Biomedical subjects

C V Jackson

Publications and source records attributed to C V Jackson.

At least 19 recordsLinked to original sources

PubMed2000

Pharmacological profile of recombinant, human activated protein C (LY203638) in a canine model of coronary artery thrombosis.

The antithrombotic activity of recombinant, human activated protein C (rh-APC, LY203638) was examined in a model of canine coronary artery thrombosis. Three doses of rh-APC (0.5, 1.0, and 2.0 mg/kg/h) were administered intravenously for 2 h. Whole blood clotting times (thrombin time, activated partial thromboplastin time), ex vivo platelet aggregation, and template bleeding times were determined. Activated partial thromboplastin time significantly increased 2- and 3.7-fold during the 2-h infusion of rh-APC (1.0 and 2.0 mg/kg/h, respectively); thrombin time did not change. Intravenous infusions of rh-APC (1.0 and 2.0 mg/kg/h) produced significant prolongations to occlusion, 186 +/- 21 and 190 +/- 22 min, respectively, compared with the vehicle and the 0.5 mg/kg/h group (86 +/- 12 and 93 +/- 17 min, respectively). Vessel patency was better at the end of the experiment in the intermediate- and high-dose groups (3 of 6 and 3 of 5 vessels, 1.0 and 2.0 mg/kg/h, respectively) compared with the vehicle and 0.5 mg/kg/h groups (0/5 and 0/6, respectively). Only the 1.0 mg/kg/h group was found to have significantly elevated template bleeding times, with peak increases seen 60 min into the drug infusion. All groups had returned to baseline values by the end of the study. There was no observed inhibition of platelet aggregation. These data demonstrate that recombinant, human activated protein C is an effective anticoagulant and antithrombotic agent in the dog.

Animals↗

PubMed1998

Intravenous administration of the glycoprotein IIb-IIIa receptor antagonist 7E3 induces reperfusion of an acute thrombotic occlusion of the canine coronary artery.

The ability of the F(ab')2 fragment of the murine monoclonal antibody 7E3 directed against the platelet glycoprotein IIb-IIIa receptor complex, to cause reperfusion of a totally occluding coronary artery thrombus was examined alone and in combination with aspirin and heparin in a canine model of coronary artery thrombosis. A localized thrombus was produced in the left circumflex coronary artery in open-chest dogs by electrolytic injury of the endothelium. Intravenous administration of a single injection of 5.0 mg/kg aspirin and heparin (80 U/kg bolus plus 30 U/kg/hr x 2 hr) maintained vessel patency for approximately 101 +/- 15 minutes. After vessels had been completely occluded for 5 minutes (in the presence of aspirin + heparin), a single intravenous injection of saline (10 ml) or 0.8 mg/kg 7E3 was administered. Reperfusion was observed in all dogs (6 of 6) receiving 7E3; 4 of 6 dogs maintained vessel patency throughout the course of the 2 hour observation period. Activated partial thromboplastin and thrombin times were elevated 1.4 and 9 fold, respectively, in groups that received heparin. Template bleeding times were significantly elevated in the groups receiving 7E3. In the control group, 2 of 5 dogs reperfused briefly, however neither were patent at the end of the observation period. A third group of 4 dogs which did not receive the aspirin + heparin regimen was allowed to occlude and 5 minutes later received a single intravenous injection of 0.8 mg/kg 7E3. None of the 4 dogs in this group reperfused at any time during the study. There were no significant differences between groups in regards to hematological or hemodynamic measurements during the experiment. We concluded from these findings that the monoclonal antibody, 7E3 can promote the dissolution of friable coronary artery thrombi that evolve during standard anticoagulant and antiplatelet therapy.

Abciximab↗

PubMed1996

Antithrombotic assessment of the effects of combination therapy with the anticoagulants efegatran and heparin and the glycoprotein IIb-IIIa platelet receptor antagonist 7E3 in a canine model of coronary artery thrombosis.

BACKGROUND: There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab')2] with both heparin and the novel tripeptide arginal antithrombin efegatran (LY294468) in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg . kg-1. h-1), heparin (80 U/kg, single injection, plus 30 U . kg-1. h-1), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (P < .05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin-treated groups, respectively). Bleeding times were increased (P < .05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation. CONCLUSIONS: The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.

Abciximab↗

PubMed1996

A family of arginal thrombin inhibitors related to efegatran.

Three new tripeptide arginal thrombin inhibitors were shown to have potent anticoagulant and antithrombotic activity: D-MePhg-Pro-Arg-H (LY287045), D-1-Tiq-Pro-Arg-H (LY294291), and D-MePhe-Pro-Arg-H (Efegatran). Efegatran and the related arginals differ mechanistically from old and from new anticoagulant agents. As illustrated with x-ray diffraction analysis of crystals of the LY294291 complex with human thrombin, the family of arginals binds thrombin with the P3, P2, and P1 residues interacting with the putative S3, S2, and S1 fibrinogen-binding sites. A hemi-acetal bond at Ser 195 was shown to contribute to the tight-binding reversible competitive thrombin inhibition properties observed with the arginal family. Tight-binding Kass values from thrombin inhibition studies correlated with thrombin clottin inhibition potency. The thrombin time (TT) assay was prolonged twofold with 33 nM Efegatran, which demonstrated an apparent Kass value of 0.8 x 10(8) L/mol (for comparison, 17 nM hirudin was required to prolong the TT assay two-fold). There are empirical anticoagulant selectivity differences between Efegatran and hirudin, manifested by large activated partial thromboplastin time (aPTT)/TT effect ratios (30 to 55) found with the arginals, as compared to the small aPTT/TT effect ratio (2 to 3) found with hirudin. The underlying anticoagulant mechanism differences between the arginals and hirudin appear to be confined to the aPTT pathway and, therefore, might involve different effects toward thrombin feedback activation of factor VIII. The arginals did not substantially inhibit other coagulation factor serine proteases. Antithrombotic effects of Efegatran and the arginal family occur at low infusion doses in dogs and appear to correlate with effects on TT without requiring perturbation of the aPTT. Selectivity properties regarding the fibrinolytic enzymes were shown to be important for successful use of the arginals in vivo as adjunctive agents during tissue plasminogen activator (t-PA) thrombolysis. The data suggest that LY287045, LY294291, and Efegatran should be expected to be useful as antithrombotic adjuncts to thrombolytic therapy with t-PA, urokinase, or streptokinase and should be expected to spare endogenous fibrinolysis. Efegatran has been evaluated in phase I clinical studies and is currently under clinical investigation in phase II protocols as a new cardiovascular anticoagulant.

Animals↗

PubMed1993

Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis: a comparison with heparin in a canine model of coronary artery thrombosis.

Direct inhibition of thrombin with agents such as hirudin and argatroban reduces reocclusion rates during experimental coronary thrombolysis. We compared the adjunctive potential of the tripeptide thrombin inhibitor D-methyl-phenylalanyl-prolyl-arginal (LY294468) during thrombolysis with tissue-type plasminogen activator (t-PA) with the less specific tripeptide thrombin inhibitor Boc-D-phenylalanyl-prolyl-arginal (LY178207) and the standard anticoagulant heparin. The left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and coronary blood flow (CBF) was measured in 26 anesthetized dogs. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the artery, producing an occlusive thrombus. Thrombolytic/adjunctive therapy was started 1 h later in the following groups: (a) t-PA alone (0.9 mg/kg, 1-h infusion), (b) t-PA + LY294468 (0.5 or 1 mg/kg/h, 2-h infusion), (c) t-PA + LY178207 (0.5 or 1 mg/kg/h, 2-h infusion), and (d) t-PA + heparin (80 U/kg bolus + 30 U/kg/h, 2-h infusion). LY294468 provided antireocclusive efficacy (time to reocclusion = > 200 min as compared with 65 min for t-PA alone; six of nine patent vessels vs. zero of six, respectively, at the end of the experiment), with no bleeding liability during t-PA-induced thrombolysis. Heparin and LY178207 were ineffective adjunctive agents. Heparin, however, significantly increased template bleeding times. LY294468 was effective as an adjunctive agent during thrombolysis and may represent a safer (less bleeding) and more effective adjunctive agent than heparin.

Animals↗

PubMed1992

Pharmacological assessment of the antithrombotic activity of the peptide thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766), in a canine model of coronary artery thrombosis.

The antithrombotic activity of the tripeptide thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766), was compared to heparin in a model of canine coronary artery thrombosis. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. Drug administration was started 15 min before initiation of intimal injury. Clotting times and ex vivo platelet aggregation were determined on citrated blood samples. Gingival template bleeding times were determined. Clotting times (thrombin time; activated partial thromboplastin time, APTT; prothrombin time, PT) increased in a dose-dependent manner with both anticoagulants. The two anticoagulants selectively inhibited thrombin-induced platelet aggregation. GYKI-14766 and heparin were found to delay thrombosis significantly when compared to vehicle-treated animals; minimum effective antithrombotic doses were 0.25 mg/kg/h and 80 U/kg + 30 U/kg/h, respectively. GYKI-14766 (0.25 mg/kg/h) had no effect on template bleeding time, APTT or PT. Heparin (80 U/kg + 30 U/kg/h), however, was associated with a 2.5- to 3.0-min increase in template bleeding time, a 1.8-fold and 1.7-fold increase in APTT and PT, respectively. Antithrombotic efficacy was achieved at doses of GYKI-14766 that did not affect APTT, PT or template bleeding time, whereas antithrombotic efficacy observed with heparin was associated with significant increases in APTT, PT and template bleeding time. These data demonstrate that the tripeptide thrombin inhibitor, GYKI-14766, could potentially prove to be a safer and more effective antithrombotic agent than heparin.

Animals↗

PubMed1992

Comparison of the thrombolytic activity of the novel plasminogen activator, LY210825, to anisoylated plasminogen-streptokinase activator complex in a canine model of coronary artery thrombolysis.

We have compared the thrombolytic efficacy of a novel single-chain, recombinant tissue-type plasminogen activator variant, LY210825, containing the second kringle and serine protease domains of native tissue-type plasminogen activator, with anisoylated plasminogen-streptokinase activator complex (APSAC). Male hounds (16-22 kg) were anesthetized, the left circumflex coronary artery was isolated and an electromagnetic flow probe was placed around the artery proximal to the first main branch for the measurement of coronary blood flow. An occlusive thrombus was formed after electrolytic injury of the intima of the coronary artery. After an occlusion period of 1 hr, either LY210825 (n = 8) or APSAC (n = 6) was administered as a single i.v. injection of 0.45 mg/kg. Blood was drawn (3.8% citrate) for determination of plasma fibrinogen, plasminogen and alpha-2 antiplasmin. Time to reperfusion was significantly faster with LY210825 than with APSAC, 20 +/- 2 vs. 54 +/- 8 min, respectively. The incidence of reocclusion was similar for both agents. APSAC produced significant depletion of alpha-2 antiplasmin, plasminogen and circulating fibrinogen, whereas LY210825 caused only slight consumption of plasminogen and only small decreases in fibrinogen. After a single injection of LY210825, thrombolytic concentrations of plasminogen activator were available immediately, whereas there was a significant delay in lytic concentrations of active streptokinase-plasmin complex. Consequently, LY210825 reperfused the coronary artery faster than did APSAC. In addition, LY210825 spared plasma fibrinogen, plasminogen and alpha-2 antiplasmin and therefore, could potentially minimize the risk of bleeding complications.

Animals↗

PubMed1990

Thrombolytic activity of a novel plasminogen activator, LY210825, compared with recombinant tissue-type plasminogen activator in a canine model of coronary artery thrombosis.

LY210825, a recombinant tissue-type plasminogen activator (rt-PA), which contains the kringle-2 and serine protease functional domains of native tissue-type plasminogen activator, was previously produced by site-directed mutagenesis in a Syrian hamster cell line. We studied the thrombolytic potential of this molecule in a canine thrombosis model. Male hounds (16-22 kg) were anesthetized; a 2.0-cm segment of the left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and the dogs were instrumented with an electromagnetic flow probe to measure coronary blood flow. An occlusive thrombus was formed after injury of the intimal surface of the LCX with an electrical current applied by a needle-tipped anode placed distal to the electromagnetic flow probe. After 1 hour of occlusion, either LY210825 or rt-PA was administered intravenously according to the following protocols: 1) a 1-hour infusion of either 0.25 mg/kg LY210825 or 0.4 mg/kg rt-PA, 2) single injections of 0.15-0.6 mg/kg LY210825, and 3) a single injection of 0.45 mg/kg LY210825 and a 3-hour infusion of 1.0 or 1.7 mg/kg rt-PA. Plasma half-lives of LY210825 and rt-PA were 58 +/- 7 and 3.3 +/- 0.3 minutes, respectively. LY210825 produced more rapid reperfusion of the LCX than did rt-PA. In the third study, 90% of the rt-PA-treated vessels reoccluded within 1 hour after cessation of drug, whereas only 25% of the LY210825-treated vessels reoccluded during a 4-hour washout period. There were significant, but relatively small, reductions produced by both plasminogen activators on plasma fibrinogen and plasminogen (25-35% decreases). Because of its longer plasma half-life, LY210825 could be administered intravenously as a single injection. In a canine model of coronary artery thrombosis, LY210825 was a more effective thrombolytic agent than was rt-PA.

Animals↗

PubMed1989

Utility of the Wang 18-gauge transbronchial histology needle in the staging of bronchogenic carcinoma.

Use of the Wang 18-gauge histology needle in TBNA was employed as a staging procedure in 29 patients with bronchogenic carcinoma and mediastinal adenopathy demonstrated on chest CT. Twenty patients had malignant aspirates; 12 had both histologic and cytologic specimens demonstrating malignancy; six patients had malignant histologic specimens; two had cancerous cytologic specimens as their only evidence of mediastinal disease. Of the nine negative aspirates, four were true negative at surgery. Five patients had false-negative aspirates. Overall sensitivity of the Wang 18-gauge histology needle in the mediastinal staging of patients with bronchogenic carcinoma was 80 percent. When patients with small cell carcinoma were excluded, sensitivity was 82 percent. The enhanced yield of the 18-gauge histology needle warrants its use in mediastinal staging of bronchogenic carcinoma. We conclude that all patients with bronchogenic carcinoma and mediastinal adenopathy demonstrated on chest CT accessible via TBNA should undergo histology needle aspiration as an initial staging procedure.

Biopsy, Needle↗

PubMed1988

Protection of myocardial function and coronary vasculature by streptokinase.

Coronary artery reperfusion established by thrombolytic agents early in the evolution of an acute myocardial infarction is known to result in the salvage of otherwise jeopardized heart muscle. Recently, experimental evidence has suggested that reactive products of oxygen are formed as a result of reperfusion and can increase the amount of myocardial tissue that becomes irreversibly damaged. The purpose of the present study was to determine if the thrombolytic agent, streptokinase, could serve to scavenge reactive species of oxygen, thereby protecting the myocardium by a mechanism independent of its ability to lyse an occlusive thrombus. Rabbit isolated hearts were perfused at a constant rate with Krebs-Henseleit buffer (25 ml/min, 31 degrees C, pH 7.4) using a modified Langendorff method. Changes in the permeability of the coronary vascular bed were determined with 125I-labeled albumin added to the perfusion buffer. An intraventricular fluid-filled latex balloon connected to a pressure transducer maintained the left ventricle in an isovolumic state and was used to detect changes in myocardial contractility throughout the study protocol. Electrolysis of the oxygenated Krebs-Henseleit perfusion buffer with a 20 mA direct current for 2 min, delivered with a stainless-steel anode (proximal) and a platinum cathode (distal), resulted in the generation of reactive products of oxygen. Perfusion of the isolated heart with buffer containing the products of electrolysis resulted in an increase in mean coronary artery perfusion pressure, from 48 +/- 3 to 121 +/- 6 mm Hg [mean +/- SEM (n = 17)], and an increase in the left ventricular end-diastolic pressure, from 10 +/- 1 to 54 +/- 6 mm Hg. The addition of streptokinase (150 U/ml) or heparin (20 U/ml) to the perfusion medium attenuated the observed increase in coronary artery perfusion pressure from 42 +/- 3 to 73 +/- 9 mm Hg (n = 9) or from 43 +/- 2 to 98 +/- 9 mm Hg (n = 9), respectively. In addition, streptokinase prevented the increase in the left ventricular end-diastolic pressure (11 +/- 1 to 36 +/- 5 mm Hg, n = 9) and preserved left ventricular function as determined by the pressure-volume relationship. Myocardial accumulation of 125I-labeled albumin after exposure of the heart to the reactive products of oxygen was attenuated by the addition of streptokinase or heparin to the buffer solution. The data suggest that streptokinase and, to a lesser extent, heparin may preserve myocardial and coronary vascular function by scavenging reactive oxygen species.

Animals↗

PubMed1988

Vitamin E and Alzheimer's disease in subjects with Down's syndrome.

People with Down's syndrome (DS) are at high risk of developing Alzheimer's disease (AD). The gene coding for superoxide dismutase-/ on chromosome 21 resulting in excess activity of the enzyme with consequent risk of oxidative damage might account for the premature ageing. Vitamin E protects against such damage. Plasma vitamin E levels measured in 12 DS subjects with AD (8.19 +/- 0.77 micrograms/ml) were lower (P less than 0.05) than in 12 DS controls (9.43 +/- 1.57 micrograms/ml). It is suggested that there may be an interaction between risk of AD and the protective action of vitamin E.

Adult↗

PubMed1988

Preoperative pulmonary evaluation.

Factors related to risk of perioperative pulmonary complications include site of incision, obstructive lung disease, prolonged anesthesia time, smoking history with productive cough, and obesity. Hypercapnia is a consistent indicator of high risk. There is no difference between spinal and general anesthesia with regard to risk of pulmonary complications. In patients being evaluated for lung resection, high-risk indicators include predicted postoperative forced expiratory volume in one second of less than 1000 mL, hypercapnia, severe dyspnea on exertion, or advanced age when it is associated with advanced cardiopulmonary disease. Newer methods of assessing cardiopulmonary reserve may prove useful in identifying which patients with one or more of these risk factors are suitable operative candidates. Prevention of postoperative complications in chronic obstructive pulmonary disease patients should begin in the preoperative period with discontinuation of smoking at least eight weeks before surgery and vigorous pulmonary toilet in the 48 to 72 hours before surgery. Prophylactic lung expansion maneuvers can be effective in decreasing the incidence of postoperative atelectasis in high-risk patients undergoing high-risk operations.

Humans↗

PubMed1987

Coronary artery vasodilation in the canine: physiological and pharmacological roles of beta-adrenergic receptors.

The role of beta 1- and beta 2-receptors as modulators of coronary artery vasodilation was studied in the anesthetized dog. The left circumflex coronary artery was cannulated and perfused under constant pressure with blood drawn from the right femoral artery. Coronary blood flow myocardial contractile force were measured with a cannulating electromagnetic flow probe and Walton-Brodie strain gauges, respectively. The left stellate ganglion was isolated distally, and the postganglionic nerves were stimulated with a bipolar electrode. Coronary artery blood flow and regional myocardial contractile force increased in response to stellate nerve stimulation and to the intracoronary administration of norepinephrine (NE), isoproterenol (ISO), and zinterol (ZIN) before selective beta 1-adrenergic receptor blockade with celiprolol (0.3 mg/kg intravenously, i.v.). The administration of celiprolol inhibited the positive inotropic response to both stellate stimulation and to the intracoronary administration of the selected beta-adrenergic receptor agonists. The increase in coronary artery blood flow observed in response to stellate stimulation or to the intracoronary administration of NE was converted to a decrease in flow in the presence of celiprolol. In contrast, however, the intracoronary administration of ISO or ZIN continued to cause coronary vasodilation despite the presence of beta 1-selective adrenergic receptor blockade with celiprolol. Addition of propranolol (1.0 mg/kg i.v.) in the presence of celiprolol completely inhibited the increase in coronary blood flow in response to ISO and ZIN.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1987

Interaction of the formed elements of blood with the coronary vasculature in vivo.

Considerable attention is being given to the interactions that occur among blood platelets, neutrophils, and the vascular endothelium. There is an increasing awareness that the various blood elements interact in the process of thrombus formation and vascular occlusion. In addition, interactions among these cells can lead to the formation and release of vasoactive substances that have the potential to modulate regional blood flow. This review focuses on the coronary vascular bed and an assessment of how cell-cell interactions, under normal physiological conditions as well as in the presence of myocardial injury, may lead to alterations in coronary vascular resistance and myocardial function. Should related events be operative in human clinical states of disease, the circulating elements of the blood may serve as targets in the development of therapeutic interventions to regulate myocardial blood flow.

Animals↗

PubMed1986

Electrolysis-induced myocardial dysfunction. A novel method for the study of free radical mediated tissue injury.

Oxygen-derived free radicals and other oxidizing species are thought to be involved in inflammation and ischemic tissue injuries. Recently, oxygen-derived free radicals also have been implicated in tissue injury of the myocardium subjected to ischemia/reperfusion. The purpose of this investigation was to determine if electrolysis of a physiological buffer would serve as a source of free radicals, and if these radicals would lead to alterations in myocardial function. Isolated Langendorff-perfused rabbit hearts perfused with buffer subjected to a 20 mA D.C. current for 2 min demonstrated significant increases in coronary perfusion pressure (37 +/- 6 mmHg), left ventricular end diastolic pressure (41 +/- 7 mmHg), and loss in left ventricular developed pressure (35 +/- 5%). The free radical scavengers, superoxide dismutase and a combination of tryptophan plus glycine, were effective in protecting the hearts from the effects of electrolysis. The presence of free radicals was semiquantitated with a radical-luminol chemiluminescent assay. In this assay a variety of radical scavengers and antioxidants were effective (i.e., dimethyl sulfoxide, nitro blue tetrazolium, ascorbate, superoxide dismutase, 1, 3-diphenylisobenzofuran, and glycine, catalase), whereas mannitol and tryptophan were not effective. The data indicate that electrolysis of a physiological buffer produces a milieu containing several reactive oxygen species or free radicals that have the potential to produce alterations in a biological system. This method has the advantage over existing protocols for the generation of radicals in that it is a blood-free and an enzyme-free system.

Animals↗

PubMed1986

Alterations in alpha 1-adrenoceptor stimulation of isolated atria from experimental diabetic rats.

This purpose of this investigation was to determine the influence of experimental diabetes (3 months) on the responsiveness of rat isolated atria to alpha 1-adrenoceptor stimulation by phenylephrine. Diabetes was chemically induced with streptozotocin (65 mg/kg i.v.) in 42- to 43-day-old, nonfasted male Sprague-Dawley derived rats. Chronotropic (right atria) and inotropic (left atria) indices were recorded in response to alpha 1-adrenoceptor stimulation by phenylephrine. These experiments were performed in the presence of beta-adrenoceptor antagonism (timolol). Isolated right atria from diabetic rats demonstrated a greater increase in heart rate in response to phenylephrine than did corresponding control atria. Left atria were supersensitive (decrease in EC50 values) and hyperresponsive to alpha 1-adrenoceptor stimulation by phenylephrine when compared with stimulation of control left atria. Diabetic left atria in response to phenylephrine were observed to exchange more radioactive calcium (45Ca2+) than control left atria, whereas both diabetic and control left atria exchanged the same amount of 45Ca2+ during basal contractile conditions. Phenylephrine had no effect on 45Ca2+ efflux from either diabetic or control atria. These results indicate that 3 months of uncontrolled experimental diabetes in the rat produces an enhancement of alpha 1-adrenoceptor activation of isolated atria, and that there is an alteration in Ca2+ mobilization which may contribute to the enhanced receptor activation.

Animals↗

PubMed1986

O2 free radical-mediated myocardial and vascular dysfunction.

In the present investigation electrolysis of a physiological buffer solution for 2 min with a constant current (20 mA, DC stainless steel anode) was observed to generate free radicals, determined by a luminol assay. Rabbit isolated hearts perfused with physiological buffer subjected to electrolysis were observed to undergo an increase in coronary artery perfusion pressure (PP) and in left ventricular end-diastolic pressure (LVEDP), 80 +/- 4 and 52 +/- 7 mmHg, respectively. Immediately after electrolysis of the physiological buffer, the hearts were observed to accumulate and retain (8-fold) more 125I-labeled albumin than hearts perfused with normal buffer without electrolysis, indicating an increased vascular permeability. The free radical scavengers, dimethyl sulfoxide (DMSO) and catalase (CAT), provided significant protection of the hearts against the changes in PP, LVEDP, and vascular permeability. This study demonstrates that toxic oxygen species generated independently of circulating blood elements or enzymatic reactions can have a direct effect on the vasculature of an isolated heart leading to alterations in cardiac function. The protection afforded by the addition of DMSO or CAT to the perfusion system would suggest that the OH. radical and H2O2 were the reactive oxygen species involved in producing the observed vascular and cardiac effects.

Animals↗

PubMed1986

Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.

Animals↗