Search PubMed⌕ Search

Biomedical subjects

L R Bush

Publications and source records attributed to L R Bush.

At least 37 records · Page 2Linked to original sources
PubMed1984

Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries.

Recent studies suggest that platelet activation and subsequent thromboxane (TX) A2 release play important roles in certain coronary syndromes. To further test this possibility, we examined the ability of a selective TXA2-synthetase inhibitor, dazoxiben (UK-37-248), to abolish cyclic flow reductions (CFRs) that occur in experimentally stenosed canine coronary arteries. CFRs, which are characterized by progressive declines in coronary blood flow and interrupted by sudden and usually spontaneous restorations of flow, were produced by placing hard plastic cylindrical constrictors (5 mm long X 4.5 mm outer diameter) on the proximal left anterior descending or circumflex coronary artery in open-chest, anesthetized dogs. Coronary blood flow was measured with pulsed Doppler flow probes placed proximal to the constrictors and regional myocardial blood flow with 15 micron radiolabeled microspheres. CFRs were observed for 1 hr, during which coronary blood flow was monitored continuously. Regional myocardial blood flow was measured before constriction, when coronary blood flow appeared to be at its nadir, and after spontaneous restorations of flow. After 1 hr dazoxiben (2.5 mg/kg iv) or an equal volume of saline was given and coronary blood flow was monitored for another hour. Dazoxiben abolished CFRs completely in 18 of 28 dogs and significantly reduced their frequency in the dogs receiving the drug (10.1 +/- 0.8 vs 3.2 +/- 1.0 per hour [+/- SE]; p less than .001, n = 28). The frequency and magnitude of variations in cyclic blood flow were unchanged after saline (8.8 +/- 0.8 vs 9.0 +/- 1.0 per hour; p = NS, n = 13). The lowest levels of coronary blood flow before and after dazoxiben were 8.6 +/- 2.2% and 48.8 +/- 5.4% of control, respectively (p less than .001, n = 28), whereas this parameter remained unchanged after saline (18.7 +/- 5.7% vs 13.4 +/- 4.1%, respectively; n = 13). The levels of TXB2 and 6-keto-prostaglandin (PG) F1 alpha (stable breakdown products of TXA2 and prostacyclin, respectively) were measured in blood collected from aortic and distal coronary arterial catheters before coronary constriction (control), during CFRs, and after administration of dazoxiben. TXB2 levels measured distal to the stenosis were increased fivefold during CFRs (352 +/- 126 vs 71 +/- 18 pg/ml plasma; p less than .03) and were reduced to preconstriction (control) levels by dazoxiben (57 +/- 12 pg/ml). Aortic TXB2 levels almost doubled with CFRs and also returned to control levels after dazoxiben.(ABSTRACT TRUNCATED AT 400 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.

Adenosine Diphosphate↗
PubMed1982

The effect of diltiazem on coronary thrombosis in the conscious canine.

The effect of diltiazem vs. saline was studied in a conscious canine model of coronary thrombosis. Diltiazem given as a 0.75 mg/kg loading dose intravenously followed by 0.4 mg/kg intravenously every 4 h for 24 h had no significant effect on thrombus wet weight, left ventricular infarct size, frequency of ventricular arrhythmias or ex vivo platelet aggregation. The search for antithrombotic agents using in vitro or ex vivo platelet aggregation studies should include concomitant in vivo thrombosis studies using therapeutic dosages of the drug in question.

Animals↗
PubMed1982

Relationship between beta-adrenergic receptor numbers and physiological responses during experimental canine myocardial ischemia.

In the present study, we evaluated the physiological responsiveness of the increased numbers of beta-adrenergic receptors in ischemic canine myocardium to in vivo stimulation by (-)-isoproterenol and epinephrine. After 1 hour of temporary proximal left anterior descending coronary artery occlusion and during a 15-minute period of reflow, dogs received (1)-isoproterenol intravenously at a rate sufficient to increase their heart rates 20--40 beats/min. Following the infusion of isoproterenol, myocardial tissue was obtained from the LV ischemic and nonischemic regions for measurement of beta-adrenergic receptor numbers, cyclic AMP content, and phosphorylase b to a conversion. beta-Adrenergic receptor numbers were significantly increased in the left ventricular (LV) ischemic tissue. The administration of (-)-isoproterenol was associated with significant increases in cyclic adenosine monophosphate content and phosphorylase b to a conversion in the LV ischemic tissue. Also, the administration of (-)-epinephrine significantly increased the phosphorylase b to a conversion in ischemic tissue over the nonischemic tissue and this conversion was blocked by pretreatment with (+/-)-propranolol. These data suggest that, in this experimental model, the increased numbers of beta-adrenergic receptors in canine LV ischemic tissue are capable of translating physiological responses when they are activated with an appropriate agonist in vivo.

Animals↗
PubMed1981

Comparative effects of aspartate and glutamate during myocardial ischemia.

The effects of amino acids aspartate (Asp) and glutamate (Glu) on recovery of contractile function and preservation of compliance were studied in globally ischemic, isolated, blood-perfused cat hearts. Ischemia-induced declines in contractility and compliance were measured with an intraventricular fluid-filled balloon. Asp and Glu were delivered to isolated hearts in physiological salt solution (PSS) containing 10 mM glucose, just prior to, and intermittently during (every 15 min for 1 min) 1 h of normothermic ischemia. Isolated hearts which received Asp and Glu showed recoveries of left ventricular (LV) developed pressure of 79 +/- 8 and 50 +/- 7% of their preischemic values, respectively, compared to 34 +/- 7% in hearts perfused only with PSS. These alterations of contractile function were paralleled by changes in LV compliance. The addition of amino-oxyacetate, and aminotransferase inhibitor, to Asp- containing PSS markedly attenuated the beneficial effects of this amino acid. The results indicate that certain amino acids can protect the ischemic myocardium, presumably through effects on intermediary metabolism.

Animals↗
PubMed1981

Protective effects of diltiazem during myocardial ischemia in isolated cat hearts.

The protective effects of diltiazem, a calcium channel blocker, were studied in isolated, blood-perfused cat hearts subjected to 60 or 90 min of global ischemia, followed by reperfusion of 60 or 120 min, respectively. Ischemia-induced alterations of left ventricular (LV) developed pressure (DP) and compliance, measured with an intraventricular fluid-filled latex balloon, were correlated with respiratory activity in vitro of mitochondria isolated from ischemic-reperfused LV myocardium. Nontreated isolated hearts sustained severe declines of LVDP as a result of 60 (-50 +/- 8%) and 90 min (-83 +/- 7%) of ischemia, whereas diltiazem-treated hearts demonstrated only minor losses of LVDP (-17 +/- 8 and -26 +/- 2%). Diltiazem prevented losses of compliance caused by 60 or 90 min of ischemia, which were severe in nontreated hearts after the latter period of ischemia. The progressive deterioration of mechanical function observed in nontreated hearts was paralleled by depressed mitochondrial oxygen consumption and respiratory control. The respiratory activity of mitochondria isolated from cat heart mitochondria. Diltiazem also prevented significant elevations of tissue and mitochondria Ca++ content, reflecting inhibition of Ca++ influx during ischemia and reperfusion. Also, recovery of ATP levels was greater after 60 min each of ischemia and reperfusion in diltiazem-treated hearts. Thus, diltiazem exerts direct, cardioprotective effects during myocardial ischemia, presumably by inhibiting transmembrane Ca++ fluxes.

Adenosine Triphosphate↗
PubMed1980

Protective effects of beta-adrenergic blockade in isolated ischemic hearts.

The protective effects of the beta-adrenergic blocking drugs, propranolol and atenolol, were tested in a model of global ischemia and assessed electron microscopically. Cats isolated hearts were perfused retrogradely with arterial blood drawn from donor cats. After a period of equilibration, isolated hearts were rendered globally ischemic for 1 h and subsequently reperfused for another hour. Hearts were then flushed with physiological salt solution followed by perfusion-fixation with cacodylate-buffered glutaraldehyde, containing ionic lanthanum. Lanthanum was included as a probe of myocardial membrane integrity. Left ventricular subendocardial samples were processed and examined electron microscopically. Nontreated hearts, which underwent normothermic ischemia and reperfusion, displayed extensive ultrastructural damage. Nonischemic and donor cat control myocardial tissue appeared normal in all respects. Hearts that received either propranolol or atenolol maintained their ultrastructural integrity, resembling controls. Ionic lanthanum proved to be reliable as a marker of membrane integrity and permeability, as nontreated hearts displayed intracellular deposition of the marker, indicating that deteriorations of membrane integrity occurred. The results suggest that beta-adrenergic blockade may be valuable in preserving myocardium subjected to ischemia and reperfusion.

Adrenergic beta-Antagonists↗
PubMed1980

Protective effects of dimethyl-propranolol (UM-272) during global ischemia of isolated feline hearts.

This study was designed to determine the effects of dimethyl-propranolol (UM-272) on myocardial injury after global ischemia of isolated feline hearts. Untreated ischemic hearts developed contracture, resulting in a leftward shift of the diastolic pressure-volume curve. Active pressure development in perfused ischemic hearts was significantly depressed compared to preischemic values. Untreated ischemic hearts exhibited increased water, sodium (Na+) and calcium (Ca++) contents and depletion of potassium (K+). The Ca++ accumulating ability of cardiac microsomal fractions isolated from untreated ischemic hearts was severely depressed. In hearts treated with UM-272, active ventricular pressure development after ischemia declined to the same extent as in untreated hearts, but ischemic contracture in treated hearts was delayed and completely reversed by reperfusion. Treated hearts were not depleted of K+ and changes in Na+ and Ca++ were significantly less than in untreated hearts. Microsomal Ca++ accumulation in the treated group was well preserved compared to that in untreated hearts. Experiments in which hearts were paced during UM-272 administration suggest that decreased myocardial oxygen consumption contributes substantially to the protective effects of UM-272. In addition, UM-272 may protect the ischemic heart through direct effects on myocardial Ca++ regulating mechanisms.

Animals↗
PubMed1980

The beneficial effects of oral ibuprofen on coronary artery thrombosis and myocardial ischemia in the conscious dog.

The nonsteroidal anti-inflammatory agent, ibuprofen, was evaluated for its in vivo antithrombotic effects in conscious canines by inducing left circumflex (LCX) coronary artery thrombosis with low amperage stimulation (50 microA for 24 hr) of the intimal surface of the vessel. Oral administration of ibuprofen (75 or 175 mg/kg in divided doses) prevented occlusive LCX thrombosis. Compared to controls, oral ibuprofen treatment resulted in a significant reduction in developed LCX thrombus mass (20 +/0 2 mg vs. 10 +/- 0.3 mg wet weight, P < .005) and left ventricular infarct mass (24 +/- 4% vs. 1 +/- 0.5%, P < .005). Scanning electron microscopy of the luminal surface of the LCX revealed minimal platelet adherence on the damaged intima in ibuprofen-treated animals. In a separate series of experiments, intervention with oral ibuprofen (12.5 mg/kg every 4 hr) reduced the extent of myocardial ischemic injury resulting from 60 min of complete LCX occlusion followed by reperfusion, whether assessed on the basis of the total left ventricular mass (18 +/- 2% vs. 9 +/- 3%, P < .02) or the area at risk (50 +/- 7% vs. 20 +/- 3%, P < .02). These results suggest that ibuprofen possesses significant antithrombotic and myocardial protective properties which may be valuable in the prevention of coronary artery thrombosis and ischemic heart disease.

Administration, Oral↗
PubMed1975

Meet Dr. Bush.

Explore the source record for details and available documents.

Dentistry↗
PubMedDate not supplied

Time-dependent changes in canine cardiac mitochondrial function and ultrastructure resulting from coronary occlusion and reperfusion.

Time-dependent changes in mitochondrial function and structure resulting from 1 hr of left circumflex coronary artery occlusion followed by 2 to 24 hr of reperfusion were examined. These changes were correlated with changes in myocardial ultrastructure, tissue water content, infarct size and mitochondrial calcium content. The heart was removed after different periods of reperfusion, and mitochondria were isolated from ischemic and nonischemic regions of the left ventricle. Tissue samples from ischemic and nonischemic myocardium also were taken for electron microscopy and tissue water content determinations. Infarct size was measured by the nitroblue tetrazolium staining method. Oxygen consumption by mitochondria isolated from ischemic and nonischemic myocardium was measured in vitro. Mitochondria from ischemic myocardium showed time-dependent decreases in rates of oxygen consumption and tightness of coupling. Electron microscopy revealed progressive ultrastructural deterioration in ischemic myocardium, including accumulation of calcium deposits within mitochondria, a finding corroborated by elevated concentrations of calcium in mitochondria isolated from the same area. Tissue wet-to-dry weight ratios were increased significantly in ischemic myocardium. A small, but significant, decrease in respiratory function was observed in mitochondria isolated from nonischemic myocardium several hrs after reperfusion; however, normal respiration was observed 24 hrs after release of occlusion. This latter observation indicates that the nonischemic zone also is affected by regional ischemia. The results obtained indicate that temporary left circumflex artery occlusion and reperfusion result in progressively decreasing mitochondrial function and structure within the ischemic myocardium, and that these changes are accompanied by cellular electrolyte alterations.

Adenosine Diphosphate↗
PubMedDate not supplied

Effect of diltiazem on extent of ultimate myocardial injury resulting from temporary coronary artery occlusion in dogs.

The calcium antagonist, diltiazem, was evaluated for its ability to reduce the extent of myocardial injury resulting from 90 min of left circumflex (LCX) coronary artery occlusion in anesthetized dogs. Administration of diltiazem (0.75 mg/kg over 10 min, followed by 600 microgram/kg/h for 4 h) was initiated 30 min prior to LCX occlusion. Regional myocardial blood flow (RMBF) was measured with radioactive microspheres 30 min after LCX occlusion, and at 45 min and 24 h after reperfusion. At 24 h, after obtaining hemodynamic and RMBF measurements, excised hearts were processed by perfusion staining to determine the percent of left ventricle (LV) perfused by LCX (area at risk) and infarct size, with triphenyltetrazolium chloride. Infarct size, expressed as a percentage of the area at risk, was significantly lower in the diltiazem-treated group compared to the control group (27 +/- 4 vs. 42 +/- 5%, respectively). The area at risk, expressed as a percentage of left ventricular mass, was similar in both groups [41 +/- 2 and 44 +/- 3% (area at risk-LV)]. In addition, the marked elevation of tissue Ca2+ content in noninfarcted and infarcted myocardium within the area at risk (18 +/- 2 and 42 +/- 8 mumol Ca2+/g) in control animals was attenuated by diltiazem (6 +/- 3 and 18 +/- 8 mumol Ca2+/g). Diltiazem did not increase blood flow to ischemic myocardium during LCX occlusion. However, reflow to the inner layers of formerly ischemic myocardium during reperfusion was significantly greater in diltiazem-treated dogs. Both arterial blood pressure and heart rate were significantly lower in the diltiazem -treated group. In addition, mortality (1 vs. 4) and occurrence of ventricular arrhythmias during reperfusion were lower in diltiazem-treated dogs. The data suggest that diltiazem reduces myocardial ischemic injury by lowering myocardial oxygen demands indirectly via favorable hemodynamic alterations, and directly by limiting transmembrane Ca2+ fluxes during ischemia and reperfusion.

Animals↗
PubMedDate not supplied

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. II. Studies with dopamine and ouabain in the barbiturate-anesthetized dog.

To test the hypothesis that selective increases in inotropic state without concomitant acceleration of heart rate would not augment acute ischemic injury in the non-failing heart of the anesthetized dog, we carried out studies in 16 dogs subjected to serial 10-min occlusions of the left anterior descending coronary artery. The severity of ischemic injury was determined by mass spectrometric measurement of the rise in intramural carbon dioxide tension (delta PmCO2) in the ischemic zone, and inotropic stimulation was provided by either dopamine or ouabain. In Group I dogs (n = 9), dopamine [4 +/- 1 (SD) micrograms/kg/min] was infused before the final occlusion to increase left ventricular (LV) dP/dt without changing heart rate; delta PmCO2 was not significantly different between control (64 +/- 21 mm Hg) and postdopamine (67 +/- 22 mm Hg) occlusions. In Group II dogs (n = 7), ouabain (0.03 mg/kg) was administered 15 min before the final occlusion, resulting in a significant increase in LV dP/dt and a slight decrease in heart rate (average 13 beats/min); delta PmCO2 was slightly decreased in the occlusion after ouabain (60 +/- 12 mm Hg) compared with the preceding occlusion without inotropic stimulation (67 +/- 13 mm Hg), p less than 0.05. Throughout the studies in both groups, there were no significant changes in collateral blood flow to the central ischemic zone, or in heart rate-systolic arterial pressure product, an estimate of myocardial oxygen consumption. Analyses of individual responses revealed that when LV dP/dt increased by 50% or more after dopamine or ouabain, ischemia was more likely to intensify.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗