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Biomedical subjects

J Z Sun

Publications and source records attributed to J Z Sun.

At least 55 records · Page 3Linked to original sources
PubMed1993

Use of aromatic hydroxylation of phenylalanine to measure production of hydroxyl radicals after myocardial ischemia in vivo. Direct evidence for a pathogenetic role of the hydroxyl radical in myocardial stunning.

A pathogenetic role of .OH in myocardial stunning has been inferred from the protective effects of .OH scavengers and iron chelators. However, conclusive demonstration of the .OH radical hypothesis of myocardial stunning requires direct verification of three major, but still unproven, assumptions: (1) .OH is produced in the stunned myocardium in vivo; (2) antioxidant therapy inhibits .OH production; and (3) such inhibition results in enhanced recovery of contractility (ie, .OH is necessary for the development of myocardial stunning). Since phenylalanine (Phe) reacts with .OH to form the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m-, and p-tyr), we used aromatic hydroxylation of Phe to detect .OH formation in the stunned myocardium. Open-chest dogs undergoing a 15-minute coronary occlusion followed by reperfusion received an intravenous infusion of Phe (54.3 mg/kg for 11.5 minutes beginning 90 seconds before reperfusion); these animals were given either no antioxidant therapy (group I, n = 15), N-2-mercaptopropionyl glycine (MPG) (group II, n = 11), or MPG combined with superoxide dismutase, catalase, and desferrioxamine (group III, n = 12). In addition, group IV (nonischemic control group, n = 6) received Phe but did not undergo coronary occlusion, whereas group V (ischemic control group, n = 16) underwent a 15-minute occlusion but did not receive Phe or antioxidants. The plasma concentrations of tyrosines in the local venous effluent and in the arterial blood were measured with high-performance liquid chromatography. In group I, production of o- and m-tyr, which are specific markers of .OH formation, began during coronary occlusion but increased dramatically immediately after reperfusion, peaking at 1 minute and continuing up to 10 minutes of reperfusion. In group II, the production of o- and m-tyr was markedly decreased throughout the first 10 minutes of reperfusion. In group III, the production of m-tyr was decreased to levels similar to those in group II, whereas the production of o-tyr was almost completely abolished. There was no appreciable production of o- or m-tyr in group IV. Recovery of contractile function (assessed as systolic wall thickening) was increased in group I vs group V. Recovery of function was further enhanced in group II, with only a slight additional improvement in group III.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Direct evidence that the hydroxyl radical plays a pathogenetic role in myocardial "stunning" in the conscious dog and demonstration that stunning can be markedly attenuated without subsequent adverse effects.

Recent studies suggest that the hydroxyl radical (.OH) plays a pathogenetic role in postischemic ventricular dysfunction (myocardial "stunning"). This concept, however, is predicated exclusively on results obtained in anesthetized open-chest preparations, which are subject to the confounding influence of many unphysiological conditions and in which both myocardial stunning and free radical generation are greatly exaggerated. The lack of supporting evidence in more physiological animal models represents a major limitation of the .OH hypothesis of stunning. Furthermore, concern has been raised that myocardial stunning may be a period of "rest" necessary for full recovery, so that attenuation of the early phase of stunning by antioxidant therapy may have subsequent detrimental effects on the resting function and/or on the return of myocardial contractile reserve. To address these issues, in phase 1 of this study conscious unsedated dogs undergoing a 15-minute coronary artery occlusion received an intravenous infusion of normal saline (n = 22), of the .OH scavenger N-2-mercaptopropionyl glycine (MPG, n = 17), or of the iron chelator desferrioxamine (DF, n = 14). Compared with control dogs, the dogs treated with MPG or DF exhibited significantly greater postischemic wall thickening throughout the first 6 hours of reperfusion; the total deficit of wall thickening during this time interval was reduced 50% by MPG and 50% by DF. The magnitude of this beneficial effect was a function of the severity of ischemia, so that the dogs with the lowest collateral flows had the greatest improvement of wall thickening. The accelerated recovery produced by MPG and DF in the first 6 hours was not followed by any deterioration of resting wall thickening at 24 or 48 hours. Furthermore, in dogs treated with MPG or DF, the increase in wall thickening elicited by maximal inotropic stimulation (isoproterenol or dopamine) was similar before stunning and shortly after resting wall thickening had normalized (24 or 48 hours after reflow); thus, despite the fact that most of the early postischemic dysfunction had been eliminated by antioxidant therapy, there was no subsequent impairment of either resting function or contractile reserve. In phase 2, production of free radicals (measured with the spin trap alpha-phenyl N-tert-butyl nitrone) was markedly (> 80%) inhibited by the same doses of MPG and DF that attenuated stunning in phase 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Beneficial effects of N-acetylcysteine and cysteine in stunned myocardium in perfused rat heart.

1. The objective of this study was to evaluate the effects of three sulphydryl (SH) compounds, N-acetylcysteine (NAC), cysteine (Cys) and cystamine, on functional recovery and ventricular arrhythmias (VF) in stunned myocardium in the isolated perfused heart of the rat. 2. Hearts (n = 7-8 per group) were perfused by the Langendorff procedure for 20 min to stabilize and then assigned to one of five groups: saline, sham, NAC, Cys and cystamine. After the stabilizing period, the drugs (at 3.6 microM min-1) or their vehicle (saline) were infused into coronary vessels throughout the experimental period. Ten min after administration of drugs, the left anterior descending coronary artery (LAD) was ligatured for 20 min and then untied to reperfuse for 30 min. In the sham group, a ligature was placed around the LAD but not tied. 3. NAC and Cys had a significant effect in attenuating myocardial stunning: the percentage recovery of rate-pressure product measured 30 min after reperfusion as an index of heart function, was improved with the NAC (98.3 +/- 4.5) and Cys groups (104.0 +/- 6.5) compared with the saline (only 73.6 +/- 3.8, P < 0.01) group. Cystamine did not show these beneficial effects. This may be due to the difference in chemical structure between NAC, Cys and cystamine since the latter does not have a free SH group with a disulphide bond formed. This phenomenon suggests that a free SH group is essential for the protective effects of compounds like NAC and Cys in myocardial injury. 4. NAC and Cys prevented the fall in coronary flow during the LAD occlusion and enhanced coronary flow during reperfusion but cystamine did not have such a beneficial effect. 5. The incidence of VF in the saline, cystamine, Cys and NAC groups was 6/8 (75.0%), 4/7 (57.1%), 3/8 (37.5%) and 2/7 (28.6%), respectively, and no significant differences (P > 0.05) were noted between the saline- and drug-treated groups. 6. An in vitro study with electron spin resonance indicated that Cys effectively scavenged the hydroxyl radical (-OH) generated by Fenton's reaction but did not scavenge superoxide generated in an irradiated riboflavin system. NAC and cystamine showed a scavenging effect on -OH to a certain extent but this effect did not reach statistical significance (P > 0.05 vs saline). 7. Our results demonstrate that NAC and Cys treatment before ischaemia and reperfusion can reduce myocardial stunning. This beneficial effect may be mainly due to their ability to preserve and enhance coronary flow during coronary occlusion and reperfusion and in part due to scavenging -OH and/or replenishing intracellular glutathione. The results also indicate that the condition of coronary perfusion can produce a great impact on postischaemic ventricular performance.

Acetylcysteine↗
PubMed1990

[Changes in calcium and water content of stunned myocardium and effects of hyperosmotic mannitol in rat heart].

In this study we investigated changes in myocardial electrolytes and water contents following 20 min of global ischemia and 40 min reperfusion in isolated rat hearts perfused by Langendorff procedure. After ischemia and reperfusion, calcium and water contents in myocardium increased by 42% (P less than 0.01) and 7.6% (P less than 0.05) respectively as compared with nonischemic myocardium, but sodium, potassium and magnesium in myocardial tissue did not change significantly (P greater than 0.05). When hyperosmotic mannitol (12%) was infused at the beginning of reperfusion and persisted for 25 min, postischemic left ventricular function was improved significantly. At 40 min of reperfusion, heart rate-left ventricular pressure product, an index of ventricular function, recovered to 85% of preischemia, and only 66.3% recovery was seen in postischemic heart without mannitol (P less than 0.01). In addition, hyperosmotic mannitol caused marked decreases in myocardial calcium, water and other cations, suggesting that nonspecific sarcolemmal permeability changes induced by ischemia/reperfusion probably is one of entry routes of calcium into the cell. We conclude that calcium overload with mild myocardial edema is involved in myocardial stunning and hyperosmotic mannitol can improve the function of stunned myocardium in isolated rat heart, which is, at least partially, due to the reduction of myocardial calcium overload and swelling.

Animals↗
PubMed1989

Alterations of coronary vascular responses to noradrenaline, acetylcholine and isoprenaline during acute myocardial ischaemia in dogs.

1. The reactivity of coronary arteries to noradrenaline (NA), acetylcholine (ACh) and isoprenaline (Iso) during acute myocardial ischaemia was studied in anaesthetized, open-chest dogs. 2. The left anterior descending coronary artery (LAD) was cannulated and perfused via an extracorporal circuit at constant flow. Ischaemia was produced by decreasing the perfusion blood flow of the LAD to 50% (moderate ischaemia) and 27% (severe ischemia) of normal. A dose of each agent which had no significant myocardial effects was chosen. Heart rate was held constant by ventricular pacing during ACh administration. 3. Under normal conditions, the infusion of NA, ACh and Iso into the LAD produced significant decreases in coronary vascular resistance (P less than 0.01). However, under either moderate or severe ischaemic conditions intracoronary NA resulted in a marked increase in coronary vascular resistance (P less than 0.01), which was completely blocked by phentolamine, an alpha-adrenoceptor blocker; intracoronary ACh and Iso did not have a significant effect on coronary vascular resistance (P greater than 0.05). 4. These results indicate that coronary arterial responsiveness to some intrinsic vasoactive substances, such as NA and ACh, is altered during acute myocardial ischaemia. This may be important in the pathophysiology of myocardial ischaemia.

Acetylcholine↗
PubMed1988

Potentiation of myocardial salvage by tissue type plasminogen activator in combination with a thromboxane synthetase inhibitor in ischemic cat myocardium.

We studied the effects of a thrombolytic agent (t-PA) and a thromboxane synthetase inhibitor (CGS-13080) in a model of myocardial ischemia and reperfusion. Occlusion of the left anterior descending coronary artery for 2 hours followed by 4 hours of reperfusion in anesthetized cats results in a large washout of creatine kinase into the blood (32 +/- 7 IU/mg protein) and an area of necrotic tissue comprising 52 +/- 5% of the area at risk and 9 +/- 0.6% of the left ventricle. Intravenous administration of t-PA (500 IU/kg.min) for 30 minutes alone at reperfusion or infusion of CGS-13080 (500 micrograms/kg.hr) had no effect on washout of creatine kinase or extent of necrotic tissue development. Administration of the same doses of both t-PA and CGS-13080 together markedly attenuated creatine kinase release to 10 +/- 2 IU/mg protein (p less than 0.01) and reduced the area of necrotic tissue to 9 +/- 2% of the area at risk and only 1.3 +/- 0.3% of the left ventricle (p less than 0.001). No significant sustained effects of these agents were observed on mean arterial blood pressure, heart rate, or the pressure rate index in these experiments. Thus, t-PA and CGS-13080 exert synergistic effects in preserving myocardial integrity in cats subjected to acute myocardial ischemia followed by reperfusion. The mechanism of this beneficial effect does not appear to be via reduced myocardial oxygen demand, increased myocardial oxygen supply, or enhanced inhibition of thromboxane A2 formation. The mechanism of this anti-ischemic effect is not clear but may involve a metabolic or a cytoprotective effect.

Animals↗
PubMed1987

Influence of atherosclerosis on vascular responsiveness in isolated rabbit vascular smooth muscle.

Coronary arteries and aortic rings were isolated from rabbits fed either a control diet or a high cholesterol (1 to 2%) diet for 8 to 11 weeks and studied for their vasoactive properties to a variety of vasoconstrictor and vasodilator agents. Perfused coronary arteries without intact endothelium constrict markedly to a thromboxane A2 agonist (i.e., carbocyclic thromboxane A2, CTA2) and dilate markedly to iloprost, a prostacyclin analog. No differences occurred between the coronary arteries isolated from control or atherosclerotic rabbits. Additional studies were conducted on rabbit aortic vascular smooth muscle rings containing functionally intact endothelium and in rings denuded of their endothelium. Acetylcholine (20 to 2000 ng/ml) neither constricted nor dilated control aortic rings without endothelium, and markedly dilated aortic rings with intact endothelium in a concentration dependent manner. In atherosclerotic aortic rings, acetylcholine constricted preparations without endothelium, and dilated rings with endothelium to a much lesser extent than that observed in control rings. Similar reductions in responsiveness occurred with adenosine diphosphate (ADP), another endothelium-dependent vasodilator, but not with iloprost, a nonendothelium-dependent dilator. No differences were observed in constrictor responses to norepinephrine. Aortae from atherosclerotic rabbits produced less prostacyclin in response to arachidonic acid than control aortae. These data point to an important role of the endothelium in modulating the vascular response to vasodilators in atherosclerotic rabbit arterial vessels.

6-Ketoprostaglandin F1 alpha↗