To examine the intracellular signaling mechanism of NO in ischemic myocardium, isolated working rat hearts were made ischemic for 30 min followed by 30 min of reperfusion. A separate group of hearts were pre-perfused with 3 mM L-arginine in the presence or absence of 650 microM of protoporphyrin, a heme oxygenase inhibitor for 10 min prior to ischemia. The release of NO was monitored using an on-line amperometric sensor placed into the right atrium. The aortic flow and developed pressure were examined to determine the effects of L-arginine on ischemic/reperfusion injury. Induction for the expression of heme oxygenase was studied by Northern hybridization. For signal transduction experiments, sarcolemmal membranes were radiolabeled by perfusing the isolated hearts with [3H] myoinositol and [14C] arachidonic acid. Biopsies were processed to determine the isotopic incorporation into various phosphoinositols as well as phosphatidic acid and diacylglycerol. cGMP was assayed by radioimmunoassay and SOD content was determined by enzymatic analysis. The release of NO was diminished following ischemia and reperfusion and was augmented by L-arginine. L-arginine reduced ischemic/reperfusion injury as evidenced by the enhanced myocardial functional recovery. Protoporphyrin modulated the effects of L-arginine. cGMP, which was remained unaffected by ischemia and reperfusion, was stimulated significantly after L-arginine treatment. The NO-mediated augmentation of cGMP was reduced by protoporphyrin suggesting that part of the effects may be mediated by CO generated through the heme oxygenase pathway. Reperfusion of ischemic myocardium resulted in significant accumulation of radiolabeled inositol phosphate, inositol bisphosphate, and inositol triphosphate. Isotopic incorporation of [3H] inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly during reperfusion. Reperfusion of the ischemic heart prelabeled with [14C] arachidonic acid resulted in modest increases in [14C] diacylglycerol and [14C] phosphatidic acid. Pretreatment of the heart with L-arginine significantly reversed this enhanced phosphodiesteratic breakdown during ischemia and early reperfusion. However, at the end of the reperfusion the inhibitory effect of L-arginine on the phosphodiesterases seems to be reduced. In L-arginine treated hearts, SOD activity was progressively decreased with the duration of reperfusion time. The results suggests for the first time that NO plays a significant role in transmembrane signaling in the ischemic myocardium. This signaling appears to be on- and off- nature, and linked with SOD content of the tissue. The signaling is transmitted via cGMP and opposes the effects of phosphodiesterases by inhibiting the ischemia/reperfusion-induced phosphodiesteratic breakdown. Our results also suggest that NO activates heme oxygenase which further stimulates the production of cGMP presumably by CO signaling. Thus, NO not only potentiates cGMP mediated intracellular signaling, it also functions as a retrograde messenger for CO signaling in heart.

Animals↗

PubMedDate not supplied

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound: mechanism of action.

The cardioprotective effects of an antilipolytic compound, nicotinic acid, on arrested-reperfused myocardium were investigated in the isolated in situ pig heart preparation. Hearts were preperfused for 15 min in the presence of (5-3H)-glucose and (U-14C)-palmitic acid. Half of the hearts were then perfused with 0.08 mM nicotinic acid for an additional 15-min period, while the remaining control hearts received unmodified perfusion. Arrest was then induced in all animals for 2 h using hypothermic K+ cardioplegia, followed by 60 min of normothermic reperfusion. In control hearts, there were significantly greater levels of long-chain acyl Co-A and acyl carnitine and lower levels of membrane phospholipids than in the nicotinic acid group. While nicotinic acid inhibited beta-oxidation during pre-ischemia and reperfusion, it also prevented the degradation of membrane phospholipids. The net result was a reduction of free fatty acid accumulation during arrest and reperfusion in the nicotinic acid group. Glycolysis, as reflected in 3H2O production, was significantly increased by nicotinic acid administration. In the control heart as compared to the nicotinic acid group, the incorporation of 14C-label from palmitate into triglyceride and cholesterol during arrest was enhanced, while incorporation into phospholipids was depressed. The cardioprotective effects of nicotinic acid were demonstrated by decreased release of creatine kinase and improved coronary blood flow, and cardiac contractility in the reperfused myocardium supplemented with nicotinic acid compared to the control group. These results suggest that nicotinic acid significantly protects the arrested-reperfused myocardium by a) preventing elevation of myocardial fatty acid levels, b) stimulating glycolysis by limiting fatty acid oxidation, c) inhibiting degradation of membrane phospholipids, and d) preventing accumulation of fatty acid metabolites with harmful detergent properties.

Animals↗

PubMedDate not supplied

Role of a nonsteroidal anti-inflammatory agent, ibuprofen, in coronary revascularization after acute myocardial infarction.

The efficacy of using a nonsteroidal anti-inflammatory agent such as ibuprofen for the salvage of ischemic and reperfused myocardium was investigated by examining its ability to improve global and regional functions as well as to preserve high-energy phosphate compounds and inhibit creatine kinase release from an isolated in-situ pig heart subjected to 1 h of normothermic regional ischemia followed by 1 h of global hypothermic arrest and 1 h of normothermic reperfusion. Preperfusion of the heart for 15 min prior to ischemic insult with 50 microM ibuprofen failed to mitigate the myocardial reperfusion injury. Ibuprofen, however, functioned as an anti-inflammatory agent, as judged by its ability to inhibit the influx of indium-111-labeled polymorphonuclear leukocytes and chromium-51 (51Cr)-labeled platelets into the ischemic and reperfused heart. It also blocked the cyclooxygenase pathway, as evidenced by the significant reduction of 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in the perfusate. Inhibition of cyclooxygenase resulted in increased accumulation of nonesterified fatty acids, particularly arachidonic acid, in the heart. These results suggest that although ibuprofen can inhibit polymorphonuclear leukocyte and platelet influx into the ischemic and reperfused heart, it causes further damage to the already ischemic heart by reducing prostacyclin concentration and increasing free fatty acids in the heart.

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Developmental profiles of protective mechanisms of heart against peroxidative injury.

The developmental profiles of the protective mechanisms of heart against peroxidative injury during neonatal growth was examined in the pigs of three different age groups. Lipid peroxidation expressed in terms of malonaldehyde formation was considerably higher in the pig hearts of the 8-10 day age group compared to that either by newborn or adult age groups. The four principal antioxidative enzymes, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase (G6PD), were enhanced during early neonatal growth and, with the exception of G6PD, all other enzymes were further enhanced during further growth to adulthood. G6PD activity dropped significantly in adult heart. The phospholipid contents of myocardial membrane between newborn and week-old pigs did not vary significantly. Total phospholipids and phosphatidylcholine contents were significantly higher in adult heart compared to those in neonatal heart. The enzymes of phospholipid synthesis and degradation, fatty acyl CoA synthetase (FACS), phospholipase A2 (PLA2), lysophospholipase (LPL), and lysophophatidylcholine acyltransferase (LPCAT) increased during early neonatal growth. During further growth to adulthood, FACS decreased, PLA2 did not change, whereas both LPL and LPCAT increased significantly. Analysis of free fatty acids showed that palmitic and stearic acids decreased during the first week of growth, but increased during further growth to adulthood. Oleic acid did not change with aging, but arachidonic acid dropped in adult heart compared to that in neonatal heart. Linoleic, palmitoleic and free fatty acids increased dramatically during the first week of neonatal growth, but dropped thereafter. These results suggest that the unusual peroxidative status of the week-old pig heart is related to the presence of high concentrations of polyunsaturated fatty acids in the membrane phospholipids and not with the antioxidative defense system.

Aging↗

PubMedDate not supplied

Pathophysiology of superoxide radical as potential mediator of reperfusion injury in pig heart.

The role of oxygen-derived free radicals in myocardial reperfusion injury was studied using the isolated in situ pig heart model. The free radical scavengers, superoxide dismutase (SOD) and catalase, protected the ischemic pig heart subjected to one hour of normothermic regional ischemia followed by one hour of global hypothermic arrest and one hour normothermic reperfusion. A significant increase in thiobarbituric acid reactive material and oxidized glutathione appeared in the perfusate demonstrating free radical-mediated lipid peroxidation during reperfusion, and this was prevented by the addition of SOD plus catalase. The values of three important antioxidative enzymes, SOD, catalase, and glutathione peroxidase, showed reduced activities after 2 hours of ischemia. These values did not change significantly after 60 minutes of reperfusion following the 2 hours ischemic insult. The concentrations of high-energy phosphate compounds including creatine phosphate (CP), adenosine triphosphate (ATP), and total adenine nucleotide were reduced significantly during ischemia and reperfusion in hearts which were not protected by SOD and catalase. The plasma creatine phosphokinase levels were lowered appreciably as a result of SOD and catalase treatment. It may be concluded from these experiments that oxygen-derived free radicals are present during reperfusion and SOD and catalase play a significant role in the protection of ischemic myocardium from reperfusion injury.

Adenine Nucleotides↗

PubMedDate not supplied

The influence of diabetes and hypertension on the results of coronary revascularization.

The effects of diabetes and hypertension on the early postoperative course of patients undergoing coronary revascularization were studied by reviewing the records of 177 patients operated upon in 1972. There were 121 nondiabetic, nonhypertensive; 32 hypertensive; ten diabetic; and 14 diabetic-hypertensive patients. The incidence of postoperative low cardiac output, renal insufficiency and arrhythmia was significantly higher in the hypertensive patient. Operative mortality ranged from 0 in diabetic patients, to 0.8 per cent in nondiabetic, nonhypertensives, to 7.1 per cent in diabetic-hypertensives and 12.5 per cent in hypertensive patients, suggesting an increased risk for the hypertensive patient. The one- to two-year follow-up results documented symptomatic improvement in 90.7 per cent of patients with little adverse effect apparent from diabetes or hypertension. Pre- and postoperative coronary angiography was carried out in 103 patients between 1968 and 1973 with a mean elapsed time between operation and postoperative angiogram of 9.3 months. The progression of atherosclerosis was graded on a 0-4 basis in both grafted and ungrafted coronary arteries. While hypertension appeared to contribute to disease progression, the incidence of vein graft and internal mammary artery bypass occlusion was not significantly affected by either diabetes or hypertension. This study has shown that while hypertension contributes to increased morbidity and mortality in the early postoperative period and an increased rate of progression of atherosclerosis, neither diabetes nor hypertension appeared to influence the one- to two-year results of coronary revascularization.

Acute Kidney Injury↗

PubMedDate not supplied

Use of extrafascially harvested radial artery for coronary artery revascularization: technical considerations.

BACKGROUND: The use of the radial artery for coronary artery revascularization was abandoned due to its tendency for spasm; the revival was attributed to improved harvesting technique as well as the use of calcium channel blockers. METHODS: Between February 1996 and June 1997, the radial artery graft was used in 77 of 89 consecutive patients undergoing coronary artery bypass graft surgery. Only the patients with positive Allen's test or forearm deformity were denied the use of the radial artery. We used an extrafascial, no-touch technique using low-strength electrocautery for harvesting the radial artery. Calcium channel blockers were not used in any of these patients. RESULTS: There were no early deaths. No patient sustained perioperative myocardial infarction or required intra-aortic balloon pump. Only one patient required inotropic agents. Three noncardiac late deaths occurred during the follow-up of 6 to 24 months. No early or late ischemic or functional forearm disability was reported in any of the patients. CONCLUSIONS: The radial artery is easy to harvest and safe to use routinely. When harvested extrafascially, diltiazem infusion may not be necessary. Maximal arterial-global revascularization using the left internal thoracic artery-to-left anterior descending coronary artery and radial artery-to-circumflex artery system may improve the early and long-term results.

Adult↗

PubMedDate not supplied

Reoperative median sternotomy using a cast spreader.

Repeat median sternotomy carries a high mortality rate secondary to a higher incidence of injury to the underlying vital structures. The reported incidence of reentry accidents may be as high as 6% to 10%. We describe a new technique of redo sternotomy using a nitrogen-powered oscillating saw and a cast spreader. The new technique was used for 89 consecutive cases without any incidence of injury to the underlying structures. The use of a case spreader during repeat median sternotomy may enhance the safety of reentry.

Humans↗

PubMedDate not supplied

Possible physiological role of myocardial fatty acid binding protein in phospholipid biosynthesis.

Accumulation of free fatty acids and their esters resulting from the degradation of membrane phospholipids is one of the major causes for the myocardial dysfunction during ischemia and reperfusion. In this communication, we have studied the possible physiological role played by fatty acid binding protein (FABP) in stimulating key enzymes involved in phospholipid biosynthesis. Purified rat heart FABP bound a maximum of either 2 mol of [1- 14C]palmitoyl coenzyme A (CoA), oleoyl CoA, or oleic acid per mol of FABP as observed by Scatchard analysis. FABP caused a threefold increase in the incorporation of [1- 14C]palmitoyl CoA into phosphatidic acid as compared to only a 1.5-fold increase by bovine serum albumin (BSA). Myocardial FABP also enhanced acyl CoA monoacylglycerophosphorylcholine acyl transferase minimally at a substrate concentration (greater than 200 microM), the activity of this enzyme was enhanced 4.5- and 2-fold by FABP and BSA, respectively. The maximum stimulation of the enzyme activity took place at the fatty acyl CoA concentration where inhibition of the enzyme activity is usually observed due to the surfactive property of acyl CoAs. These results thus indicate that under abnormal pathophysiological conditions such as ischemia, when acyl CoA concentration increases, FABP may protect acyl CoA monoacylglycerophosphorylcholine acyl transferase as well as stimulate glycerophosphate acyl transferase to limit the loss of membrane phospholipids, suggesting a possible role of FABP in phospholipid biosynthesis.

Acyl Coenzyme A↗

PubMedDate not supplied

A clinical comparison of potassium and magnesium-potassium crystalloid cardioplegia: metabolic considerations.

Controlled metabolic studies were used to gauge the relative efficacy of two cardioplegic solutions in 28 patients (14 in each group) undergoing multiple coronary artery bypass grafts. A solution containing magnesium-potassium (Plegisol) was compared to a standard potassium crystalloid cardioplegic solution. Measurements of coronary blood flow, coronary vascular resistance, coronary arteriovenous oxygen difference, myocardial oxygen consumption and extraction, and myocardial lactate and potassium extraction and release were all measured in the isolated, vented, paced, beating heart, before and for 15 minutes after a one hour arrest interval during which time revascularization was completed. During cardioplegic administration, the infusion flow rate, myocardial oxygen consumption and extraction, and lactate and potassium release and uptake were noted. The results indicate that during cardioplegic administration, the total oxygen consumed for both potassium and magnesium-potassium solutions did not significantly differ. The flow rate of the Mg-K solution was significantly higher than that of the potassium solution alone (510 vs. 398 ml/min). There was no lactate production during Mg-K administration, but 0.13 mEq/min of lactate was produced while potassium crystalloid cardioplegia was given. During myocardial reperfusion, oxygen extraction was maintained near prearrest levels in both groups. The only significant difference noted between the potassium and magnesium-potassium solutions were the higher coronary blood flow and oxygen consumption immediately upon reperfusion in the Mg-K group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

A comparison of blood and Fluosol-DA for cardiopulmonary bypass.

Fluosol-DA was compared to blood as a pump prime for total cardiopulmonary bypass in the pig animal model. Nineteen pigs weighing between 14 and 22 kg were studied, nine with blood and ten with Fluosol. Metabolic and hemodynamic measurements were determined before, during and after 60 minute bypass to establish the adequacy of Fluosol to sustain perfusion as compared to blood. The measurements and subsequent calculations included blood gases, arterial and mixed venous oxygen content, oxygen extraction and consumption, cardiac output, systemic and pulmonary vascular resistance and arterial, venous, pulmonary artery and left atrial pressures. The result showed a significant decrease in hematocrit during bypass in the Fluosol group as compared to blood perfusion (20 vs. 30%). While the arterial oxygen content fell from control levels with Fluosol during bypass, in the blood prime group, oxygen content remained at pre-control levels. Whole body oxygen consumption decreased during bypass, in both groups equally, but this decrease did not lead to acidosis and was stable during recovery. Oxygen and carbon dioxide transport were adequately maintained during bypass in both Fluosol and blood groups. Systemic pressures remained stable during bypass and were lower, but stable, during recovery. Pulmonary vascular resistance was elevated in both groups during recovery which probably explains a concomitantly decreased cardiac output. There was a 40% mortality in both experimental groups secondary to postpump pulmonary hypertension. It is concluded that Fluosol is a satisfactory oxygen carrying agent to be used instead of blood during cardiopulmonary bypass, and in the pig model both blood and Fluosol were associated with a high incidence of pulmonary hypertension.

Animals↗

PubMedDate not supplied

Nonthrombogenic aortic and vena caval bypass using heparin-coated tubes.

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Animals↗