Biomedical subjects

S Bunting

Publications and source records attributed to S Bunting.

At least 55 records · Page 3Linked to original sources

PubMed1995

Pressor and bradycardic effects of centrally administered relaxin in conscious rats.

The current study tested the hypothesis that centrally administered relaxin elevates arterial pressure in conscious rats and that this hypertensive effect is mediated, at least in part, by central or peripheral vasopressin. Injection of human relaxin (0.068 or 0.34 microgram in 200 nL artificial cerebrospinal fluid) into the right lateral ventricle of conscious, unrestrained Sprague-Dawley rats caused significant dose-related increases in arterial pressure and decreases in heart rat. The pressor and bradycardic responses to intracerebroventricular injections of relaxin were significantly blunted by pretreatment with either intracerebroventricular or intravenous injection of a vasopressin receptor (V1) antagonist, suggesting that the cardiovascular effects of central relaxin are mediated, at least in part, by V1 receptors in the brain and perhaps also by vasopressin released into the peripheral circulation. Neither intracerebroventricular injection of the vehicle alone nor intravenous injection of relaxin (0.34 microgram) altered arterial pressure or heart rate. In contrast to the above, intravenous injections of relaxin (40 micrograms/kg) elicited pressor and tachycardic responses that were not blunted by pretreatment with either intracerebroventricular or intravenous injection of the V1 receptor antagonist. Together, these data suggest that in the central nervous system relaxin contributes to the regulation of cardiovascular function and that the mechanisms for the cardiovascular effects of central and peripheral relaxin are distinct.

Animals↗

PubMed1995

Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor.

PURPOSE: Recent experimental studies have established the feasibility of therapeutic angiogenesis; in all cases, this has been achieved with local administration of angiogenic growth factors. This study was designed to investigate the hypothesis that systemic administration of an angiogenic growth factor specifically mitogenic for endothelial cells--vascular endothelial growth factor (VEGF)--could augment collateral vessel development in a rabbit ischemic hindlimb model. METHODS: Ten days after the ligation of the external iliac artery and excision of the common and superficial femoral arteries in one limb of New Zealand white rabbits, heparin (800 IU, n = 13), VEGF (1 mg, n = 3; 5 mg, n = 5), heparin (800 IU) + VEGF (1 mg, n = 5; 5 mg, n = 7), or saline solution (n = 8) was injected as a single bolus in a marginal ear vein. Collateral vessel formation and limb perfusion were assessed 10 and 30 days after treatment. RESULTS: Animals in both VEGF-treated groups had a significantly higher (p < 0.01) increase in calf blood pressure ratio at day 10 (control, 0.44 +/- 0.02; heparin, 0.47 +/- 0.02; VEGF, 0.60 +/- 0.01; heparin+VEGF, 0.61 +/- 0.02) and day 30 (control, 0.49 +/- 0.05; heparin, 0.48 +/- 0.02; VEGF, 0.70 +/- 0.03; heparin+VEGF, 0.73 +/- 0.03). Both VEGF-treated groups had a significantly higher (p < 0.05) angiographic score at day 30 (control, 0.28 +/- 0.01; heparin, 0.28 +/- 0.01; VEGF, 0.37 +/- 0.01; heparin+VEGF, 0.38 +/- 0.02). Maximum flow reserve at day 30 in the ischemic limb was higher (p < 0.05) in VEGF-treated rabbits (control, 1.87 +/- 0.07; heparin, 1.92 +/- 0.08; VEGF, 2.42 +/- 0.16; heparin+VEGF, 2.33 +/- 0.12). Capillary density was higher (p < 0.01) in the ischemic muscles of VEGF-treated rabbits (control, 156 +/- 10/mm2; heparin, 178 +/- 8/mm2; VEGF, 230 +/- 10/mm2; heparin+VEGF, 233 +/- 8/mm2). CONCLUSIONS: This series of in vivo experiments demonstrates that intravenous administration of VEGF, with or without heparin, results in both anatomic and physiologic evidence of enhanced collateral vessel formation in the rabbit ischemic hindlimb. Single-bolus systemic administration of VEGF may be a feasible therapeutic strategy in patients with lower-extremity ischemia.

Animals↗

PubMed1995

Protection against endotoxic shock by bactericidal/permeability-increasing protein in rats.

Bactericidal/permeability-increasing protein (BPI) is a neutrophil primary granule protein that inhibits effects of LPS in vitro. The current study examined the effects of BPI on hemodynamics, mortality, and circulating endotoxin and cytokines in conscious rats with endotoxic shock. Catheters were implanted into the right femoral artery and vein. 1 d later, human recombinant BPI (10 mg/kg) or vehicle was intravenously injected immediately, 30 min, or 2 h after intravenous injection of LPS (7.5 mg/kg). Mean arterial pressure (MAP) and heart rate were monitored and blood was collected before and after injection. BPI given immediately or 30 min after LPS prevented the LPS-induced reduction in MAP at 4-8 h and markedly reduced mortality. BPI given 2 h after LPS injection had no protective effect. BPI treated immediately after LPS reduced the circulating levels of endotoxin and IL-6 but increased the circulating levels of TNF. We propose that BPI exerts its protective effect through a TNF-independent mechanism, by inhibiting endotoxin-stimulated production of IL-6.

Animals↗

PubMed1995

Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency.

Proliferation of vascular cells has been previously shown to contribute to spontaneous development of coronary collaterals. Recent studies from several laboratories have established that collateral artery growth in both the heart and limb can be enhanced by administration of angiogenic growth factors, or therapeutic angiogenesis. In this study, we sought (1) to define the extent and time course of endothelial cell (EC) and smooth muscle cell (SMC) proliferation accompanying spontaneous collateral development during limb ischemia and (2) to determine the extent to which proliferative activity of ECs and SMCs is augmented during therapeutic angiogenesis with vascular endothelial growth factor (VEGF), a heparin-binding EC-specific mitogen. Ten days after induction of limb ischemia by surgically excising the femoral artery of rabbits, either VEGF (500 to 1000 micrograms) or saline was administered as a bolus into the iliac artery of the ischemic limb. Cellular proliferation was evaluated by bromodeoxyuridine labeling for 24 hours at day 0 (immediately before VEGF administration) and at days 3, 5, and 7 after VEGF, EC proliferation in the midzone collaterals of VEGF-treated animals increased 2.8-fold at day 5 (P < 0.05 versus control), and returned to baseline levels by day 7. SMC proliferation in midzone collaterals also increased 2.7-fold in response to VEGF (P < 0.05). No significant increase in EC or SMC proliferation was observed in either the stem or re-entry collaterals of VEGF-treated animals compared with untreated ischemic control animals. Reduction of hemodynamic deficit in the ischemic limb measured by lower limb blood pressure was documented at day 7 after VEGF (P < 0.01 versus untreated, ischemic control). These data thus (1) establish the contribution of cellular proliferation to collateral vessel development in limb ischemia and (2) support the concept that augmented cellular proliferation contributes to the enhanced formation of collateral vessels after therapeutic angiogenesis with VEGF.

Animals↗

PubMed1994

Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb.

This study was designed to assess the physiological consequences of augmented vascularity induced by administration of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in a rabbit model of hindlimb ischemia. Ten days after excision of the common and superficial femoral arteries from one hindlimb of 24 New Zealand White rabbits, VEGF (n = 15) or saline (control; n = 9) was selectively injected into the ipsilateral internal iliac artery. Limb perfusion was evaluated immediately pre-VEGF (baseline) and again at days 10 and 30. A Doppler guide wire was advanced to the internal iliac artery to record flow velocity at rest and at maximum flow velocity provoked by intra-arterial injection of papaverine. At baseline and at day 10, no differences in flow parameters were observed between the control and the VEGF-treated animals. By day 30, however, flow at rest (P < 0.05), maximum flow velocity (P < 0.001), and maximum blood flow (P < 0.001) were all significantly higher in the VEGF-treated group. These physiological findings complement previous-anatomic studies by providing evidence that a single intra-arterial bolus of VEGF augments flow, particularly maximum flow, in the rabbit ischemic hindlimb. These data thus support the notion that VEGF administration represents a potential treatment strategy for certain patients with lower extremity ischemia.

Animals↗

PubMed1994

Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.

Angiography↗

PubMed1994

Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia.

BACKGROUND: Despite major advances in both surgical and percutaneous revascularization techniques, limb salvage and relief of ischemic pain cannot be achieved in many patients with diffuse peripheral vascular disease. Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiological and pathological angiogenesis. In this study, the therapeutic potential of intramuscularly administered VEGF was investigated in a rabbit model of chronic hindlimb ischemia. METHODS AND RESULTS: Ischemia was induced in the hindlimb of 24 New Zealand White rabbits by ligation of the distal external iliac artery and complete excision of the femoral artery. Ten days after the induction of limb ischemia (day 0), saline (group A, n = 7) or the 165-amino acid isoform of recombinant human VEGF (group B: 200 micrograms, n = 6; group C: 500 micrograms, n = 7; group D: 1000 micrograms, n = 4) was administered intramuscularly into the ischemic limb daily for 10 days. Angiography on day 30 after initiation of therapy revealed statistically significant dose-dependent augmentation of collateral vessels in the ischemic limb (angiographic score: group A, 13.0 +/- 1.1; group B, 21.2 +/- 1.8; group C, 27.3 +/- 1.4; group D, 31.5 +/- 2.5). Capillary density in the thigh muscles on day 30 was 1.6 times greater in VEGF groups versus controls (176 +/- 15.3 versus 113 +/- 27.3 per square millimeter, P < .05). Amelioration of the hemodynamic deficit in the ischemic limb was documented by calf systolic blood pressure ratio (group A, 0.52 +/- 0.02; group B, 0.67 +/- 0.02; group C, 0.73 +/- 0.01; group D, 0.82 +/- 0.03). "Clinical" improvement (incidence of calf muscle atrophy and distal limb necrosis: group A, 85.7%; group B, 33.3%; group C, 14.3%; group D, 0%) was greater in VEGF-treated than in control animals, again in a dose-dependent fashion. CONCLUSIONS: These findings demonstrate a significant dose-dependent augmentation in limb perfusion accompanied by evidence of increased collateral formation after intramuscular administration of VEGF in ischemic rabbit hindlimbs. This study thus supports the hypothesis that administration of VEGF to stimulate angiogenesis may represent a new therapeutic modality in the management of arterial insufficiency.

Animals↗

PubMed1994

Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis.

Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha-aspartyl- cyclic (1-->5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-propyl-L-arginyl-glycyl-L-alpha- aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1-->9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 micrograms/kg, ex vivo ADP-induced platelet aggregation with ID50 of 10 micrograms/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +/- 9 to 1,100 +/- 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 micrograms/kg, ex vivo platelet aggregation with an ID50 of 50 micrograms/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 micrograms/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induced ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 +/- 0.4 to 12 +/- 2 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1993

RGD-containing peptides inhibit adhesion of 293 cells transfected with GpIIb/IIIa to fibrinogen: comparison to inhibition of platelet aggregation.

Cyclic RGD-containing peptides caused a dose-dependent inhibition of binding of human embryonic kidney cells transfected with recombinant GpIIb/IIIa (r293 clone B) to human fibrinogen coated on to non-tissue culture plates. The inhibitory activity, IC50, of a panel of seventeen RGD-containing peptides ranged from 0.12 to 89.2 microM. These IC50 values correlated with those determined by the inhibition of platelet aggregation (r = 0.99). Even though there was a correlation, there were differences between the platelet aggregation and the bioadhesion assay. The binding of r293 clone B to fibrinogen was not increased by ADP suggesting that GpIIb/IIIa expressed on the surface of r293 clone B cells may be in the 'activated' form. Moreover, preincubation of r293 clone B cells with a monoclonal antibody (mAb) specific for GpIIIa (4B12) resulted in a dose-dependent decrease of binding to fibrinogen while a mAb specific for GPIIb (2D2) had no effect. Neither of these mAbs inhibited platelet aggregation. The binding of r293 clone B cells to fibrinogen required Ca2+ or Mg2+. This cell-based bioadhesion method can provide a tool for screening potential GpIIb/IIIa antagonists and investigating the interaction of GpIIb/IIIa and fibrinogen not possible with platelet aggregation.

Adenosine Diphosphate↗

PubMed1993

Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation.

G4120, L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha- aspartyl-cyclic(1-->5)-sulfide, 5-oxide, a synthetic cyclic Arg-Gly-Asp-containing pentapeptide, has a high affinity (dissociation constant of 4 nM) for the platelet glycoprotein (GP) IIb/IIIa receptor. The effects of its intravenous or endobronchial administration on thrombolysis, reocclusion, and bleeding time prolongation induced with 0.45 mg/kg bolus injections of recombinant tissue-type plasminogen activator in combination with intravenous heparin (4,000-unit bolus and 1,000 units each hour) were studied in a canine model consisting of an erythrocyte-rich blood clot in the left anterior descending coronary artery. Coronary patency was monitored for 3 hours both by ultrasonic flow probe and by repeat coronary angiography. Four groups of six to 10 dogs were studied with intravenous infusions of 0, 0.1, 0.2, or 0.3 mg/kg G4120 over 60 minutes. G4120 at a dose of 0.3 mg/kg reduced the time to reflow from a mean control value of 45 to 8 minutes (p = 0.036) and delayed reocclusion (p = 0.001). Four groups of five or six dogs were studied with endobronchial instillation of G4120 in a randomized, blinded study design using 0, 0.13, 0.25, or 0.5 mg/kg G4120. Endobronchial G4120 at a dose of 0.5 mg/kg reduced the time to reflow from a mean control value of 52 to 7 minutes (p = 0.039) and abolished cyclic reocclusion and reflow (p = 0.008). G4120 induced a dose-related transient prolongation of the template bleeding time and inhibition of ADP-induced platelet aggregation. G4120, a synthetic low-molecular-weight GPIIb/IIIa inhibitor that may be produced by chemical synthesis, may be of clinical value as a conjunctive agent for thrombolysis in patients with ischemic coronary syndromes.

Animals↗

PubMed1992

Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Asp-sulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model.

Platelet aggregation plays an important role in the pathogenesis in arterial thrombotic disorders. The binding of fibrinogen via the Arg-Gly-Asp (RGD) recognition sequence to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor is an essential step of platelet aggregation induced by various physiologic agonists, and RGD-containing peptides that bind to the GPIIb/IIIa receptor inhibit thrombus formation in vivo. L-cysteine, N-(mercaptoacetyl)D-tyrosyl-L-arginylglycyl-L alpha-aspartyl-cyclic (1----5)-sulfide, 5-oxide (G4120), a cyclic RGD-containing synthetic pentapeptide, inhibits adenosine diphosphate (ADP)-induced platelet aggregation with 50% inhibition (IC50) at a concentration of 0.05 microgram/mL in human plasma, 0.12 microgram/mL in hamster plasma, and 11 micrograms/mL in rat plasma. Corresponding values for the linear tetrapeptide Arg-Gly-Asp-Phe (RGDF) were 7 and 100 micrograms/mL in human and hamster plasma. The antithrombotic effects of G4120 and RGDF were evaluated in a hamster model consisting of a mural platelet-rich femoral vein thrombus induced by standardized endothelial cell damage. Bolus intravenous injection of G4120 was followed by a biphasic disappearance of G4120 from plasma with t1/2 alpha of 3.7 minutes and t1/2 beta of 63 minutes, corresponding to a plasma clearance of 5.2 +/- 0.68 mL/min. Bolus intravenous injection of G4120 inhibited ex vivo platelet aggregation with 0.5 mumol/L ADP and in vivo thrombus formation in a dose-dependent manner, with ID50 of 11 and 11 micrograms/kg, respectively. Bolus injection of RGDF inhibited in vivo thrombus formation; 43% inhibition was obtained at a dose of 30 mg/kg. Thus, this hamster platelet-rich femoral vein thrombosis model may be useful for the investigation of the antithrombotic properties of platelet GPIIb/IIIa antagonistic peptides. The cyclic synthetic peptide G4120 appears to have a very potent antithrombotic activity in vivo.

Amino Acid Sequence↗

PubMed1992

G4120, an Arg-Gly-Asp containing pentapeptide, enhances arterial eversion graft recanalization with recombinant tissue-type plasminogen activator in dogs.

The effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial thrombus model consisted of a 3 cm everted (inside-out) carotid arterial segment inserted into a transsected femoral artery which occludes within 30 min with platelet-rich material and which is resistant to recanalization with 0.5 mg/kg rt-PA. The venous thrombus was a 125I-fibrin labeled whole blood clot produced in the contralateral femoral vein. In 5 dogs given an intravenous bolus of 0.05 mg/kg G4120 followed by a continuous infusion of 0.05 mg/kg per hour for 3 h (group I), arterial occlusion persisted throughout a 4 h observation period and was still present at 24 h in all dogs; the extent of venous clot lysis after 120 min was 27 +/- 7%. In 5 dogs given the same infusion of G4120 in combination with 0.5 mg/kg rt-PA over 60 min, recanalization of the arterial graft occurred in all dogs, within 13 +/- 2 min and persisted throughout the observation period of 4 h (p = 0.01 versus G4120 or rt-PA alone); at 24 h, however, all grafts were occluded. Venous clot lysis in this group was 75 +/- 8% (p = 0.002 versus G4120 alone and p = NS versus rt-PA alone). Pathologic analysis revealed platelet-rich or mixed thrombus with platelet-rich and erythrocyte-rich zones.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

Cyclic RGD peptide analogues as antiplatelet antithrombotics.

Stimulation of platelets activates GPIIbIIIa, the heterodimeric integrin receptor, to bind fibrinogen (Fg), which results in platelet aggregation. GPIIbIIIa/Fg binding inhibitors are potentially suitable for acute use during and after thrombolytic therapy as antithrombotic agents. Incorporation of the tripeptide sequence Arg-Gly-Asp (RGD), a common structural element of many integrin ligands, into cyclic peptides produced a series of peptides of the general structure BrAc-(AA1)-RGD-Cys-OH, which were prepared by solid-phase peptide synthesis. Cyclization was accomplished by reaction of the N-terminal bromoacetyl group with the cysteine sulfhydryl at pH 8 at high dilution, resulting in thioether-bridged cyclic peptides [cyclo-S-Ac-(AA1)-RGD-Cys-OH]. Use of alpha-substituted bromoacetyl groups gave rise to an analogous series of acetyl-substituted thioether-bridged cyclic peptides. Oxidation of the thioethers produced separable diastereomeric sulfoxide-bridged cyclic peptides. After thorough evaluation in a GPIIbIIIa ELISA assay and a platelet aggregation assay, G-4120 (70A; AA1 = D-Tyr; sulfoxide bridge) was selected for further investigation as an antithrombotic agent. G-4120 was equipotent in the platelet aggregation assay to kistrin, a highly potent inhibitor of fibrinogen-mediated platelet aggregation isolated from snake venom (IC50 = 0.15 microM).

Amino Acid Sequence↗

PubMed1992

Evidence that S-nitrosothiols are responsible for the smooth muscle relaxing activity of the bovine retractor penis inhibitory factor.

Inhibitory factor (IF), an extract of the bovine retractor penis muscle, when treated with acid, becomes a vasodilator with properties similar to endothelium-derived relaxing factor (EDRF). EDRF has been proposed to be nitric oxide (NO), long known to be a potent vasodilator. Recently, biologically active IF was proposed to be NO, as well, generated by acid activation of inorganic nitrite. We compared acid-activated IF with acid-activated nitrite and found that NO formation was not sufficient to explain the properties of acid-activated IF. Endothelium-denuded rings of rabbit aorta were used to test the smooth muscle-relaxing properties of IF and nitrite. Although both IF (0.5 ml) and nitrite (1 microM) relaxed phenylephrine-contracted rabbit aorta to a similar extent after acid activation (approximately 30%), several significant differences were observed. IF was most active when acid activated by a 5-min, pH 2 step followed by neutralization; nitrite was relatively inactive when acid activated in this manner, and was most active when assayed immediately after acidification to pH 2. Purging with argon for 5 min reduced the smooth muscle-relaxing activity of 1.0 microM nitrite from 27 +/- 2 to 10 +/- 2% relaxation, whereas the activity of IF was not changed by argon purging (control, 31 +/- 2% relaxation; argon purged, 34 +/- 2% relaxation). When IF samples were assayed for nitrite content, the amount of nitrite found (0.5-5 nmol/0.5 ml sample) was not sufficient to explained the observed smooth muscle relaxing activity. Furthermore, acid-activated IF significantly stimulated cyclic GMP production by platelet-soluble guanylate cyclase from 3.2 +/- 0.2 to 12.4 +/- 0.4 pmol/min/mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Voices and paradigms: perspectives on critical and feminist theory in nursing.

Nurse scientists have explored a variety of research methods and a number of philosophic approaches to expand the discipline's ability to describe and investigate nursing's phenomena of interest. This article discusses the similarities and differences in world views, epistemologies, methodologies, and methods of two of these paradigms: critical theory and feminist theory. Attributes of these two stances are contrasted, and the relationship between the methods of analysis and the philosophic point of view are explored. An example of nursing research is given, with discussion of how the approach would differ if the nurse scientist were using critical versus feminist theory as a frame of reference.

Female↗

PubMed1991

Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation.

BACKGROUND: Kistrin is a 68-amino acid polypeptide from the venom of the Malayan pit viper Agkistrodon rhodostoma, which inhibits the platelet GPIIb/IIIa receptor. Its effect on thrombolysis, reocclusion, and bleeding associated with administration of recombinant tissue-type plasminogen activator (rt-PA) was studied in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Coronary patency was monitored for 2 hours by ultrasonic flow probe and repeated coronary angiography. The rt-PA was given as 0.45-mg/kg bolus injections at 15-minute intervals until recanalization or to a maximum of four boluses. Four groups of four or five dogs were studied: a control group that received intravenous heparin (4,000-unit bolus and 1,000 units each hour) and three groups that received heparin and 0.48, 0.24, or 0.12 mg/kg kistrin, administered as a 10% bolus injection and an infusion during a 60-minute period. In the control group, reflow occurred in four of five dogs within 37 +/- 47 minutes but was followed by cyclic reflow and reocclusion. Kistrin at a dose of 0.48 and 0.24 mg/kg reduced the time to reflow to 6 +/- 5 and 10 +/- 3 minutes, respectively, and abolished reocclusion. With 0.12 mg/kg kistrin, reflow occurred in all four animals, within 27 +/- 23 minutes, and reocclusion occurred in two animals. Kistrin induced a dose-related prolongation of the template bleeding time: with 0.48 mg/kg kistrin, the bleeding time was prolonged from 3.8 +/- 1.3 minutes before infusion to 29 +/- 2 minutes during infusion, but it was shortened to 8.3 +/- 2.6 minutes at 90 minutes after the end of infusion. Kistrin also caused a dose-related inhibition of platelet aggregation with ADP and collagen: with 0.48 mg/kg kistrin, platelet aggregation was abolished during the infusion but had partially recovered toward the end of the observation period. Pathological examination of recanalized coronary arterial segments of dogs given 0.48 or 0.24 mg/kg kistrin revealed widely patent arteries with some platelets layered on the damaged intimal surface. CONCLUSIONS: Kistrin increases the rate and extent of thrombolysis with a reduced dose of rt-PA, and it prevents reocclusion. At an effective dose, it is associated with a transient prolongation of the bleeding time and inhibition of platelet aggregation. Kistrin may offer promise as adjunctive treatment to thrombolytic agents in patients with acute myocardial infarction.

Animals↗

PubMed1990

Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors.

The purification, complete amino acid sequence, and biological activity are described for several homologous snake venom proteins that are platelet glycoprotein (GP) IIb-IIIa antagonists and potent inhibitors of platelet aggregation. The primary structures of kistrin (from Agkistrodon rhodostoma), bitan (from Bitis arietans), three isoforms of trigramin (from Trimeresusus gramineus), and an isoform of echistatin (from Echis carinatus) were determined by automated sequence analysis and fast atom bombardment mass spectrometry analysis. Each of the protein in this family, which range from 47 to 83 residues, contains an Arg-Gly-Asp amino acid sequence found in protein ligands that binds to GPIIb-IIIa, a high (17 +/- 1%) cysteine content conserved in the primary sequence, and a homologous N-terminal region absent only in the echistatin isoforms. Each protein directly inhibits the interaction of purified platelet GPIIb-IIIa to immobilized fibrinogen about 100 times more effectively than does the pentapeptide Gly-Arg-Gly-Asp-Ser; IC50 values range from 1.1 to 3.0 nM. The IC50 value for the inhibition of platelet aggregation, using human platelet-rich plasma stimulated with ADP, ranges from 110 to 550 nM for the various proteins, about 1000-fold more potent than Gly-Arg-Gly-Asp-Ser. Kistrin binds reversibly to both resting and ADP-activated human platelets with high affinity (Kd = 10.8 nM and 1.7 nM, respectively) and to purified GPIIb-IIIa with a lower affinity (Kd = approximately 100 nM). Finally, kistrin injected at 1.0 mg/kg into rabbits reversibly inhibits platelet aggregation ex vivo over 30 min without induction of thrombocytopenia. We propose that these proteins are members of a general class of proteins found in the venom of pit vipers that inhibit platelet aggregation by antagonism of the GPIIb-IIIa-fibrinogen interaction and as such serve as potential antithrombotic agents.

Amino Acid Sequence↗

PubMed1990

Feminism and nursing: historical perspectives.

Feminists have often criticized nursing for lack of commitment to women's movements. This article addresses the contradictions and conflicts in the relationship of feminism and nursing from a historical perspective. Different feminist epistemologies, those of enlightened liberal, cultural, and radical feminism, are examined historically and their relevance to nursing is discussed. A reflexive theory, proposed by Harding, is used to conceptualize the differing responses, feminist and nonfeminist, of women and nurses, as alternative reactions to the many types of patriarchy they have encountered.

Authoritarianism↗