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Biomedical subjects

J Loscalzo

Publications and source records attributed to J Loscalzo.

At least 127 records · Page 7Linked to original sources
PubMed1995

Antithrombotic therapy.

Antithrombotic therapy has evolved from initially limited available agents into numerous treatment options. Thrombin inhibitors have major therapeutic uses in a myriad of thromboembolic disorders. Standard indirect inhibitors, such as heparin and warfarin, have been troublesome clinically owing principally to nonhemostatic side effects and to relative nonselectivity. These drug options may soon be supplemented and possibly supplanted by more selective, direct inhibitors with a finely honed, exclusive effect on thrombin. This approach may, in turn, provide superior, safer therapies for prevention and propagation of thrombus in many cardiovascular diseases.

Humans↗
PubMed1995

Endothelial injury, vasoconstriction, and its prevention.

The endothelial cell is an important determinant of vascular tone, and performs this function by the elaboration of several factors that modulate the contractile state of the vascular smooth muscle cell. In response to physical and molecular factors in the vasculature, the endothelial cell maintains basal vascular tone by the elaboration of prostacyclin, endothelium-derived relaxing factor, and endothelium-derived hyperpolarizing factor, all of which reduce vascular smooth muscle tone. With progressive dysfunction of or injury to the endothelium, however, vascular smooth muscle tone increases in response to reduced production or availability of these endothelium-derived vasorelaxants and increased production of the vasoconstrictor substances, endothelin and endothelium-derived constricting factor(s). Common determinants of endothelial dysfunction that contribute substantially to the progress of vascular diseases include hypercholesterolemia, hypertension, tobacco use, and diabetes mellitus. Current approaches to the reversal or attenuation of the progression of vascular diseases in which the endothelium plays an important role focus on pharmacotherapeutic methods by which to restore normal endothelial function.

Animals↗
PubMed1995

Vasorelaxant and second messenger effects of maxadilan.

Maxadilan is a potent vasodilator isolated from salivary gland extracts of the sand fly. Although cutaneous vasodilatation is probably the most important physiologic effect of maxadilan (i.e., assisting the sand fly in obtaining a blood meal), it also has effects on other vascular beds. In rabbit isolated aorta, recombinant maxadilan exhibited endothelium-independent relaxations with an IC50 of 24 nM for norepinephrine-induced (1 microM) contractions. Synthetic maxadilan had one-third the potency, with a corresponding IC50 of 74 nM for norepinephrine-induced (1 microM) contractions. Pretreatment with a number of receptor and channel blockers, including tetraethylammonium (1 mM), glyburide (1 microM), barium (0.5 mM), indomethacin (10 microM), propranolol (10 microM), cimetidine (10 microM) and nifedipine (10 microM) did not affect maxadilan-induced relaxations. After treatment with maxadilan, contractions recurred very slowly over approximately 40 min. At a concentration of 1 microM, maxadilan induced a 2- to 3-fold increase in cellular cyclic AMP levels. Maxadilan's activity was selective according to vessel type, with maximal activity in rabbit aorta and mesenteric artery and no activity in porcine and bovine coronary arteries. These studies suggest that maxadilan acts by raising the intracellular levels of cyclic AMP in the smooth muscle of selected blood vessels.

Animals↗
PubMed1995

Platelets and plasminogen activation.

Platelets serve as a site for assembly of the proteins of the plasminogen activator system. Once bound to the platelet surface, tissue-type plasminogen activator manifests enhanced catalytic activity. Plasmin, once formed, also binds to the platelets surface and, at low concentrations, renders the platelet dysfunctional by cleaving glycoprotein IIIa selectively in the presence of bound fibrinogen. At higher concentrations (approximately 1 caseinolytic unit/ml), plasmin activates the platelet directly. Activated platelets also bind plasminogen and tissue-type plasminogen activator, and manifest enhanced catalytic efficiency of plasminogen activation. These observations suggest that plasminogen activation by tissue-type plasminogen activator is an autocatalytic process on the platelet surface, and that unique reciprocating mechanisms govern the interaction between platelets and the components of the plasminogen activator system.

Blood Platelets↗
PubMed1994

The fibrin(ogen)olytic properties of cathepsin D.

Fibrin(ogen) is important for hemostasis and is cleared from sites of vascular injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that non-plasmin pathways may also be important for endogenous fibrinolysis. We have recently described an alternative, plasmin-independent fibrinolytic pathway in activated human monocytes that utilizes the integrin Mac-1 (CD11b/CD18), which directly binds and internalizes fibrin, resulting in its lysosomal degradation. The identity of the lysosomal fibrinolytic enzyme(s) responsible for monocyte/macrophage-mediated fibrinolytic is unknown. Protease inhibitor studies now suggest that an aspartyl protease is responsible for this fibrinolytic activity. We, therefore, examined the fibrinolytic properties of cathepsin D, a lysosomal aspartyl protease, and report that cathepsin D possesses both fibrinogenolytic and fibrinolytic activity. Cathepsin D cleavage of fibrinogen follows Michaelis-Menten kinetics with a Michaelis constant, Km, of 1.5 microM; catalytic rate constant, kcat, of 1.4 x 10(-3) s-1; and catalytic efficiency, kcat/Km, of 9.3 x 10(-4) microM-1 s-1. A pH-activity profile of fibrinogen digestion by cathepsin D demonstrates a pH optimum of 3.5 with 50% residual activity at pH 5.0. Fibrinolysis was assessed by fibrin plate and fibrin clot lysis assays. Cathepsin D possesses significant fibrinolytic activity over a dose range of 100 nM to 10 microM and is able to lyse fibrin, as well as albumin-enriched and albumin/red cell-enriched fibrin clots. Cathepsin D cleaves the alpha-, beta-, and gamma-chains of FGN, generating multiple low-molecular-weight fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Kinetics and mechanism of platelet-surface plasminogen activation by tissue-type plasminogen activator.

Plasminogen and tissue-type plasminogen activator bind to the platelet surface, and as a result, the catalytic efficiency of plasminogen activation is significantly enhanced. The plasmin that is generated on or near the platelet is known to affect a number of platelet surface events. For this reason, we examined the effect of plasmin on platelet-surface plasminogen activation and its determinants. Specifically, we measured the effects of plasmin treatment of platelets (1 caseinolytic unit/mL for 1 h at 37 degrees C) on plasminogen, tissue-type plasminogen activator, and plasmin binding to the unactivated and ADP-activated platelet surface; and on the kinetics of plasminogen activation on the platelet surface. Following plasmin treatment, the number of plasminogen binding sites on unactivated platelets increased by 78% (from 46,000 +/- 4000 to 88,000 +/- 9000 sites/platelet), while the number of tissue-type plasminogen activator sites did not change, and the number of diisopropyl fluorophosphate (DFP)-inactivated plasmin (DFP-plasmin) binding sites decreased by 31% (from 92,000 +/- 11,000 to 65,000 +/- 7000 sites/platelet); the dissociation constants (Kds) for each of these binding processes did not change significantly following treatment. On ADP-activated platelets, plasmin treatment increased the number of plasminogen binding sites by 41% (from 188,000 +/- 17,000 to 265,000 +/- 25,000 sites/platelet), decreased the number of plasmin binding sites by 28% (from 219,000 +/- 41,000 to 157,000 +/- 24,000 sites/platelet), and did not affect the number of tissue-type plasminogen activator sites; again, the Kds for each of these binding processes did not change significantly following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1994

Relation of restenosis after excimer laser angioplasty to fasting insulin levels.

Several studies have shown that diabetes mellitus increases the risk of restenosis after coronary intervention, but the role of insulin in restenosis has not been defined. The relation between fasting insulin levels and restenosis was evaluated prospectively at 6-month angiographic follow-up in 70 patients undergoing excimer laser coronary angioplasty of 75 lesions. Restenosis (> 50% diameter narrowing on quantitative angiography) was observed at 37 of 75 treated sites (49%). Although patients with glucose intolerance and noninsulin-dependent diabetes mellitus showed a trend toward increased restenosis (restenosis rate 69%; odds ratio for restenosis 2.7 [95% confidence interval 0.76, 9.82]; p = 0.124), those with increased fasting insulin levels > 15 muU/ml had reduced restenosis (restenosis rate 24%; odds ratio 0.22 [0.07, 0.67]; p = 0.008). Other factors including fasting serum glucose, glycated hemoglobin and lipoprotein fraction were not predictive of restenosis. The relation between insulin levels and restenosis after excimer laser angioplasty may provide insights into the biology of vascular injury and repair after coronary intervention.

Angioplasty, Balloon, Coronary↗
PubMed1994

Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences.

Plasmin exposure modulates platelet aggregation responses, but a direct effect of plasmin on the platelet fibrinogen receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), has never been conclusively shown in a plasma milieu. To examine this issue, we incubated platelets in platelet-rich plasma with plasmin and measured the effect of this treatment on platelet aggregation, fibrinogen binding, and the structural integrity of GPIIb/IIIa. Plasmin treatment reduced maximal reversible fibrinogen binding in a dose-dependent fashion, and this reduction in binding was accompanied by a correlative reduction in the maximal rate of aggregation. Immunoblots performed with polyclonal antibodies against GPIIb/IIIa showed that GPIIIa had been cleaved by plasmin, but this cleavage was detected only after subsequent degradation of the solubilized GPIIb/IIIa with Staphylococcus aureus V8 (Glu-C) endoprotease. Peptide sequence analysis showed that cleavage occurred at the lys444-pro445 bond in the first cysteine-rich repeat domain of GPIIIa a unique proteolytic event observed only in the presence of plasma fibrinogen. These observations suggest that plasmin modifies GPIIIa by a unique proteolytic event in plasma that is dependent on fibrinogen binding and, consequently, is accompanied by significant reductions in fibrinogen binding and aggregation response.

Amino Acid Sequence↗
PubMed1994

Recent observations on the role of hemostatic determinants in the development of the atherothrombotic plaque.

Recent evidence suggests that hemostatic determinants play a major role in the evolution of the atherothrombotic plaque. Platelets can serve as cholesterol donors for macrophages, thereby facilitating foam cell formation. Lipoprotein(a) inhibits fibrinolysis and may also contribute to atherogenesis by serving as a ligand for the scavenger receptor. By complexing with fibrin(ogen) in atheromatous lesions, lipoprotein(a) attenuates clearance of this protein, promoting atherogenesis and vascular dysfunction. These observations suggest that thrombotic determinants are critical for the development of the atheromatous plaque, and may guide the appropriate selection of potential therapeutic options in the future.

Arteriosclerosis↗
PubMed1994

Antiplatelet effects of a novel antianginal agent, nicorandil.

Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1994

Nitric oxide and the cardiovascular system.

Nitric oxide is a simple diatomic molecule that functions as a cellular messenger in a number of organ systems, included among which is the cardiovascular system. Serving several physiologic roles in the cardiovascular system, nitric oxide is an important determinant of basal vascular tone, regulates myocardial contractility, and modulates platelet-vessel wall interactions. From the perspective of cardiovascular pathophysiology, nitric oxide has been implicated in the pathogenesis of essential hypertension, atherosclerosis, and the hypotension associated with shock states. This review will focus in detail on the chemistry, biology, and pathobiology of nitric oxide as it relates to cardiovascular function.

Cardiovascular Diseases↗
PubMed1994

Recombinant human macrophage colony-stimulating factor reduces plasma cholesterol and carrageenan granuloma foam cell formation in Watanabe heritable hyperlipidemic rabbits.

Previous studies have demonstrated that short-term administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) reduces plasma cholesterol in rabbits, nonhuman primates, and human subjects. This study extended the dose schedule of rhM-CSF to 8 weeks of continuous intravenous infusion (CIV) in the Watanabe heritable hyperlipidemic (WHHL) rabbit and expanded the scope to include an assessment of macrophage-derived foam cell development. Ten male WHHL rabbits were injected subcutaneously with 1% carrageenan to promote formation of a macrophage-rich foam cell granuloma. Rabbits were infused with either vehicle or rhM-CSF at 100 micrograms/kg per day (weeks 1 through 5) followed by 300 micrograms/kg per day (weeks 6 through 8). rhM-CSF (100 micrograms/kg per day) decreased total plasma cholesterol by 45% at 2 weeks compared with controls. The gradual return of plasma cholesterol toward control concentrations over the subsequent 3 weeks correlated with the appearance of circulating antibodies specific to rhM-CSF. Granuloma weights at harvest (8 weeks after infusion) were significantly lower (2.8 +/- 0.7 g, mean +/- SEM) in rhM-CSF-treated rabbits relative to controls (7.1 +/- 1.5 g, P < .05). Granulomas from rabbits treated with rhM-CSF contained lower concentrations of cholesterol (2.0 +/- 0.7 versus 6.1 +/- 1.5 micrograms/mg, P < .03) and cholesteryl ester (0.7 +/- 0.4 versus 3.9 +/- 1.2 micrograms/mg, P < .03) than controls. Histological evaluation revealed that granulomas from the rhM-CSF-treated rabbits were more fibrous and contained fewer foam cells than those from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

17 beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.

BACKGROUND: Cardiovascular events are less prevalent in premenopausal women and women receiving estrogen replacement than in postmenopausal women or men. Endothelium-derived relaxing factor (EDRF) is an important local modulator of vascular tone, and abnormal endothelial function is related, in part, to the oxidative modification of low-density lipoprotein (LDL). Estrogens possess substantial antioxidant activity and inhibit LDL modification in vitro. METHODS AND RESULTS: We investigated the effects of 17 beta-estradiol (E2) on endothelial vasomotor function in cholesterol-fed miniature swine. Animals underwent ovariectomy or a sham procedure and received E2 or placebo via implant yielding three groups: sham, ovariectomy (E2 placebo), and implant (E2 implant). After 16 weeks, coronary arteries were harvested and endothelial function was examined in vitro. Vessels from the sham and implant groups demonstrated preserved endothelium-dependent relaxation to bradykinin, substance P, and A23187. Vessels from the ovariectomy group exhibited impaired relaxation to bradykinin and substance P (P < .05 versus sham and implant groups) but not to A23187. Plasma E2 levels were strongly correlated with the response to bradykinin (R = .82, P < .001), substance P (R = .64, P < .01), and A23187 (R = .65, P < .01). Compared with the ovariectomy group, LDL derived from the sham and implant groups was markedly resistant to ex vivo oxidation (P < .05), and this effect correlated with preserved endothelium-dependent relaxation to bradykinin (R = .62, P < .03) and substance P (R = .61, P < .03). CONCLUSIONS: Thus, E2 preserves endothelial function in cholesterol-fed swine in association with protection of LDL against oxidative modification. These data suggest that E2 may, in part, favorably affect vascular function and coronary artery disease by virtue of its antioxidant properties.

Animals↗
PubMed1994

Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction.

BACKGROUND: Pulmonary vascular resistance (PVR) is frequently elevated in patients with advanced heart failure. Nitric oxide (NO), which contributes to the activity of endothelium-derived relaxing factor, causes relaxation of pulmonary arteries and veins in vitro. Inhalation of NO gas causes pulmonary vasodilation in patients with primary and secondary forms of pulmonary hypertension. METHODS AND RESULTS: To test the hypothesis that inhalation of NO gas lowers PVR in patients with heart failure, we studied the hemodynamic effects of a 10-minute inhalation of NO (80 ppm) in 19 patients with New York Heart Association class III (n = 5) and class IV (n = 14) heart failure due to left ventricular (LV) dysfunction. Although inhalation of NO had no effect on pulmonary artery pressures, the PVR decreased by 31 +/- 7% (P < .001) due to a 23 +/- 7% increase (P < .001) in pulmonary artery wedge pressure and despite a 4 +/- 2% (P < .05) decrease in cardiac index. The magnitude of the decrease in PVR with inhaled NO was inversely related (r = -.713; P < .001) to the baseline PVR. Inhaled NO had no effect on heart rate, systemic arterial pressure, systemic vascular resistance, or LV peak +dP/dt or -dP/dt. CONCLUSIONS: In patients with heart failure due to LV dysfunction, inhalation of NO causes a decrease in the PVR associated with an increase in LV filling pressure. These findings predict that inhaled NO, if used alone at this dose (80 ppm), may have adverse effects in patients with LV failure.

Administration, Inhalation↗
PubMed1994

Methylene blue reverses endotoxin-induced hypotension.

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.

Animals↗
PubMed1994

The biology of nitrogen oxides in the airways.

Nitrogen oxides (NOx), regarded in the past primarily as toxic air pollutants, have recently been shown to be bioactive species formed endogenously in the human lung. The relationship between the toxicities and the bioactivities of NOx must be understood in the context of their chemical interactions in the pulmonary microenvironment. Nitric oxide synthase (NOS) is a newly identified enzyme system active in airway epithelial cells, macrophages, neutrophils, mast cells, autonomic neurons, smooth muscle cells, fibroblasts, and endothelial cells. The chemical products of NOS in the lung vary with disease states, and are involved in pulmonary neurotransmission, host defense, and airway and vascular smooth muscle relaxation. Further, certain patients with pulmonary hypertension, adult respiratory distress syndrome and asthma may experience physiologic improvement with NOx therapy, including inhalation of nitric oxide (NO.) gas. Both endogenous and exogenous NOx react readily with oxygen, superoxide, water, nucleotides, metalloproteins, thiols, amines, and lipids to form products with biochemical actions ranging from bronchodilation and bacteriostasis (S-nitrosothiols) to cytotoxicity and pulmonary capillary leak (peroxynitrite), as well as those with frank mutagenic potential (nitrosamines). Recent discoveries demonstrating the relevance of these species to the lung have provided new insights into the pathophysiology of pulmonary disease, and they have opened a new horizon of therapeutic possibilities for pulmonary medicine.

Amino Acid Oxidoreductases↗