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Biomedical subjects

R E Goldstein

Publications and source records attributed to R E Goldstein.

At least 127 records · Page 7Linked to original sources
PubMed1985

Unique coronary vasodilator induction by leukotriene D4.

Coronary blood flow (CBF) and myocardial contractility decrease markedly in response to intracoronary administration of leukotriene D4 (LTD4). With steady infusion, however, both CBF and contractility escape, approaching preinfusion values despite ongoing LTD4 administration. To clarify the mechanism of this escape, we reinfused plasma from the coronary vein draining the myocardial area receiving LTD4. Introducing this plasma into a coronary artery caused a marked rise in coronary flow for the duration of the plasma infusion. Coronary flow reduction with vasopressin or mechanical occlusion matching that caused by LTD4 failed to elicit vasodilator production. Thus a unique coronary vasodilator factor is induced by LTD4. Whole blood or platelet-rich plasma incubated with LTD4 in vitro produced the same pattern of coronary dilation on intracoronary infusion; LTD4 incubation with platelet-poor plasma failed to elicit a vasodilation. The vasodilator factor is stable and is not potassium, a prostaglandin, catecholamine, histamine, serotonin, adenosine, adenosine diphosphate, or platelet-activating factor. Production of this leukotriene-induced vasodilator factor may account for the escape from LTD4-induced coronary constriction.

Adenosine↗
PubMed1985

Effects of calcium entry blockers on coronary constriction and myocardial ischemia due to leukotriene D4.

Recent studies show that leukotrienes (LTs) produce profound coronary artery constriction. Although calcium entry blockers are commonly used to remedy coronary vasospasm, their capacity to interfere with LT-mediated coronary constriction is unknown. Therefore, we compared effects of intracoronary LTD4 before and during treatment with calcium entry blockers in the in situ, blood-perfused hearts of domestic pigs. Intravenous administration of verapamil (0.1-1.6 mg/kg), nifedipine (10 or 100 micrograms/kg) or diltiazem (0.6-2.0 mg/kg) sufficient to increase base-line coronary blood flow (CBF) and decrease mean arterial pressure did not change decrement in CBF after LTD4. Infusion of verapamil (0.01-0.04 mg/min) into the left anterior descending coronary artery raised pre-LTD4 CBF almost 2-fold without alteration in mean arterial pressure, heart rate or left ventricular end-diastolic pressure. Intracoronary boluses of LTD4 (0.3, 1.0 and 3.0 micrograms) during verapamil infusion into the same vessel caused dose-dependent decreases in CBF identical to those observed when LTD4 was injected during control infusion. ECGs showed myocardial ischemia during severe flow reduction after high dose intracoronary LTD4 (3.0 or 10.0 micrograms). When the same LTD4 doses were injected during intracoronary verapamil, electrocardiographic changes did not occur despite similar decreases in CBF. The capacity of verapamil to prevent LTD4-induced ischemia may be caused by higher residual CBF after LTD4 even though the magnitude of LTD4-induced CBF decrement was unaltered. LTD4-induced coronary constriction seems to be mediated by a mechanism unrelated to calcium entry channels blocked by verapamil, nifedipine or diltiazem.

Animals↗
PubMed1984

Acute takeoffs of the coronary arteries along the aortic wall and congenital coronary ostial valve-like ridges: association with sudden death.

Congenital coronary artery anomalies have been associated with sudden death. Twenty-two patients who were victims of sudden death (mean age 46) and who had no significant anatomic cause of death were examined at autopsy and compared with 19 patients who died of known causes (control group). The hearts of these 41 patients were examined for abnormalities of acute angle takeoff of the coronary artery and presence of ostial valve-like ridges. Of the 22 patients who died suddenly, 13 (59%) had acute angle takeoff of the coronary artery and 9 (41%) had ostial valve-like ridges. Of the 19 control subjects, 4 (21%) had acute angle takeoff and only 2 (11%) had an ostial valve-like ridge. The difference was statistically significant (p = 0.015 and 0.031, respectively). It is suggested that aortic root dilation may compress coronary arteries with acute angle takeoff and that ostial valve-like ridges may act as occlusion valves. Thus, either may cause acute obstruction of the proximal coronary artery and lead to sudden death. A very lethal combination for sudden death would be the presence of severe coronary artery disease, an acute angle takeoff and an ostial valve-like ridge.

Adult↗
PubMed1984

Blood flow to infarct and surviving myocardium: implications regarding the action of verapamil on the acutely ischemic dog heart.

After coronary occlusion, myocardium originally supplied by the occluded vessel ultimately separates into infarct and surviving muscle. To clarify this process, evolution of collateral blood flow to infarct and to surviving myocardium was retrospectively analyzed after permanent left anterior descending occlusion in 24 closed chest dogs. Microspheres were injected before occlusion and 5 and 20 minutes and 4 hours after occlusion. Ten minutes after occlusion, dogs received either verapamil, 0.4 mg/kg, followed by 0.6 mg/kg per hour for 6 hours (n = 10) or equivalent saline solution (n = 14). These dogs were sacrificed 3 days later, the distribution of the occluded artery was defined by dye perfusion and infarcted myocardium was determined by triphenyltetrazolium staining of heart slices. Surviving muscle within the distribution of the occluded artery was divided into medial regions adjacent to the infarct (medial adjacent) and remote from the infarct (medial remote) and lateral regions adjacent to infarct (lateral adjacent) and remote from the infarct (lateral remote). In both control and verapamil groups, collateral flows in all regions increased significantly by 140 to 400% over 4 hours. However, the relative magnitude of collateral flow to different regions showed a consistent order: infarct less than medial adjacent less than medial remote less than lateral remote. There were no significant differences in regionally matched flows or size of infarction between control and verapamil-treated groups. Collateral perfusion begins to show distinctive patterns of change in infarct and surviving muscle very soon after coronary occlusion. Collateral flow within subdivisions of the occluded coronary artery bed increases as distance from the infarct increases, with lateral segments having higher flows than medial segments. This relation persists during the first 4 hours after occlusion. In this study, verapamil neither increased collateral flow to the occluded bed nor altered minimal flow requirements for myocardial survival.

Animals↗
PubMed1984

Effect of platelet-activating factor on coronary circulation of the domestic pig.

The platelet-activating factor released by white blood cells and platelets has been shown to be 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC). To fully understand the cardiovascular actions of this substance, we examined the effects of AGEPC on coronary blood flow (CBF) and other hemodynamic parameters in anesthetized open-chest domestic pigs. Mean arterial blood pressure (MBP), electrocardiogram, heart rate (HR), left ventricular pressure, and CBF were continuously recorded. AGEPC was injected (bolus, 0.1 ml) into the left anterior descending coronary artery at increasing doses of 0.03-10 nmol. Intracoronary AGEPC produced biphasic changes in CBF: a dose-dependent increase in CBF (up to 50%) followed by a decrease (up to 92%) in CBF. The changes in CBF were not directly related to any systemic effect, although MBP was reduced consistently after a dose higher than 1 nmol of AGEPC. The increase in CBF produced by AGEPC was not affected by pretreatment with indomethacin (6 mg/kg) or FPL 55712 (1 or 3 mg), an inhibitor of slow-reacting substance of anaphylaxis (SRS-A). The decrease in CBF produced by AGEPC was attenuated by FPL 55712 and blocked by indomethacin. These data suggest that AGEPC release from aggregating platelets might play a major role in modulating CBF and cardiac function in states involving platelet-coronary interaction.

Animals↗
PubMed1984

Length of left main coronary artery. Lack of correlation to coronary artery dominance and bicuspid aortic valve: an autopsy study of 54 cases.

Previous coronary angiographic data have suggested that the left main length of the coronary artery correlated with dominance (origin of the posterior descending branch) and bicuspid aortic valves. In our autopsy study with direct measurements of left main lengths, 41 patients with tricuspid aortic valves and 13 with bicuspid aortic valves were examined for right, left, or codominance. There was no statistically significant difference in either coronary dominance or the length of left main coronary artery between the congenital bicuspid and tricuspid aortic valves. Age, sex, heart weight, extent of coronary artery disease, left ventricular wall thickness, and site of prior infarction did not correlate with left main length or dominance. Thus, short left main lengths do not correlate with coronary dominance or with aortic valves. Angiographic assessment of left main coronary artery length is subject to magnification, oblique projection, and catheter position errors.

Adult↗
PubMed1983

Clinical and electrophysiologic assessment of oral flecainide acetate for recurrent ventricular tachycardia: evidence for exacerbation of electrical instability.

Four patients with recurrent, symptomatic ventricular tachycardia (VT) refractory to conventional antiarrhythmic agents were given flecainide acetate to control arrhythmias. Ventricular stimulation studies were performed in all patients before and 1 to 2 weeks after initiation of oral flecainide therapy. Before flecainide, all patients had easily inducible VT that was morphologically identical to their spontaneously occurring arrhythmia. Flecainide increased the mean PR interval (from 0.17 to 0.23 second), mean QRS duration (from 0.08 to 0.12 second) and mean ventricular effective refractory period (from 235 to 270 ms). Mean corrected QT interval did not change (0.51 second). In 2 patients, VT could not be induced during follow-up stimulation studies. One patient has been treated successfully for 10 months, with no clinically apparent episodes of VT. One patient had recurrent nonsustained VT and was withdrawn from the study as a treatment failure after 6 months of therapy. Two patients had inducible, polymorphous VT that degenerated into ventricular fibrillation that required 2 countershocks before the successful restoration of sinus rhythm. One of these patients had VT stimulation by atrial pacing at a cycle length of 320 ms in the postflecainide electrophysiologic study. VT was not inducible by atrial pacing during this patient's preflecainide study. Thus, sustained oral flecainide administration may precipitate serious electrical instability in susceptible patients, and ventricular stimulation studies and other clinical variables may be useful in selecting patients with recurrent VT who may benefit or may be endangered by oral flecainide therapy.

Administration, Oral↗
PubMed1983

Effects of FPL-55712 or indomethacin on leukotriene-induced coronary constriction in the intact pig heart.

Intracoronary leukotriene D4, 0.1-3.0 micrograms (0.2-6.0 nmol), produced dose-dependent decreases in coronary flow of anesthetized pigs. Pretreatment with intracoronary FPL-55712 (0.1, 0.3 and 1.0 mg) reduced coronary constriction due to 1.0 micrograms leukotriene D4 by up to 77%. FPL-55712 did not produce sustained alterations in coronary flow, left ventricular end-diastolic pressure, systemic arterial pressure, or heart rate. Indomethacin pretreatment (6 mg/kg i.v.) had no effect on leukotriene-induced coronary constriction. Inhibition produced by FPL-55712 may be useful in disease states involving leukotriene-mediated coronary constriction.

Animals↗
PubMed1983

Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart.

Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C4 and D4 administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C4, D4, and E4 into the coronary artery of the domestic pig. Increasing doses (0.1, 0.3, 1.0, and 3.0 micrograms) of leukotrienes C4, D4, and E4 were injected into the left anterior descending coronary artery of 8 open-chest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean +/- standard error); C4 = 80 +/- 9%, p less than 0.001; D4 = 81 +/- 3%, p less than 0.001; E4 = 64 +/- 12%, p less than 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 micrograms) of leukotrienes C4 and D4. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection. We conclude that leukotrienes C4, D4, and E4 are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory changes.

Animals↗
PubMed1983

The effects of nitroglycerin-methoxamine combination on infarct size in conscious dogs.

The effect of nitroglycerin combined with methoxamine in reducing infarct weight was studied in conscious dogs. Ten minutes after permanent left anterior descending (LAD) coronary artery occlusion, 10 dogs received nitroglycerin (450 micrograms bolus IV, then 300 micrograms/min for 4 hours) and methoxamine as needed to maintain blood pressure and heart rate. No dogs in heart failure. Ten control dogs received saline solution. Dogs were sacrificed 3 days later. The region at risk of infarction was delineated by simultaneously perfusing the aortic root with Evans blue and the distal LAD artery with saline solution under equal pressures. Slices of stained hearts were incubated with tetrazolium to identify infarct. Total weight of left ventricle (LV), risk region, and infarct was measured. Nitroglycerin-treated dogs showed no difference from control dogs in infarct weight (26.2 +/- 5.9 gm +/- SE vs 27.7 +/- 5.6 gm), percent risk region/LV (36.0 +/- 1.4% vs 37.9 +/- 3.1%), or present infarct/LV (23.5 +/- 5.2% vs 24.8 +/- 4.9%). In a subgroup with risk region/LV less than or equal to 35%, nitroglycerin reduced infarct weight by 45% (8.8 +/- 8.5% vs 15.9 +/- 7.9%), percent infarct/LV by 49% (7.1 +/- 6.8% vs 13.8 +/- 6.6%), and percent infarct/risk region by 41% (23.0 +/- 22.0% vs 38.9 +/- 15.9%). Because of the small number of dogs in the study, differences were not significant. In dogs with risk region/LV greater than 35%, nitroglycerin had no effect. Thus, in dogs without overt heart failure, nitroglycerin may salvage ischemic tissue within small areas at risk of infarction, but the results are not definitive. However, our results clearly demonstrate that in the absence of failure, nitroglycerin does not reduce the size of large infarcts.

Animals↗
PubMed1983

Role of cellular proteinases in acute myocardial infarction. I. Proteolysis in nonischemic and ischemic rat myocardium and the effects of antipain, leupeptin, pepstatin and chymostatin administered in vivo.

To test the hypothesis that cellular proteinases contribute to ischemic myocellular death, measurements were made of tyrosine release (an index of overall proteolysis) from incubated slices of nonischemic and ischemic myocardium obtained at various times after coronary artery occlusion in rats. Proteolysis failed to increase in ischemic myocardium throughout the first 24 hours of occlusion, when irreversible damage develops, indicating that cellular proteinases do not undergo generalized activation in this phase. These data represent the first assessment of myocardial proteolysis throughout the development of ischemic death, and suggest that cellular proteinases do not play a causal role in this process. However, the possibility remains that ischemia selectively accelerates the breakdown of vital proteins, a phenomenon that may not be detected by measuring overall proteolysis. To determine whether future studies on the effects of proteolytic inhibition on infarct size are feasible, the ability of the proteinase inhibitors antipain, leupeptin, pepstatin and chymostatin, given in vivo, to interfere with proteolysis in ischemic myocardium was also evaluated. Leupeptin (10 or 40 mg/kg) inhibited proteolysis in a dose-related fashion (-49 and -72%, respectively, p less than 0.001). Antipain (20 mg/kg) decreased protein breakdown by 60% (p less than 0.001). The combination of antipain (20 mg/kg), leupeptin (40 mg/kg) and pepstatin (5 mg/kg) suppressed proteolysis almost completely at both 15 minutes (-88%, p less than 0.001) and at 6 hours (-72%, p less than 0.05) of ischemia, that is, throughout the development of irreversible injury. These results demonstrate that whatever proteolysis is occurring during acute myocardial infarction is largely mediated by cathepsins A, B, D, L and H and by calcium-activated neutral protease (that is, the enzymes sensitive to the inhibitors used). Because antipain, leupeptin and pepstatin significantly suppress such proteolysis, these agents might be useful in further assessing any potential contribution of cellular proteinases to the production of ischemic myocellular death. In addition, this study provides a new experimental model that affords serial assessments of regional myocardial proteolysis during the evolution of myocardial infarction.

Animals↗