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Biomedical subjects

J A Ware

Publications and source records attributed to J A Ware.

At least 91 records · Page 5Linked to original sources
PubMed1987

Effect of hydralazine on the elimination of antipyrine in the rat.

The concomitant administration of hydralazine with metoprolol or propranolol substantially increases the oral bioavailability of these beta-blockers, presumably via reduction of the first-pass effect. It has been suggested that this effect may be secondary to a decrease in the intrinsic clearance of propranolol, possibly by inhibition of oxidative metabolism. To examine the possibility that hydralazine alters oxidative metabolism in vivo, the effect of hydralazine on the pharmacokinetics of antipyrine was examined in the rat. The oral administration of hydralazine hydrochloride, 7.5 mg/kg, 15 min prior to antipyrine administration reduced antipyrine clearance from 9.66 +/- 1.18 to 8.19 +/- 0.76 ml/min/kg (P less than 0.05). Hydralazine was observed to cause substantial hypothermia. The study was repeated in temperature-regulated animals and no alteration in antipyrine clearance was found. Two doses of hydralazine in temperature-regulated rats also failed to alter antipyrine clearance. Thus, it appears that the effect of hydralazine on antipyrine clearance is secondary to the hypothermic effect of hydralazine and not due to a direct inhibition of cytochrome P-450-mediated enzyme activity.

Administration, Oral↗
PubMed1987

Synergism of platelet-aggregating agents. Role of elevation of cytoplasmic calcium.

When a pair of platelet agonists, each in subthreshold concentration, is added together or in sequence to a platelet suspension, the platelet response is enhanced. Addition of two agonists to platelets loaded with aequorin also enhanced the observed rise in cytoplasmic ionized calcium ([Ca2+]i) in response to the second agonist if the agonists were added within 20 s of each other. Enhancement of aggregation and secretion required that an increase in [Ca2+]i (as indicated by aequorin but not necessarily indo-1) followed the first agonist, but not that the [Ca2+]i remain elevated until addition of the second agonist. Enhancement was not prevented by aspirin, ADP scavengers, or chelators of extracellular Ca2+. We conclude that a rise in [Ca2+]i induced by a first agonist "primes" platelets for an augmented functional response to a second agonist, which is not, however, determined by the [Ca2+]i at the time of addition of the second agonist.

Adenosine Diphosphate↗
PubMed1986

Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial.

Bleeding after cardiopulmonary bypass remains a cause for concern, requiring reexploration of the chest in approximately 3 percent of patients who have had operations on the heart. We examined the possibility that this problem might be alleviated by desmopressin acetate (DDAVP), which increases the plasma level of von Willebrand factor and improves hemostasis in mild hemophilia and other conditions associated with defective platelet function. In a double-blind, prospective, randomized trial, we studied the effect of intraoperative desmopressin acetate in 70 patients undergoing various cardiac operations requiring cardiopulmonary bypass. Patients undergoing uncomplicated primary coronary-artery bypass grafting were not included. The drug significantly reduced mean operative and early postoperative blood loss (1317 +/- 486 ml in the treated group vs. 2210 +/- 1415 ml in the placebo group); of the 14 patients whose 24-hour blood loss exceeded 2000 ml, 11 had received the placebo. Plasma levels of von Willebrand factor were higher after desmopressin acetate than after placebo. Patients with the most bleeding had relatively low levels of von Willebrand factor before operation, suggesting a role for this factor in the hemorrhagic tendency induced by extracorporeal circulation. There were no untoward side effects of desmopressin acetate. We conclude that the administration of desmopressin acetate can be recommended to reduce blood loss in patients undergoing complex cardiac operations. The beneficial effect of the drug on hemostasis after cardiopulmonary bypass may be related to its effect on von Willebrand factor.

Adult↗
PubMed1986

Inhibition of human platelet aggregation and cytoplasmic calcium response by calcium antagonists: studies with aequorin and quin2.

Calcium antagonists inhibit platelet aggregation, but whether this action is due to inhibition of the effect of agonists on cytoplasmic ionized calcium concentration is unknown. We studied this problem by loading gel-filtered platelets with either quin2 or aequorin and stimulating them with epinephrine, arachidonate, thrombin, the calcium ionophore A23187, 1-oleoyl-2-acetyl glycerol, or adenosine diphosphate in media with or without extracellular calcium. In response to all of these agonists, aequorin indicated an increase in cytoplasmic calcium that accompanied or preceded platelet aggregation. In calcium-containing media, verapamil, nifedipine, and diltiazem inhibited these effects in a concentration-dependent fashion, except for those produced by thrombin and A23187. Removal of extracellular calcium with EGTA reduced the calcium response to arachidonate, adenosine diphosphate, and 1-oleoyl-2-acetyl glycerol, and the calcium response and aggregation were further inhibited by the calcium antagonists. In general, strong inhibition of the aequorin cytoplasmic calcium signal by approximately 100 microM concentrations of nifedipine, verapamil, and diltiazem was correlated with inhibition of platelet aggregation, but high concentrations of the inhibitors were required. Since inhibition by the calcium antagonists of the cytoplasmic calcium response and aggregation exceeded the effect of simple removal of extracellular calcium, these drugs may affect internal redistribution of calcium in human platelets.

Adenosine Diphosphate↗
PubMed1986

Effect of common agonists on cytoplasmic ionized calcium concentration in platelets. Measurement with 2-methyl-6-methoxy 8-nitroquinoline (quin2) and aequorin.

Because of controversy regarding the relationship of cytoplasmic ionized calcium concentration ([Cai2+]) to platelet activation, we studied the correlation of platelet aggregation and ATP secretion with [Cai2+] as determined by 2-methyl-6-methoxy 8-nitroquinoline (quin2) and aequorin in response to ADP, epinephrine, collagen, the Ca2+ ionophore A23187, and thrombin. Both indicators showed a concentration-dependent increase in [Cai2+] in response to all agonists except epinephrine when gel-filtered platelets were suspended in media containing 1 mM Ca2+. With epinephrine, a rise in [Cai2+] was indicated by aequorin, but not by quin2; [Cai2+] signals, aggregation, and secretion were suppressed by EGTA. ADP [0.5 microM] produced a rise in [Cai2+] that was registered by both aequorin and quin2 in platelets in Ca2+-containing media; addition of EGTA to the medium raised the threshold concentration of ADP to 5.0 microM for both indicators. Collagen produced progressive concentration-related increases in [Cai2+] and aggregation in aspirin-treated aequorin-loaded platelets. Quin2 failed to indicate a rise in [Cai2+]at lower collagen concentrations with EGTA or aspirin. [Cai2+] response to A23187 and thrombin was reduced by addition of EGTA to platelets loaded with either aequorin or quin2. With all five agonists in all conditions tested, aequorin [Cai2+] signals occurred at the same agonist concentration as that or lower than that which produced platelet shape change, aggregation, or secretion. Platelet activation was better correlated with changes in [Cai2+] indicated by aequorin than with the response of quin2, possibly because aequorin is more sensitive to local zones of [Cai2+] elevation.

Adenosine Diphosphate↗
PubMed1986

Platelet protein phosphorylation, elevation of cytosolic calcium, and inositol phospholipid breakdown in platelet activation induced by plasmin.

Studies have been performed on the biochemical mechanism of platelet activation induced by the fibrinolytic protease plasmin. In washed human platelets, greater than or equal to 1.0 caseinolytic units (CU/ml plasmin induced aggregation. Platelet [14C]serotonin release was stimulated by 1.0 CU/ml plasmin to an extent comparable to that induced by 1.0 U/ml thrombin. A dose- and time-dependent phosphorylation of the platelet 47,000- and 20,000-kD proteins was noted in 32PO4-labeled platelets incubated with plasmin; phosphorylation was not affected by extracellular Ca2+, but was completely inhibited by an increase in platelet cyclic AMP. Phosphorylation of these platelet proteins suggested that plasmin may act on platelets by stimulating a rise in cytosolic calcium concentration ([Cai2+]) and activating inositol phospholipid-dependent phospholipase C and protein kinase C. Using both quin2 fluorescence and aequorin luminescence as indicators, plasmin was found to elevate platelet [Cai2+] in the presence or absence of extracellular Ca2+. Phospholipase C activation was shown by the generation of [3H]diglyceride in [3H]arachidonic acid-labeled platelets and [32P]phosphatidic acid in 32PO4 labeled platelets exposed to plasmin. Plasmin did not induce formation of thromboxane A2 (TXA2). Only small amounts of this eicosanoid were detected late in the time course after plasmin stimulation. Our results indicate that plasmin causes platelet aggregation and secretion associated with phosphorylation of the 47,000- and 20,000-kD proteins, Ca2+ mobilization, and phospholipase C and protein kinase C activation.

Blood Platelets↗
PubMed1986

Platelet aggregation by fibrinogen polymers crosslinked across the E domain.

There is evidence that platelet interactions with artificial surfaces are mediated by plasma proteins, especially fibrinogen, adsorbed on the surfaces. Multiple site interactions between fibrinogen molecules adsorbed in high concentration and receptors in the unactivated platelet may be sufficient for platelet adhesion and subsequent activation. To examine this hypothesis, we prepared soluble polymers of fibrinogen. Polymers produced by interaction of fibrinogen with Fab'2 fragments of antibodies against fibrinogen's E (central) domain (Fg-Fab'2(E] induced, in gel-filtered platelets, aggregation and serotonin release, which were blocked by monoclonal antibodies against the GPIIb/IIIa complex, by Fab fragments against the D domain, and by metabolic inhibitors; aggregation was attenuated but not abolished by enzymatic removal of ADP (with CP/CPK) or by blockage of ADP binding sites (with FSBA), and when secretion was inhibited by aspirin. Fg-Fab'2(E) also induced a dose-dependent elevation in cytoplasmic Ca2+ (measured by Aequorin luminescence) which was attenuated by CP/CPK and by FSBA, and was eliminated by metabolic inhibitors and by anti-IIb/IIIa antibody. Fibrinogen complexes crosslinked with dimethylsuberimidate or Factor XIII neither aggregated gel-filtered platelets nor inhibited platelet aggregation by ADP and fibrinogen, probably because of inaccessibility of lysine residues in the D (terminal) domain of fibrinogen, which are thought to be required for platelet binding. Thus, soluble complexes of fibrinogen having multiple available platelet receptor recognition sites activate gel-filtered platelets and may provide a useful model for platelet-surface interactions mediated by adsorbed fibrinogen.

Adenosine Diphosphate↗
PubMed1985

Aequorin detects increased cytoplasmic calcium in platelets stimulated with phorbol ester or diacylglycerol.

A biochemical pathway to platelet activation involving protein kinase C has been deemed "Ca2+-independent", because the intracellular fluorophore quin2 indicates no rise in cytoplasmic [Ca2+] in platelets stimulated by certain agonists. However, unlike quin2, the Ca2+-sensitive photoprotein aequorin demonstrates a rise in [Ca2+] when platelet aggregation is induced by phorbol ester or diacylglycerol. Aequorin and quin2 appear to report different aspects of Ca2+ homeostasis, and the absence of a quin2 signal may not be sufficient to establish that a metabolic pathway is "Ca2+-independent".

Aequorin↗
PubMed1985

Concurrent measurement of platelet ionized calcium concentration and aggregation: studies with the lumiaggregometer.

Platelet aggregation and aequorin-indicated cytoplasmic ionized calcium concentration ([Cai2+]) were measured simultaneously using a modification of a commercially available instrument, the Chronolog Whole Blood Lumiaggregometer. The [Cai2+] rise in response to arachidonic acid, the Ca2+-ionophore A23187, collagen, and epinephrine occurred either before or simultaneously with platelet shape change or aggregation. PGD2 caused concentration-dependent inhibition of both the [Cai2+] rise and aggregation. However, suppression of the [Cai2+] rise alone did not fully account for the inhibition of aggregation due to the elevated cAMP produced by PGD2. Agonist-induced elevation of [Cai2+] did not depend on platelet aggregation, but was enhanced by close platelet-to-platelet contact. Concurrent measurement of platelet aggregation and [Cai2+] may further clarify pathways to platelet activation.

Aequorin↗
PubMed1985

Tricuspid regurgitation during pregnancy: two-dimensional and pulsed Doppler echocardiographic observations.

Although precordial murmurs occur frequently during pregnancy, their origin is rarely known. To investigate the nature of these murmurs, 2-dimensional (2-D) and pulsed Doppler echocardiography was performed in 81 asymptomatic pregnant women who had new systolic precordial murmurs. End-systolic right atrial dimensions, early diastolic tricuspid anular diameters, and end-diastolic right ventricular diameters were measured from the apical 4-chamber view and compared with measurements from 26 young nonpregnant women without known heart disease. Tricuspid regurgitation (TR) was detected by pulsed Doppler echocardiography in 35 of 81 pregnant women. Thirty-two pregnant women had normal 2-dimensional and pulsed Doppler echocardiographic findings. Other valvular or congenital lesions were detected in 14 pregnant women. The right-sided intracardiac diameters were larger in all groups of pregnant women than in non-pregnant control subjects (p less than 0.001). The tricuspid anular diameter was larger in the pregnant women with TR than in pregnant women with normal pulsed Doppler echocardiographic findings (24 +/- 2 vs 22 +/- 3 mm, p less than 0.015). No patient had clinical difficulty associated with a murmur. Functional TR, therefore, often occurs in pregnancy and appears to be a result of dilation of the tricuspid anulus. TR may contribute to the development of murmurs in pregnant women.

Adolescent↗
PubMed1985

Measurement of ionized calcium in blood platelets with the photoprotein aequorin. Comparison with Quin 2.

The Ca2+-sensitive photoprotein aequorin (Mr = 20,000) was introduced into human blood platelets by incubation with 10 mM EGTA and 5 mM ATP. Platelet cytoplasmic and granule contents were retained during the loading procedure, and platelet morphology, aggregation, and secretion in response to agonists were normal after aequorin loading. Luminescence indicated an apparent resting cytoplasmic ionized calcium concentration [( Cai2+]) of 2-4 microM in media containing 1 mM Ca2+ and of 0.8-2 microM in 2-4 mM EGTA. The Ca2+ ionophore A23187 and the enzyme thrombin produced dose-related luminescent signals in both Ca2+-containing and EGTA-containing media. Peak [Cai2+] after A23187 or thrombin stimulation of aequorin-loaded platelets was 2-10 microM, while peak [Cai2+] determined using Quin 2 as the [Cai2+] indicator was at least 1 log unit lower. In platelets loaded with both aequorin and Quin 2, the aequorin signal was delayed but not reduced in amplitude. Aequorin loading of Quin 2-loaded cells had no effect on the Quin 2 signal. Ca2+ buffering by Quin 2 (intracellular concentration greater than 1 mM) is also supported by a reciprocal relationship between [Quin 2] and peak [Cai2+] stimulated by A23187 in the presence of EGTA. Parallel experiments with Quin 2 and aequorin may identify inhomogeneous [Cai2+] in platelets and give a more complete picture of platelet Ca2+ homeostasis than either indicator alone.

Aequorin↗
PubMed1985

Measurement of platelet ionized calcium.

We measured ionized cytoplasmic calcium in human blood platelets by two techniques: one based on the fluorescence of intracellular Quin 2 and the other based on the luminescence of the calcium sensitive photoprotein, aequorin. Platelet activation (shape change, aggregation, secretion) induced by thrombin, ADP, epinephrine, collagen, A23187, or phorbol ester was invariably preceded or accompanied by a rise in platelet free calcium indicated by aequorin, but in some cases Quin 2 failed to detect the elevation of calcium concentration. Aequorin appears to be sensitive to localized changes in cytoplasmic calcium levels, while Quin 2 reflects average or diffuse calcium values. Failure of Quin 2 to indicate a rise in free calcium levels in association with a platelet activity does not establish the process as "calcium independent".

Aequorin↗
PubMed1984

Conduction system abnormalities in symptomatic mitral valve prolapse: an electrophysiologic analysis of 60 patients.

This study examined the site of atrioventricular (AV) block in mitral valve prolapse (MVP). Sixty symptomatic patients with MVP underwent electrophysiologic study; 49 had documented arrhythmias and 28 had syncope. Eight patients had spontaneous second- or third-degree AV block and 10 had chronic bundle branch block. Electrophysiologic study revealed abnormal sinus node function in 8 patients, prolonged HV interval in 10, intra-Hisian delay in 9, and functional bundle branch block in 15. Dual AV nodal pathways were demonstrated in 24 patients. Comparison with 101 similarly symptomatic patients without MVP revealed a greater prevalence of dual AV nodal pathways in the MVP patients. Infranodal conduction abnormalities and dual AV nodal pathways are frequently revealed by electrophysiologic testing in symptomatic patients with MVP.

Adolescent↗
PubMed1984

Intravascular microaggregation and in vitro platelet aggregation in coronary artery disease.

To investigate in vivo and in vitro microaggregation in coronary artery disease, we obtained blood samples from the coronary sinus (CS), pulmonary artery (PA), and aorta (AO) in patients undergoing cardiac catheterization. An electronic particle size analyzer was used to quantify microaggregates 13 to 81 mu in diameter in blood. In the first group of 58 patients, preformed circulating microaggregates and platelet responsiveness to ADP were assessed in AO and PA blood only. The coronary artery disease patients did not have significantly higher volumes of preformed in vivo aggregates in either AO or PA blood. However, the mean aggregate size in response to 0.2 microM ADP in vitro was larger in both AO and PA blood in patients with coronary disease [12.4 +/- 0.9 vs. 9.4 +/- 1.4 X 10(3) mu3 (AO); 12.5 +/- 0.9 vs. 8.3 +/- 0.7 0.7 X 10(3) mu3 (PA)]. In a second group of 46 patients, CS, AO and PA samples were compared using the same methods. The volume of microaggregates preformed in vivo was significantly greater in CS blood than in PA or AO blood in patients with and without coronary disease. The volume and mean size of aggregates induced by ADP in vitro were smaller in CS blood compared to PA. In conclusion, the volume of in vivo microaggregates is increased in CS blood, independent of coronary disease, but significant volumes are not found in PA or AO blood. Patients with coronary disease have more reactive platelets to in vitro aggregatory agents in AO and PA samples of similar hematocrit.

Adenosine Diphosphate↗
PubMed1984

Platelet-mediated thrombosis in stenosed canine coronary arteries: inhibition by nicergoline, a platelet-active alpha-adrenergic antagonist.

The effects of nicergoline, a new agent that blocks alpha-adrenergic receptors and inhibits platelet phospholipase, were evaluated in a canine model of platelet-mediated coronary thrombosis. In 48 open chest dogs, the circumflex coronary artery was stenosed by plicating the artery wall with a suture. Thirty-four of the 48 dogs exhibited cyclic reductions in flow in the stenotic vessel, followed by a sudden return to control levels. The reductions in flow were unabated in all but two dogs after heparin administration (1,000 U/kg per h), unaffected by large doses of nitroglycerin and nifedipine and associated with platelet aggregates in the stenotic segment (demonstrated by histologic and electron microscopic examination). These observations support the conclusion that the flow reductions were caused by platelet aggregation rather than by fibrin deposition or vasospasm. Twenty dogs were monitored for 1 hour after heparin administration and then assigned to a control (n = 7) or nicergoline-treated (n = 13; 1 mg/kg intravenously) group. In control dogs, cyclic reductions in flow continued unchanged for another hour, whereas in the treated group they were markedly decreased in 1 dog and completely abolished in the other 12 dogs. Aspirin (30 mg/kg intravenously) suppressed flow reductions in all control dogs, confirming the primary role of platelet aggregation in the phenomenon. This study provides a modified model of platelet-mediated thrombosis in stenosed coronary arteries. Furthermore, the results indicate that nicergoline can effectively interfere with platelet function in vivo. The potent antithrombotic activity exhibited by nicergoline might enhance the therapeutic usefulness of this vasodilator.

Animals↗
PubMed1984

Effect of digoxin on ejection fraction in elderly patients with congestive heart failure.

To assess the effect of oral digoxin on left ventricular systolic function in elderly patients, radionuclide angiography was performed on 20 patients 74 years old or older before and after several weeks of oral digoxin. The mean age was 83.8 years. All had congestive heart failure or cardiomegaly, and all were in sinus rhythm. The ejection fraction was 0.36 +/- 0.10 (mean +/- SD) before digoxin; 0.45 +/- 0.09 after digoxin (P less than 0.01). A comparison group that did not receive digoxin had no significant improvement in ejection fraction. In ten patients serial radionuclide angiograms were repeated after increasing serum digoxin concentrations. Six demonstrated maximal improvement in ejection fraction at serum digoxin concentrations of 0.4-1.0 ng/ml. It is concluded that oral digoxin improves left ventricular ejection fraction in elderly patients with congestive heart failure or cardiomegaly who are in sinus rhythm. Some of these patients achieve maximal improvement in ejection fraction at serum digoxin concentrations of less than 1.0 ng/ml.

Administration, Oral↗