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Biomedical subjects

J Loscalzo

Publications and source records attributed to J Loscalzo.

At least 145 records · Page 8Linked to original sources
PubMed1994

Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits.

Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.

Acetylcholine↗
PubMed1994

In vivo transfer of nitric oxide between a plasma protein-bound reservoir and low molecular weight thiols.

Plasma albumin reacts with nitric oxide (NO) to form the bioactive adduct, S-nitroso-albumin (S-NO-albumin). The limited intracellular access of S-NO-albumin suggests the need for a vascular transfer mechanism of NO from a large plasma S-NO-albumin pool to effect biologic function. To study the role of low molecular weight (LMW) thiols in NO transfer in vivo, we administered intravenous S-NO-albumin (1-300 nmol/kg) to rabbits before and after an intravenous infusion of L-cysteine or N-acetyl-L-cysteine. S-NO-albumin produced dose-dependent hypotension that was significantly augmented by prior infusion of either LMW thiol. LMW thiol infusion significantly accelerated the rate of onset and reduced the duration of action of the hypotension induced by S-NO-albumin. The hemodynamic effects of S-NO-albumin after pretreatment with LMW thiols were mimicked by administration of the corresponding LMW S-nitrosothiol. The transfer of NO from albumin to L-cysteine was directly measured in rabbit plasma using a novel technique that couples high performance liquid chromatography to electrochemical detection. These data demonstrate that NO exchange between plasma protein thiol-bound NO and available LMW thiol pools (transnitrosation) occurs in vivo.

Acetylcysteine↗
PubMed1994

Inhibition of sphincter of Oddi function by the nitric oxide carrier S-nitroso-N-acetylcysteine in rabbits and humans.

Nitric oxide (NO) is an inhibitor of gastrointestinal smooth muscle. Model systems of the gut predict the NO will complex with biological thiol (SH) groups, yielding S-nitrosothiols (RS-NO), which may limit the propensity to form mutagenic nitrosamines. The inhibitory effects of NO and its biologically relevant adducts on sphincter of Oddi (SO) motility have been inferred from animal studies; however, their importance in regulating human SO is not known. The objectives of this study were to (a) provide histologic confirmation of nitric oxide synthase (NOS) in human SO; (b) characterize the pharmacology of S-nitroso-N-acetylcysteine (SNAC), an exemplary S-nitrosothiol, on SO motility in a rabbit model; and (c) study the effects of topical SNAC on SO motility in humans. Immunocytochemical and histochemical identification of NOS was performed in human SO. The pharmacologic response of SNAC was defined in isolated rabbit SO using a standard bioassay. Topical SNAC was then applied to the duodenal papilla in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) and biliary manometry. NOS was localized to nerve fibers and bundles of the SO in rabbits and humans. SNAC inhibited spontaneous motility (frequency and amplitude) as well as acetylcholine-induced elevations in SO basal pressure in the rabbit model. In patients undergoing ERCP and biliary manometry, topical SNAC inhibited SO contraction freqency, basal pressure, and duodenal motility. NOS is localized to neural elements in human SO, implicating a role for NO in regulating SO function. Supporting this concept, SNAC is an inhibitor of SO and duodenal motility when applied topically to humans during ERCP. Our data suggest a novel clinical approach using local NO donors to control gastrointestinal motility and regulate sphincteric function.

Acetylcysteine↗
PubMed1994

Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro.

S-Nitrosothiols (RS-NO) relax tracheal smooth muscle from a variety of animal species, and may have physiological relevance. We therefore studied their effects on human bronchial smooth muscle. S-Nitroso adducts of glutathione, cysteine, N-acetylcysteine and bovine serum albumin relaxed tissues contracted with methacholine with mean IC50 +/- S.E.M. of 3.3 (+/- 14), 22 (+/- 45), 25 (+/- 22) and 36 (+/- 7.1) microM, respectively; they were more potent as inhibitory agonists than the corresponding reduced thiol, NaNO2, or theophylline, but less potent than isoproterenol (P < .001). Despite large differences in their molecular weights and dissociation kinetics, the IC50 of these RS-NO did not differ significantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediating relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 microM) increased tissue cGMP levels 4-fold, and 8-bromo-cGMP caused modest tissue relaxation which was potentiated by the phosphodiesterase inhibitor, dipyridamole (1 microM). However, the guanylyl cyclase inhibitors, methylene blue (100 microM) and LY 83583 (50 microM), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), while altering the accumulation of cGMP. Further, hemoglobin (100 microM) failed to inhibit relaxation by S-NO-AC.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1993

Usefulness and tolerability of hirulog, a direct thrombin-inhibitor, in unstable angina pectoris.

In an open-label pilot study of 20 patients with unstable angina (Braunwald class I-IIIB), hirulog was administered as a continuous intravenous infusion for 5 days in a dose of 0.2 mg/kg/hour to produce an activated partial thromboplastin time of approximately 200% of control. The primary end points of the study were: death, development of a transmural myocardial infarction, and intractable angina needing interventions such as an intraaortic balloon pump insertion, angioplasty and surgery. The secondary end points were the presence of an intracoronary thrombus detected on angiography and hemorrhagic complications during therapy. There was no death or transmural infarction in this study cohort; however, 1 patient developed intractable angina. Intracoronary thrombus was documented in 2 patients. Infusion of hirulog resulted in a steady prolongation of the activated partial thromboplastin time without any hemorrhagic or other adverse effect. Hirulog appears to be an effective antithrombotic agent that is tolerated well and may have advantages over heparin in the management of patients with unstable angina.

Aged↗
PubMed1993

Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.

Recent evidence suggests that dietary therapy with lipid-soluble antioxidants may be beneficial for patients with atherosclerotic vascular disease but the potential mechanism(s) for these observations remain obscure. Abnormalities in endothelium-dependent control of vascular tone develop early in the course of atherosclerosis and may result from oxidative modification of low density lipoproteins. We examined the role of dietary antioxidants in preserving normal endothelial cell vasodilator function in cholesterol-fed rabbits with particular attention to possible effects on serum lipoproteins, low density lipoprotein oxidation, and atherogenesis. Male New Zealand White rabbits were fed diets containing no additive (controls), 1% cholesterol (cholesterol group), or 1% cholesterol chow supplemented with either beta-carotene (0.6 g/kg of chow) or alpha-tocopherol (1000 international units/kg of chow) for a 28-day period. After dietary therapy, thoracic aortae were harvested for assay of vascular function and for pathologic examination and tissue antioxidant levels. Compared to controls, acetylcholine- and A23187-mediated endothelium-dependent relaxations were significantly impaired in vessels from the cholesterol group (P < 0.001), whereas vessels from animals treated with beta-carotene or alpha-tocopherol demonstrated normal endothelium-dependent arterial relaxation. Preservation of endothelial function was associated with vascular incorporation of alpha-tocopherol and beta-carotene but was unrelated to plasma lipoprotein levels, smooth muscle cell function, or the extent of atherosclerosis. Increased low density lipoprotein resistance to ex vivo copper-mediated oxidation was observed only in the alpha-tocopherol group. Our results suggest that dietary antioxidants may benefit patients with atherosclerosis by preserving endothelial vasodilator function through a mechanism related to vascular tissue antioxidant content and not reflected by assay of low density lipoprotein resistance to ex vivo oxidation.

Acetylcholine↗
PubMed1993

Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway.

Fibrin(ogen) (FGN) is important for hemostasis and wound healing and is cleared from sites of injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that nonplasmin pathways may be important in fibrin(ogen)olysis, as well. Given the proximity of FGN and monocytes within the occlusive thrombus at sites of vascular injury, we considered the possibility that monocytes may play an ancillary role in the degradation and clearance of fibrin. We found that monocytes possess an alternative fibrinolytic pathway that uses the integrin Mac-1, which directly binds and internalizes FGN, resulting in its lysosomal degradation. At 4 degrees C, FGN binds to U937 monocytoid cells in a specific and saturable manner with a kd of 1.8 mumol/L. Binding requires adenosine diphosphate stimulation and is calcium-dependent. At 37 degrees C, FGN and fibrin monomer (FM) are internalized and degraded at rates of 0.37 +/- 0.13 and 0.55 +/- 0.03 microgram/10(6) cells/h by U937 cells, 1.38 +/- 0.02 and 1.20 +/- 0.30 microgram/10(6) cells/h by THP-1 cells, and 2.10 +/- 0.20 and 2.52 +/- 0.18 micrograms/10(6) cells/h by human peripheral blood mononuclear cells, respectively. The serine protease inhibitors, PPACK and aprotinin, and the specific elastase inhibitor, AAPVCK, do not significantly inhibit degradation. However, degradation is inhibited by chloroquine, suggesting that a lysosomal pathway is involved. Factor X, a competitive ligand with FGN for the Mac-1 receptor, also blocks degradation, as does a monoclonal antibody to the alpha-subunit of Mac-1. Autoradiography of radioiodinated, internalized FGN shows that FGN proteolysis by the pathway produces a unique degradation pattern distinct from that observed with plasmin. In a fibrin clot lysis assay, Mac-1-mediated fibrinolysis contributed significantly to total fibrinolysis. In summary, FGN is internalized and degraded by activated human monocytoid cells via Mac-1 in the absence of plasmin, thereby providing an alternative fibrinolytic pathway. Thus, in addition to the function of cell adhesion, integrins may also act as receptors that mediate the internalization and degradation of bound ligands.

Antibodies, Monoclonal↗
PubMed1993

Salivary gland extracts from the deerfly contain a potent inhibitor of platelet aggregation.

Salivary gland extracts of the deerfly contain a potent inhibitor of platelet aggregation, which assists the insect in obtaining a blood meal. The extract prevents platelet aggregation induced by ADP, thrombin, and collagen and inhibits fibrinogen binding to the glycoprotein IIb/IIIa receptor on platelets. The active component in deerfly salivary gland extract appears to be a protein that is comparatively more potent than the disintegrins present in viper venoms. Isolation and characterization of this protein may provide different directions in therapeutics and studies of normal platelet physiology.

Adenosine Diphosphate↗
PubMed1993

A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds.

Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.

Animals↗
PubMed1993

The platelet function defect of cardiopulmonary bypass.

The use of cardiopulmonary bypass (CPB) during cardiac surgery is associated with a hemostatic defect, the hallmark of which is a markedly prolonged bleeding time. However, the nature of the putative platelet function defect is controversial. In this study, blood was analyzed at 10 time points before, during, and after CPB. We used a whole-blood flow cytometric assay to study platelet surface glycoproteins in (1) peripheral blood, (2) peripheral blood activated in vitro by either phorbol myristate acetate, the thromboxane (TX)A2 analog U46619, or a combination of adenosine diphosphate and epinephrine, and (3) the blood emerging from a bleeding-time wound (shed blood). Activation-dependent changes were detected by monoclonal antibodies directed against the glycoprotein (GP)Ib-IX and GPIIb-IIIa complexes and P-selectin. In addition, we measured plasma glycocalicin (a proteolytic fragment of GPIb) and shed-blood TXB2 (a stable breakdown product of TXA2). In shed blood emerging from a bleeding-time wound, the usual time-dependent increase in platelet surface P-selectin was absent during CPB, but returned to normal within 2 hours. This abnormality paralleled both the CPB-induced prolongation of the bleeding time and a CPB-induced marked reduction in shed-blood TXB2 generation. In contrast, there was no loss of platelet reactivity to in vitro agonists during or after CPB. In peripheral blood, platelet surface P-selectin was negligible at every time point, demonstrating that CPB resulted in a minimal number of circulating degranulated platelets. CPB did not change the platelet surface expression of GPIb in peripheral blood, as determined by the platelet binding of a panel of monoclonal antibodies, ristocetin-induced binding of von Willebrand factor, and a lack of increase in plasma glycocalicin. CPB did not change the platelet surface expression of the GPIIb-IIIa complex in peripheral blood, as determined by the platelet binding of fibrinogen and a panel of monoclonal antibodies. In summary, CPB resulted in (1) markedly deficient platelet reactivity in response to an in vivo wound, (2) normal platelet reactivity in vitro, (3) no loss of the platelet surface GPIb-IX and GPIIb-IIIa complexes, and (4) a minimal number of circulating degranulated platelets. These data suggest that the "platelet function defect" of CPB is not a defect intrinsic to the platelet, but is an extrinsic defect such as an in vivo lack of availability of platelet agonists. The near universal use of heparin during CPB is likely to contribute substantially to this defect via its inhibition of thrombin, the preeminent platelet activator.

Blood Coagulation Disorders↗
PubMed1993

PPACK attenuates plasmin-induced changes in endothelial integrity.

In order to determine whether plasmin affects endothelial cell integrity directly, confluent bovine aortic endothelial cells were treated with plasminogen and a plasminogen activator. The permeability of the monolayer to [125I]-albumin was shown to be increased significantly (P < 0.01) with a concomitant decrease in viability. Plasmin activity correlated significantly with endothelial cell permeability (p < 0.004; r = 0.82). Coincubation with D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone, a tripeptide inhibitor of plasmin, reduced the increase in endothelial permeability induced by plasmin by 59% (p = 0.033). Monolayers studied in parallel were stained with rhodamine-phalloidin to visualize F-actin. There were significant morphologic changes in the endothelial monolayers exposed to plasmin compared to control monolayers, and these changes could be attenuated by coincubation with D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone. These studies show that: 1) plasmin induces significant increases in endothelial cell permeability with accompanying morphologic changes; and 2) these deleterious functional and morphologic effects can be attenuated by coincubation with the plasmin inhibitor, D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone.

Actins↗
PubMed1993

Reciprocating autocatalytic interactions between platelets and the activation system.

Under normal circumstances, the platelet surface serves as a site of assembly for plasminogen (PGN) and tissue-type plasminogen activator (t-PA) and facilitates PGN activation. Since the plasmin (Pn) produced on the platelet surface can modulate a variety of platelet properties, we examined the effects of Pn on platelet-surface PGN activation. We incubated platelets with Pn (one caseinolytic unit/ml for one hr at 37 degrees C) and measured the effects of this treatment on the binding of PGN, Pn, and t-PA to unactivated platelets; and on the kinetics of PGN activation on the platelet surface. Pn treatment increased the number of PGN binding sites by 78% (from 46,000 to 88,000 sites/platelet) without affecting affinity (KD = 2.2 microM). Pn treatment had a modest effect on (DFP-inactivated) Pn binding but did not modify t-PA binding; however, treatment increased the catalytic efficiency of t-PA approximately two-fold. Importantly, all of these effects occurred without evidence for platelet activation by Pn. These observations imply that PGN activation may be an autocatalytic process on the platelet surface and provide evidence for a unique reciprocating mechanism governing the interaction between platelets and the plasminogen activation system.

Blood Platelets↗
PubMed1993

Lipoprotein(a) binds to human platelets and attenuates plasminogen binding and activation.

Lipoprotein(a) [Lp(a)] is a unique lipoprotein consisting of a low-density lipoprotein moiety (LDL) covalently linked to apoprotein(a). Previous work has demonstrated that Lp(a) can compete with plasminogen (PGN) for binding to endothelial and mononuclear cells and can inhibit PGN activation in cell-free systems. We have assessed the binding of Lp(a) to platelets and the influence of binding on the activation of PGN by tissue-type plasminogen activator (t-PA) in this system. In direct binding experiments, Lp(a) bound specifically, saturably, and reversibly to platelets with an estimated apparent Kd of 0.20 microM. Scatchard analysis revealed a single class of binding sites with 81,000 +/- 22,000 particles of Lp(a) bound at saturation. Interestingly, Lp(a) bound to a similar extent to thromboasthenic platelets. Activation of platelets with ADP or thrombin reduced Lp(a) binding capacity by approximately 50% without changing affinity. Lp(a) also inhibited the binding of PGN to platelets with an IC50 of approximately 0.23 microM. Over a similar concentration range, LDL did not inhibit PGN binding to platelets. In addition, Lp(a) inhibited PGN binding to plasmin-treated platelets with an IC50 of approximately 0.2 microM. Kinetic experiments demonstrated that Lp(a) acted as a competitive inhibitor of PGN activation by t-PA on the platelet surface, with an estimated Ki of 0.49 microM. In the presence of platelets, Lp(a) decreased the kcat/Km for t-PA by 3-fold, owing primarily to an increase in the Km of t-PA for PGN. In contrast, LDL did not alter the kinetics of PGN activation by t-PA on the platelet surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1993

Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease.

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.

Amino Acid Sequence↗
PubMed1993

Peroxynitrite-induced rat colitis--a new model of colonic inflammation.

BACKGROUND: Excessive production of nitric oxide, characteristic of inflamed states, may have deleterious effects through its facile conversion (in the presence of O2) to peroxynitrite, which promotes lipid and sulfhydryl oxidation. This study assessed the effect of peroxynitrite on the rat colon. METHODS: Peroxynitrite was administered intrarectally to rats. One, 3, 7, and 21 days after treatment, a distal colonic segment was isolated and tissue was obtained for histological evaluation and determination of myeloperoxidase activity and NOX, and eicosanoids generation. RESULTS: Within 24 hours, the exposed segment was edematous and congested with occasional hemorrhagic mucosal ulceration. On day 7, the lumen was narrow; at day 21, there were signs of stenosis. Histological analysis showed transmucosal necrosis, acute inflammation, and exudative edema 24 hours after treatment. Surface re-epithelization and infiltration of granulation tissue were present at 1 week. Resolution of edema, mucin repletion, thickening of muscularis mucosa and propria, and fibrosis were observed at 3 weeks. Significant increase in NOX generation and myeloperoxidase and NO synthase activities were observed at 24 hours, whereas enhanced leukotriene generation was observed only at 21 days. CONCLUSIONS: Peroxynitrite-induced colonic inflammation provides a novel model of NO-related tissue injury and offers the opportunity to further explore the potential role of NO in the pathogenesis of inflammatory bowel disease.

Animals↗
PubMed1993

Sodium nitroprusside, an endothelium-derived relaxing factor congener, increases platelet cyclic GMP levels and inhibits epinephrine-exacerbated in vivo platelet thrombus formation in stenosed canine coronary arteries.

Sodium nitroprusside (SNP), a nitrosovasodilator, increases platelet cyclic GMP levels and inhibits platelet activity in vitro. The antiplatelet properties of SNP are not well established in vivo, however, and consequently are not appreciated by clinicians. In our established model of mechanically stenosed canine coronary arteries (MSCA) with intimal damage, periodic acute platelet thrombus formation (APTF) occurs, followed by embolization distally, which then causes cyclic flow reductions (CFRs) in coronary blood flow. Aspirin (ASA) abolished platelet-mediated CFRs in our model, but they recur when epinephrine (EPI) is infused (0.2 microgram/kg/min). SNP was given continuously intravenously (i.v.) to 17 dogs with MSCA; CFRs were abolished in all dogs by SNP at 4.4 +/- 2.7 micrograms/kg/min (mean +/- SD). Mean arterial blood pressure (MAP) decreased by 19 +/- 9 mm Hg (p < 0.001) from control, while heart rate (HR) increased 35 +/- 20 beats/min (p < 0.001). Platelet cyclic GMP levels were 2.9 +/- 1.1 pmol/10(8) platelets before SNP infusion, and increased to 4.3 +/- 1.6 pmol/10(8) platelets (p < 0.05) when CFRs were abolished. CFRs were not renewed during the continued SNP infusion when EPI was infused at 0.2 microgram/kg/min for 20 min in 11 dogs, but CFRs returned within 5-25 min after the SNP infusion was terminated. The return of CFRs occurred together with a decrease in platelet cyclic GMP levels to 3.3 +/- 1.4 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs.

The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with the use of inhibitors of nitric oxide synthase (NOS) and by direct measurement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 microM NG-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), which was approximately 100-fold greater than the ID50 of control lungs which was 0.39 nmol/kg, (0.16-0.79, P < 0.0001). This inhibitory effect could be overcome with excess L- but not D-arginine. In contrast, VIP-induced relaxation of isolated guinea pig trachea was not modified by inhibitors of NOS. To confirm that VIP infusion resulted in NO generation in whole lungs, we measured NO equivalents in lung effluent by two distinct technologies. We found that VIP injection caused a significant increase in NO equivalents from 0.11 +/- 0.04 microM to 0.78 +/- 0.15 microM (P < 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibitor methylene blue were less responsive to VIP [ID50 4.0 nmol/kg (1.5-10), P < 0.005 compared with control lungs], consistent with a physiologically significant guanosine 3',5'-cyclic monophosphate-dependent mechanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.

Animals↗