractile force and the rate of contraction, compared to non-transgenic control mouse hearts. The infarct size was also lower in transgenic mouse hearts compared to those of non-transgenic controls. In concert, following ischemia, release of creatine kinase from the transgenic hearts was significantly lower than the control group. The results of this study indicate that increased GSHPx-1 expression renders the heart more resistant to myocardial ischemia reperfusion injury.

Analysis of Variance↗
PubMed1996

Hypercoagulability following multiple trauma.

We sought evidence of hypercoagulability in 59 seriously injured trauma patients. An extended coagulation profile (consisting of tissue plasminogen activator antigen concentration, plasminogen activator inhibitor, serum antithrombin III, protein C antigen, functional protein C, protein S antigen, D-dimer, and prothrombin fragment 1.2) was compared to control values. Laboratory evidence of hypercoagulability was seen in 85% (n = 50) of the patients. Patients with an Injury Severity Score (ISS) > or = 16 (n = 36) had significantly elevated levels of D-dimer and decreased levels of functional protein C compared to patients with an ISS < or = 15 (n = 23). Functional protein C had a negative correlation (r = -0.44; p < 0.001) with the ISS. A hypercoagulable state exists immediately following severe trauma. Greater injury severity may increase this hypercoagulable state. Decreased levels of functional protein C best correlated with increased injury severity.

Adult↗
PubMed1996

The role of protein kinase in C ischemic/reperfused preconditioned isolated rat hearts.

Protein kinase C (PKC) has been implicated in the preconditioning-induced cardiac protection in ischemic/reperfused myocardium. We studied the effect of PKC inhibition with calphostin C (25, 50, 100, 200, 400, and 800 nM), a potent and specific inhibitor of PKC, in isolated working nonpreconditioned and preconditioned ischemic/reperfused hearts. In the nonpreconditioned groups, all hearts underwent 30 min of normothermic global ischemia followed by 30 min of reperfusion. In the preconditioned groups, hearts were subjected to four cycles of ischemic preconditioning by using 5 min of ischemia followed by 10 min reperfusion, before the induction of 30 min ischemia and reperfusion. At low concentrations of calphostin C (25, 50, and 100 nM), the PKC inhibitor had no effect on the incidence or arrhythmias or postischemic cardiac function in the nonpreconditioned ischemic/reperfused groups. With 200 and 400 nM of calphostin C, a significant increase in postischemic function and a reduction in the incidence of arrhythmias were observed in the nonpreconditioned ischemic/reperfused groups. Increasing the concentration of calphostin C to 800 NM, the recovery of postischemic cardiac function was similar to that of the drug-free control group. In preconditioned hearts, lower concentrations (< 100 nM) of calphostin C did not change the response of the myocardium to ischemia and reperfusion in comparison to the preconditioned drug-free myocardium. Two hundred and 400 nM of the PKC inhibitor further reduced the incidence of ventricular fibrillation (VF) from the preconditioned drug-free value of 50% to 0 (p < 0.05) and 0 (p < 0.05), respectively, indicating that the combination of the two, preconditioning and calphostin C, affords significant additional protection. Increasing the concentration of calphostin C to 800 nM blocked the cardioprotective effect of preconditioning (100% incidence of VF). The recovery of cardiac function was similarly improved at calphostin C doses of 200 and 400 nM and was reduced at 800 nM (p < 0.05). With 200 and 400 nM of calphostin C, both cytosolic and particulate PKC activity were reduced by approximately 40 and 60%, respectively, in both preconditioned and preconditioned/ischemic/reperfused hearts. The highest concentration of calphostin C (800 nM) resulted in almost a complete inhibition of cytosolic (100%) and particulate (85%) PKC activity correlated with the abolition of preconditioning-induced cardiac protection. In conclusion, calphostin C protects the ischemic myocardium obtained from intact animals, provides significant additional protection to preconditioning at moderate doses, and blocks the protective effect of preconditioning at high concentrations. The dual effects of calphostin C appear to be strictly dose and "enzyme inhibition" related.

Animals↗
PubMed1996

The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts.

OBJECTIVE: Studies have shown that the diabetic heart exhibits abnormalities in cellular ion transport, which can affect susceptibility to reperfusion-induced ventricular fibrillation (VF), tachycardia (VT) and functional derangements. It has been shown that "preconditioning" renders the heart very resistant to a subsequent prolonged ischemic episode. This phenomenon has been extensively studied in healthy myocardium, but such a study has not been previously done in diseased (hypertrophic or myopathic) hearts. METHODS: We studied the incidence of reperfusion-induced VF, VT, cardiac function, and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia/reperfusion in isolated hearts from rats with streptozotocin-induced diabetes. Following 2, 4, 6, and 8 weeks of diabetes, hearts were isolated and subjected to 30 min global ischemia followed by reperfusion. RESULTS: In the 2-week diabetic group the total incidence of VF and VT was reduced from their non-diabetic age-matched control value of 100 and 100% to 42 (P < 0.05) and 42% (P < 0.05), respectively. Such a reduction in the incidence of VF and VT was not observed with progressive diabetes (4, 6, and 8 weeks). In the 2-week diabetics, the reduction in the VF and VT was reflected in the improvement of postischemic function, the reduction of ischemia and reperfusion-induced Na+ and Ca2+ gains, and the prevention in K+ and Mg2+ loss. This diabetes-induced initial protection was not seen in the 4- and 6-week diabetics, and a deterioration of postischemic function was observed in the 8-week diabetics. Four cycles of preconditioning, each consisting of 5 min ischemia followed by 10 min reperfusion, failed to reduce the incidence of VF and VT, improve cardiac function, and prevent ion shifts induced by 30 min ischemia followed by 30 min reperfusion in 4- and 8-week diabetics. CONCLUSIONS: In the early phase of diabetes the heart is more resistant to ischemia/reperfusion than the non-diabetic heart. Preconditioning does not afford protection against a prolonged period of ischemia in diabetics, indicating that preconditioning may be a "healthy heart phenomenon".

Animals↗
PubMed1995

Improved 4- and 6-hour myocardial preservation by hypoxic preconditioning.

BACKGROUND: A brief hypoxic episode can precondition myocardium against a subsequent ischemic-reperfusion injury. The present study sought to determine whether intracellular ionic alterations, induced expression of heat-shock proteins (hsps), and/or catalase are involved in the cellular mechanisms by which hypoxic preconditioning can preserve postischemic function in a model of prolonged hypothermic storage. METHODS AND RESULTS: Two groups of isolated working rat hearts were studied: control (CON) and hypoxically preconditioned (HP) hearts. Hearts were arrested at 4 degrees C with St Thomas' cardioplegic solution and immersion-stored for either a 4- or 6-hour period. Myocardial function (ie, heart rate, aortic flow, coronary flow, developed pressure, and its first derivative dP/dtmax) was determined at baseline, after preconditioning, and during reperfusion. At similar time points, myocardial [Na+]i, [K+]i, [Mg2+]i, and [Ca2+]i were measured using an atomic absorption spectrophotometer, and the induction of hsp 70 and catalase mRNAs was assayed using Northern blot analysis. After 4 and 6 hours of hypothermic storage, aortic flow, dP/dtmax, and [K+]i were increased, whereas [Na+]i and [Ca2+]i were decreased significantly in the HP group compared with the CON group. Steady state mRNA levels of catalase and hsp 70 were increased from baseline levels only in the HP group, with a peak (2.8- and 2.4-fold versus baseline) after 4 hours of storage. CONCLUSIONS: Our results indicate that intracellular ionic alterations and upregulation of catalase and hsp 70 gene expression may contribute to the mechanisms underlying hypoxic preconditioning, leading to improved postischemic function during prolonged hypothermic storage of hearts.

Animals↗
PubMed1995

Oxidative stress adaptation improves postischemic ventricular recovery.

Adaptation to various forms of stress has been found to be associated with increased cellular tolerance to myocardial ischemia. In this study, the effects of myocardial adaptation to oxidative stress was examined by injecting rats with endotoxin (0.5 mg/kg) and its non-toxic derivative, lipid A (0.5 mg/kg). Both compounds exerted oxidative stress within 1 h of treatment as evidenced by enhanced malonaldehyde formation. The oxidative stress disappeared steadily and progressively with time in concert with the appearance of the induction of glutathione and antioxidative enzymes that included superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. After 24 h of endotoxin or lipid A treatment, the amount of oxidative stress and antioxidant enzyme levels were significantly lower and higher, respectively, compared to those at the baseline levels. Corroborating these results, both endotoxin and lipid A provided protection against myocardial ischemia and reperfusion injury as evidenced by a significantly improved postischemic recovery of left ventricular functions. The data presented here demonstrates that a controlled amount of oxidative stress induces the expression of intracellular antioxidants that can result in enhanced myocardial tolerance to ischemia. This suggests that myocardial adaptation to oxidative stress may be a potential tool for reduction of ischemic/reperfusion injury.

Adaptation, Physiological↗
PubMed1995

Hypoxic preconditioning enhances functional recovery after prolonged cardioplegic arrest.

The purpose of this study was to assess the ability of hypoxic preconditioning to improve myocardial salvage after prolonged hypothermic cardioplegic arrest. Isolated working rat hearts were arrested at 4 degrees C with St. Thomas' Hospital cardioplegic solution and immersion stored for 4 or 6 hours. Two groups were studied, control and hypoxically preconditioned (HP) hearts. After 4 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 8.7 +/- 1.6 mL/min, 17.8 +/- 1.6 mL/min, and 2,064 +/- 123 mm Hg/s, respectively, in control hearts (n = 11) and 25.7 +/- 2.5 mL/min, 27.1 +/- 2.5 mL/min, and 2,655 +/- 93 mm Hg/s, respectively, in HP hearts (n = 11) (p < 0.05). After 6 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 3.5 +/- 1.2 mL/min, 18.8 +/- 0.4 mL/min, and 1,622 +/- 226 mm Hg/s, respectively, in control hearts (n = 6) and 21.5 +/- 3.2 mL/min, 25.5 +/- 2.3 mL/min, and 2,439 +/- 239 mm Hg/s, respectively, in HP hearts (n = 6) (p < 0.05). After 6 hours' preservation, adenine nucleotides and creatine phosphate levels were not significantly different between the two groups, but lactate dehydrogenase release was significantly increased (p < 0.05) in control versus HP hearts (4.66 +/- 0.58 IU/L versus 1.98 +/- 0.28 IU/L). We conclude that hypoxic preconditioning reduces cellular necrosis and preserves myocardial function after prolonged hypothermic cardioplegic arrest.

Adenine Nucleotides↗
PubMed1995

L-arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion.

BACKGROUND: This study evaluated whether the nitric oxide precursor L-arginine could reduce ischemia/reperfusion injury by preventing leukocyte-endothelial interactions. METHODS: Normothermic regional ischemia was induced in the open-chest working pig heart for 30 minutes followed by 90 minutes of reperfusion. A preischemic 10-minute intravenous infusion of 4 mg.kg-1.min-1 of L-arginine (n = 12) was compared with 12 control pigs. Nitric oxide release was measured from the coronary sinus using an amperometric probe. Left ventricular function, malonaldehyde, creatine kinase, myocardial oxygen extraction, and the soluble adhesion molecules (intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) were measured. RESULTS: Nitric oxide release was significantly reduced from baseline throughout ischemia/reperfusion only in the control group. Systolic and diastolic function, and myocardial oxygen extraction were also significantly decreased during early reperfusion in the control compared with the L-arginine group. Peak creatine kinase release was not significantly different between groups. The incidence of ventricular fibrillation, malonaldehyde release, and soluble intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 were each significantly decreased during reperfusion in the L-arginine group. CONCLUSIONS: L-Arginine reduced lipid peroxidation, plasma levels of soluble adhesion molecules, myocardial stunning, and arrhythmias. These results support an excessive endothelial injury/inflammatory response after regional ischemia/reperfusion that can be ameliorated through augmented nitric oxide.

Animals↗
PubMed1995

Constitutive nitric oxide release is impaired after ischemia and reperfusion.

Myocardial ischemia and reperfusion may result in endothelial dysfunction and reduced release of nitric oxide. With the use of an amperometric sensor, the first direct measurements of constitutive nitric oxide release from a beating heart were measured from the coronary effluent of isolated working rat hearts subjected to ischemia and reperfusion. Rats, six to eight per group, were randomly studied as follows: control (no pretreatment) and pretreatment with the nitric oxide donor L-arginine (3 mmol/L), its enantiomer D-arginine (3 mmol/L), nitric oxide inhibitor N omega-nitro-L-arginine methyl ester (100 mumol/L), and combined N omega-nitro-L-arginine methyl ester/L-arginine. Isolated hearts were pretreated for 10 minutes before 30 minutes of global ischemia and 30 minutes of reperfusion. A nonischemic control group (n = 4) was continuously perfused with oxygenated unsupplemented buffer. After ischemia/reperfusion, hearts supplemented with L-arginine recovered significantly (p < 0.05) increased developed pressure, first derivative of the aortic pressure (dP/dtmax), and aortic flow compared with all other hearts that underwent ischemia/reperfusion. In addition, nitric oxide release was significantly (p < 0.05) increased during reperfusion in the L-arginine group. During reperfusion, the recovery of aortic flow correlated with nitric oxide release (r = 0.81, p < 0.0001). We conclude that after ischemia/reperfusion, endothelial dysfunction results in decreased nitric oxide release, which can be ameliorated with L-arginine pretreatment. The direct cytoprotective properties of nitric oxide may contribute to improved functional recovery in hearts pretreated with L-arginine. Augmentation of the L-arginine/nitric oxide pathway may provide a new approach for improved recovery after cardiovascular operations.

Animals↗
PubMed1995

New frontiers in myocardial protection: harnessing the heart's endogenous protective systems.

Researchers have continued to search for therapeutic agents to protect the heart during ischemia and reperfusion. Recent studies have suggested that harnessing the heart's endogenous systems for self-preservation may provide improved protection from ischemic injury. Two such phenomena, preconditioning and heat-shock protein synthesis, have been shown to uniformly reduce myocardial damage. This review highlights the newest research in myocardial protective strategies and suggests avenues of future investigation.

Adaptation, Physiological↗
PubMed1995

Alpha-1 adrenergic receptor agonist-induced preconditioning in isolated working rat hearts.

The aim of this study was to determine whether pharmacologic preconditioning, without a short episode of myocardial hypoxia or ischemia, could improve myocardial function after a prolonged period of ischemia. Isolated rat hearts were perfused with .01, .1 or 1 mg/L of phenylephrine for 5 min followed by a 10-min washout period (preconditioning) before the induction of 30 min of normothermic global ischemia and 30 min of reperfusion. Hearts preconditioned with increasing concentrations of phenylephrine (an alpha-1 adrenergic receptor agonist) produced a reduction in the incidence of reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT). Preconditioning of the hearts with the highest dose of phenylephrine (1.0 mg/L), after 30 min of ischemia, reduced the incidence of reperfusion-induced VF and VT from their nonpreconditioned control values of 87% and 100% to 33% (P < .05) and 50% (P < .05), respectively. After 30 min of ischemia, the recovery of myocardial function was significantly improved in phenylephrine-preconditioned groups. Thus, .1 and 1.0 mg/L of phenylephrine increased aortic flow from its nonpreconditioned control value of 10.8 +/- .9 ml/min to 22.4 +/- 2.4 ml/min (P < .05) and 26.5 +/- 1.5 ml/min (P < .05), respectively. Phenylephrine (1.0 mg/L) preconditioning significantly reduced ischemia/reperfusion-induced tissue Na+ and Ca2+ gains and prevented K+ and Mg2+ loss measured by an atomic absorption spectro-photometer. Our results show that alpha-1 adrenergic stimulation (preconditioning) can prevent postischemic abnormalities in intracellular ions, reperfusion arrhythmias, and contractile function without the inhibition of O2 delivery.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1995

Hypoxic preconditioning preserves antioxidant reserve in the working rat heart.

OBJECTIVE: The aim was to examine whether intracellular antioxidants play a role in myocardial preservation following hypoxic preconditioning. METHODS: Isolated working rat hearts were subjected to 30 min ischaemia and 30 min reperfusion. Control hearts were compared to hearts preconditioned with 10 min hypoxia. Left ventricular function and lactate dehydrogenase (LDH) release were measured in each group. Ascorbate dependent (ADAR) and thiol dependent (TDAR) components of the endogenous myocardial antioxidant reserve were assessed using electron spin resonance spectroscopy. RESULTS: a Hypoxic preconditioning had no effect on left ventricular function after 10 min reoxygenation. During reperfusion, the hypoxically preconditioned hearts had a significantly increased survival rate, aortic flow, developed pressure, and dP/dtmax, and a reduced lactate dehydrogenase release, compared to non-preconditioned controls (P < 0.05). Preconditioned hearts also had significantly higher preservation of baseline ADAR (79%) and TDAR (96%) compared with control hearts, (70%) and (77%), respectively (P < 0.05). CONCLUSIONS: Hypoxic preconditioning enhances functional recovery and reduces cell necrosis following global ischaemia in the working rat heart. This phenomenon may, in part, be mediated through enhanced ascorbate and thiol components of the antioxidant reserve.

Animals↗