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Biomedical subjects

J D Folts

Publications and source records attributed to J D Folts.

At least 55 records · Page 3Linked to original sources
PubMed1989

Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors.

We studied the dose-response effects of the F(ab')2 fragments of murine monoclonal antibodies to the platelet GPIIb/IIIa receptor (7E3 and 10E5) on in vivo platelet thrombus formation in a well-characterized monkey model in which the carotid artery is stenosed and thrombus formation is provoked and augmented by intimal damage and the infusion of subaggregating doses of epinephrine. Both antibodies abolished thrombus formation with a mean dose of -0.2 mg/kg. Ex vivo platelet aggregation was not always abolished at doses that abolished thrombus formation; similarly, bleeding times were only moderately prolonged (9.1 +/- 1.4 minutes) at these doses. Increasing the dose above that required to abolish thrombus formation consistently produced abolition of ex vivo platelet aggregation, marked prolongation of the bleeding time (14.2 +/- 1.5 minutes), and nearly quantitative blockade of GPIIb/IIIa receptors. We conclude that in a significant percentage of animals, the extent of GPIIb/IIIa blockade required to prevent vasoocclusive thrombus formation in this model is less than that required for abolition of platelet aggregation, and that the preservation of only a minority of functional GPIIb/IIIa receptors might be adequate to maintain a nearly normal bleeding time.

Animals↗
PubMed1988

Epinephrine potentiation of in vivo stimuli reverses aspirin inhibition of platelet thrombus formation in stenosed canine coronary arteries.

In 18 anesthetized dogs with a 70% mechanically produced coronary artery stenosis, blood flow measured with an electromagnetic flowmeter showed cyclical reductions in flow due to periodic acute platelet thrombus formation. These were abolished in eight of nine dogs with 2.5 mg/kg of aspirin given intravenously and in nine of nine dogs with 5 mg/kg of aspirin. However in 14 of 18 dogs the cyclical flow reductions were temporarily renewed with the infusion of epinephrine 0.4 microgram/kg/min. Human platelets inhibited with aspirin can be reactivated with physiologic amounts of epinephrine. We postulate that in patients with atherosclerotic stenotic lesions the use of aspirin to inhibit arterial thrombus formation may be less effective when they have elevated catecholamines.

Animals↗
PubMed1988

Relative effects of cigarette smoke and ethanol on acute platelet thrombus formation in stenosed canine coronary arteries.

In 10 open chest dogs with mechanically stenosed coronary arteries acute platelet thrombus formation with subsequent embolisation reduced coronary blood flow cyclically by -10.2(3.3) ml.min-2 (as measured with an electromagnetic flow probe). Ventilating the dogs with cigarette smoke increased the flow reduction to -13.5(4.6) ml.min-2. Ethanol 1.0 ml.kg-1 iv completely abolished acute thrombus formation and flow reductions in all 10 dogs. Repeat ventilation with cigarette smoke after ethanol failed to renew flow reductions in nine of the 10 dogs. It is suggested that ethanol effectively inhibits the exacerbating effects of cigarette smoke on acute platelet thrombus formation when both are being used simultaneously.

Animals↗
PubMed1987

The effects of cardioteratogenic doses of caffeine on cardiac function in the 3-day chick embryo.

The effects on embryonic cardiac function of caffeine administration (two non-cardioteratogenic and two cardioteratogenic doses) to Hamburger-Hamilton stage 19 (3-3 1/2 days of incubation) chick embryos were investigated. Using microcinephotoanalysis, we have determined that caffeine (1.0-4.7 mg/egg), within the initial three hours after treatment, produced a dose-dependent decrease in end diastolic volume, stroke volume, cardiac output, and ejection fraction. These effects were sustained for a longer period of time following dosing at a cardioteratogenic level (3.5-4.7 mg/egg). Caffeine (1.0-4.7 mg/egg) also increased cardiac rate with a maximum increase of 30% seen 60 minutes after treatment with doses of 2.7 mg and 3.5 mg. However, the increase in cardiac rate was not related to dose. At 20 hours after treatment, caffeine increased stroke volume, ejection fraction and cardiac output relative to the controls. End-diastolic volume and cardiac rate were not changed. These results are evidence for a biphasic effect of cardioteratogenic dosing with caffeine during the first 20 hours after treatment--initially a sustained decrease in cardiac output, suggesting decreased flow through the embryonic heart, followed by an increase in ejection fraction, suggesting increased cardiac workload.

Animals↗
PubMed1987

The accumulation of a platelet protein, thrombospondin, at the site of arterial thrombus formation: preliminary report.

There are many methods available for the detection of thrombosis, none of which are noninvasive, rapid and accurate. Thrombospondin is a platelet protein that is present in the developing thrombus and may be an effective substance to use for imaging thrombosis. Vascular stenosis and thrombosis were produced in coronary, carotid and femoral arteries in eleven adult mongrel dogs. 131I labeled thrombospondin was administered to each animal to determine whether the radiotracer accumulated at the site of thrombus formation. The radioactivity per gram of vessels with thrombi was significantly different from the control vessels or whole blood (p = 0.0037 and p = 0.0015, respectively, paired t-test). This preliminary work suggests that iodinated thrombospondin accumulates at the site of thrombus formation. Labeled thrombospondin may be a rapid, safe and accurate method of detecting arterial thrombosis.

Animals↗
PubMed1987

Digital subtraction angiographic imaging of coronary flow reserve.

Recent studies have demonstrated that subjective assessment of the severity of coronary artery stenoses results in poor interobserver concordance and poor correlation with physiologic significance as determined by Doppler measurements of coronary flow reserve. Use of the coronary flow reserve as an integrated measure of the effect of stenosis geometry has been emphasized within the context of quantitative cinemetric analysis. The comparison of two parametric digital subtraction angiographic flow images obtained before and after hyperemic intervention has led to calculation of flow reserve values that correlate well with electromagnetic flowmeter data in dogs. By means of a similar model relating blood flow and image variables, single flow ratio images have been formed. These parametric images provide a two-dimensional display of the ratio of hyperemic flow to baseline flow. Linear temporal interpolation of data from a sequence of cardiac phase-matched subtraction images is used to improve the resolution of the displayed flow ratios. Summation of flow variables measured within the perfusion bed was used to calculate a value for the overall coronary flow reserve and to characterize the significance of isolated lesions in an open-chest canine preparation. A linear regression calculation relating parametric image flow ratio values to electromagnetic flowmeter measurements resulted in a linear fit of y = .96x - 0.19 with a correlation coefficient of .90. The direct visual representation of flow ratio distribution provided by the parametric imaging method may aid in the interpretation of multiple complex lesions as well as of single lesions.

Angiography↗
PubMed1986

Phasic mitral blood flow and regional left ventricular dimensions: possible mechanism of active assist to ventricular filling.

Postsystolic myocardial segment shortening (PSS) has been observed in dogs and humans by means of ultrasonic crystals but has never been studied specifically. In this study, both subendocardial and subepicardial regional function in the basal circumflex and midventricular anterior myocardium (LAD) was studied during late systole and early diastole with ultrasonic crystals. Fifteen open-chest dogs were instrumented with electrocardiographic leads; Millar catheters for measurement of left ventricular pressure, left ventricular dP/dt, and aortic blood pressure; flow probes for determination of aortic and mitral blood flow; and subendocardial and subepicardial crystal pairs to measure subendocardial segment length shortening velocity (dL/dt). Crystal pairs were placed in the subendocardial left oblique mode and the extreme subendocardial right oblique mode (-50 and +50 degrees from equator) in the lateral basal (circumflex, n = 9) and anterior midventricular myocardium (LAD, n = 6). Subendocardial segments showed PSS averaging 34 +/- 7% of the total shortening distance in the circumflex bed and 21 +/- 2% in the LAD bed (p = NS). The rate of subendocardial segment shortening during PSS increased 273 +/- 42.6% (p less than .05) relative to the rate of segment shortening during ejection in the circumflex bed and 126 +/- 40% (p less than .05) in the LAD bed (p = NS). The most rapid diastolic increase in subendocardial length (peak +dL/dt) occurred immediately after subendocardial PSS. Subendocardial diastolic peak +dL/dt occurred after the onset of mitral inflow during the acceleration limb of the rapid ventricular filling phase. Overlying subepicardial segments began lengthening 82 +/- 12 msec before onset of subendocardial segment lengthening in the circumflex bed and 63 +/- 9 msec before subendocardial lengthening in the LAD bed (p less than .05), indicating that the subepicardial segment had begun to lengthen while subendocardial segment shortening continued after end-systole. Onset of early segmental subepicardial lengthening varied with respect to the point of end-systole. Early segmental subepicardial lengthening with subendocardial PSS may be a mechanism by which the rapid filling phase of the left ventricle is actively potentiated by storing potential energy released as early diastolic elastic recoil.

Animals↗
PubMed1986

Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model.

A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

Animals↗
PubMed1986

Inhibition of canine platelet aggregation by barbiturates.

The ability of barbiturates to affect in vitro platelet aggregation of canine platelets was examined. Platelet-rich plasma was incubated with thiamylal, pentobarbital, and barbital for 10 minutes before the addition of the aggregating stimulus. All three barbiturates produced a concentration-related inhibition of platelet aggregation induced by adenosine diphosphate (ADP) and collagen. The inhibitory effect of the barbiturates could not be overcome by increasing the concentration of extracellular calcium. In contrast to ADP- and collagen-induced aggregation, no inhibitory effect was observed on aggregation initiated by A23187, 12-O-tetradecanoylphorbol-13-acetate, or phospholipase C. In further studies, the ADP-induced rise in free cytosolic calcium was blocked by the barbiturates. These findings suggest that barbiturates may interfere with the rise in internal calcium associated with agonist-receptor stimulation of platelets.

Adenosine Diphosphate↗
PubMed1985

Subendocardial and subepicardial segmental function changes in the dog heart due to gradual coronary flow reduction by an acutely developing thrombus.

Regional myocardial dynamics were assessed during continuous, gradual coronary flow reductions caused by spontaneous thrombus formation in the stenosed left circumflex coronary artery of eight open chest dogs. Contractile changes in the subendocardial and subepicardial layers were measured by ultrasonic crystal techniques. Segment length shortening was continuously measured as coronary flow reductions occurred. Contractile dysfunction in the subendocardium preceded that in the subepicardium. At lowest flow levels the subendocardial function degenerated to severe holosystolic bulging whereas some systolic shortening was maintained in the subepicardium. Exponential equations derived to express changes in end diastolic segment length and end systolic length as a function of coronary blood flow for both subendocardium and subepicardium indicated that increases in end systolic length were a more sensitive index of ischaemia than increases in end diastolic length for both the subendocardium and subepicardium during coronary flow reduction. Comparison of exponential curves of end diastolic segment length vs coronary blood flow in subendocardium and subepicardium showed a small but significant difference (p less than 0.02). Comparison of exponential curves of end systolic length vs coronary blood flow in subendocardium and subepicardium showed a large difference in changes at end systole occurring between subendocardium and subepicardium (p less than 0.001). Active contraction of the subepicardium may serve to limit the extent of paradoxical systolic segment lengthening in the underlying ischaemic myocardium and thus help to preserve ventricular function during acute gradual coronary flow limitation.

Animals↗
PubMed1984

Inhibition of epinephrine-exacerbated coronary thrombus formation by prostacyclin in the dog.

We studied the effect of intravenous prostacyclin (PGI2) infusion on epinephrine exacerbation of platelet-mediated acute coronary thrombus formation in an in vivo canine model of coronary artery stenosis. Platelet thrombi form in mechanically stenosed dog circumflex coronary arteries, producing cyclical reductions in coronary blood flow (CRF) as measured with an electromagnetic flowmeter probe. In the present study nine of 10 dogs exhibited spontaneously occurring CRF. With epinephrine (E) infusions of 10 micrograms/min CRF frequency increased 64% (p less than 0.025), CRF magnitude increased 27.1% (p less than 0.05), and the rate of flow decline increased 112.8%, indicating that the rate of thrombus formation increased with E infusion (p less than 0.005). When an identical E infusion was accompanied by simultaneous PGI2 infusion (150 ng/kg/min), CRF were abolished in nine of 10 dogs and markedly inhibited in the other. After the 10 min of simultaneous E and PGI2 infusion, E infusion alone was continued. There was a recurrence of CRF within 2.49 +/- 0.89 min after cessation of PGI2 infusion. However, CRF frequency in the subsequent 10 min was less than the frequency of CRF during the initial E infusion (p less than 0.10) and not significantly different from that of the control period (no E infusion). The rate of flow decline and magnitude during the final E infusion after cessation of PGI2 infusion were not significantly different from those of the initial E infusion. Prostacyclin infusion in the coronary care unit may be potentially beneficial in cases of acute myocardial ischemia where elevated catecholamines are a thrombogenic stimulus.

Animals↗
PubMed1984

Inhibition of platelet shape-change by sodium thiamylal.

Canine platelets were treated in vitro with sodium thiamylal and allowed to surface activate on glass coverslips. Platelet surface activation was markedly inhibited by sodium thiamylal at concentrations as low as 2 X 10(-4) M and this inhibitory effect was most pronounced after pretreating the platelets for 30 minutes with sodium thiamylal. Treatment with sodium thiamylal prevented spreading platelets from reaching the fully spread stage. Additional experiments demonstrated that sodium thiamylal need not be present in the medium during the activation process in order to exert its effect. Preliminary platelet aggregation studies show sodium thiamylal in the 10(-4) - 10(-3) M range to be capable of inhibiting aggregation induced by adenosine diphosphate.

Animals↗
PubMed1982

Blood flow reductions in stenosed canine coronary arteries: vasospasm or platelet aggregation?

In 67 dogs with a 60-80% coronary stenosis produced by an external constricting plastic ring, blood flow measured with an electromagnetic flowmeter showed cyclical flow reductions of varying magnitude and duration, and then an abrupt return to control flow. In 45 dogs, heparin did not prevent these flow reductions, but ibuprofen (Motrin) or indomethacin abolished them. With incremental doses of each of these drugs, the cyclical flow reduction and the platelet function in vitro were diminished proportionately. In 10 more dogs, during low flow, pinching or poking the narrowed vessel suddenly restored normal flow. Topical application of papaverine and nitroglycerin proximal to the stenosis did not abolish the cyclic flow reduction, although a transient fall in systemic pressure indicated that they had been absorbed. Seven dogs had the constricting cylinder and flow probe chronically implanted for 4-6 weeks. A single oral dose of aspirin, 20 mg/kg, abolished their cyclic flow reductions for 2-4 days. In five dogs with 70% stenosis in the circumflex coronary artery, coronary arteriography was performed before coronary flow reduction and when coronary blood flow was low. This showed that there was a considerable additional reduction in the size of the mechanically constricted lumen during spontaneous flow reduction. In one dog, a nonopacified mass was dislodged from the area of constriction in 67 msec and this restored the lumen to its control diameter. Similar rapid clearing was filmed in two more dogs. In no case was vasospasm observed. These results suggest that obstruction from platelets aggregated in the narrowed lumen caused the cyclic flow reductions.

Animals↗
PubMed1982

The effects of cigarette smoke and nicotine on platelet thrombus formation in stenosed dog coronary arteries: inhibition with phentolamine.

This study was undertaken to examine in vivo the effects of cigarette smoke on cyclic reductions in coronary flow due to platelet thrombus formation in the stenosed coronary arteries of anesthetized dogs. The circumflex coronary artery of 21 mongrel dogs was stenosed 60 - 80%, with blood flow measured with an electromagnetic flow probe. After the administration of cigarette smoke, plasma epinephrine was elevated nine times the control level (p less than 0.001) and peak mean blood pressure was elevated one and one-half times control (p less than 0.01). The hematocrit increased several percent (p less than 0.01) with cigarette smoke, although blood gases and pH remained unchanged. In all 21 dogs, spontaneous reductions in coronary blood flow were greatly exacerbated in the stenosed circumflex artery as evidenced by the number of flow reductions, the increased size of the reductions and the rate of flow reduction. Nicotine administered intravenously in doses comparable to those achieved through absorption of cigarette smoke by the lungs provoked similar responses of alpha-adrenergic stimulation and potentiation of the platelet thrombus formation. An alpha-adrenergic antagonist, phentolamine, was given (3 mg/kg) intravenously to inhibit the exacerbated platelet thrombus formation due to cigarette smoke or infused nicotine. In 18 of 21 dogs, an acute occlusive platelet thrombus was prevented 15 minutes after phentolamine and after phentolamine and after a cigarette smoke or nicotine challenge. This study confirms a link between cigarette smoking, platelet formation, and the potential for humans to develop an acute occlusive platelet thrombus in a diseased and stenotic coronary artery.

Animals↗
PubMed1982

Possible platelet thrombi formation in dog and human femoral arteries.

Atherosclerosis is a ubiquitous condition that commonly produces vessel stenosis and progresses ultimately to vascular occlusion. It is thought by many that platelets collect on sites of atherosclerosis and exacerbate its progression. We have previously shown that platelet thrombi can form within 10 minutes in the stenosed coronary arteries of a dog and can produce acute cyclical reduction in blood flow measured with an electromagnetic flowmeter (EMF). This is followed by sudden restoration of flow as the platelet thrombus breaks loose and is carried distally (Circulation 54:365-370, 1976). In five dogs, blood flow was measured simultaneously in a femoral artery stenosed 70%, exposed proximally with an EMF, and monitored distally over intact skin with a Doppler ultrasonic flowmeter (DUF). Cyclical reductions in blood flow were detected by both the EMF and the DUF, presumably due to platelet thrombi forming in the stenosed femoral artery and then breaking loose and moving distally. These flow reductions could be consistently abolished with aspirin (ASA). In ten patients with angiographically proven substantial stenoses of the femoral or popliteal arteries who were not taking ASA, the popliteal blood flow velocity was measured with a DUF. Six of the ten patients showed cyclical blood flow velocity reductions during 30 minutes of observation. These flow velocity reductions were similar to those observed in the stenosed dog femoral arteries. One hour after taking 600 mg ASA orally, five of the six patients no longer showed flow velocity reductions. Eight male control subjects who were not on ASA and had no known stenoses had no flow velocity reductions when studied with the DUF. Since many factors, such as cigarette smoking, diabetes, and elevated plasma lipids, are known to increase human platelet aggregation, we postulate that platelet thrombi may form in stenosed peripheral arteries, hasten the development of atherosclerosis, and reduce blood flow. This postulate would be compatible with the increased incidence and accelerated development of clinically significant atherosclerosis noted in such patients. Claudication may be more than just the response to "increased demand"; thrombus degeneration may lead to the elaboration of vasospastic substances. If these findings are confirmed by further investigations, the potential for successful therapeutic intervention may be quite significant.

Journal Article↗