摘要:

Impaired myocardial contractility in septic shock is protracting, which may be caused by cytokine-induced nitric oxide (NO) synthesis in the heart. However, the cellular mechanism by which cytokines induce nitric oxide synthase (NOS) in cardiocytes remains obscure.Methods and ResultsWe studied the effect of human recombinant interleukin-1β (IL-1β) on synthesis of NO2−NO3−(NOx) and the expression of NOS mRNA and protein in cultured neonatal rat cardiocytes. IL-1β dose-dependently (0.1 to 10 ng/mL) stimulated NOxproduction as a function of time (6 to 48 hours). Northern blot analysis using complementary DNAs for rat brain-type constitutive (c) NOS and mouse macrophage-type inducible (i) NOS as probes showed that IL-1β induced expression of mRNA for iNOS but not for cNOS, starting after 6 hours and reaching a maximum after 48 hours in cardiocytes. IL-1β similarly induced iNOS mRNA expression in cultured adult rat cardiocytes in a time-dependent manner. Western blot analysis using specific antibody against the N-terminal fragment of mouse iNOS revealed the expression of 130-kD iNOS-like protein in IL-1β-treated cardiocytes. Northern blotting and immunocytochemical study revealed that IL-1β-induced iNOS mRNA and iNOS-like immunoreactivity were exclusively localized to cardiac myocytes but also to nonmyocytes, to a lesser extent.N−monomethyl- L-arginine, an NOS inhibitor, completely blocked the IL-1β-induced NOxproduction, whose effect was reversed by L-arginine but not by D-arginine. Dexamethasone inhibited the IL-1β-induced NO2, production as well as iNOS mRNA expression. Cycloheximide and actinomycin D completely inhibited the IL-1β-induced NOxproduction and iNOS mRNA expression. Neither a calmodulin inhibitor (W-7), a protein kinase C inhibitor (calphostin C), nor a Ca2+channel antagonist (nicardipine) showed any effect on the IL-1β-induced NOxproduction.ConclusionsThese data demonstrate that IL-1β induces macrophage-type iNOS mRNA expression mainly by cardiac myocytes but also by nonmyocytes to a lesser extent, and subsequent de novo protein synthesis of iNOS leads to excessive local production of NO by cardiocytes.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+is not known.Methods and ResultsInhibitors of the voltage-gated Na+channel were used to investigate the effect of Na+channel blockade on hypoxic Na+loading, Na+dependent Cal2+loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+]i) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (PO2< 0.02 mm Hg). Both [Na+]iand [Ca2+]iincreased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]iand [Ca2+]iwas significantly attenuated by 1 μmol/L R 56865. Tetrodotoxin (60 μmol/L), a selective Na+-channel blocker, also markedly reduced the rise in [Ca2+]iduring hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was re-duced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P< .05). Lidocaine reduced hypercontracture dose dependently with 13% of cells hypercontracting in 100, μmol/L lidocaine, 42% in 50 μmol/L lidocaine, and 93% in 25 μmol/L lidocaine. The Na+-H+exchange blocker, ethylisopropylamiloride (10 μmol/L) was also effective, limiting hypercontracture to 12%. R 56865, lidocaine, and ethylisopropylamiloride were also effective in preventing hypercontracture in normoxic myocytes induced by 75 μmol/L veratridine, an agent that impairs Na+channel inactivation. Ethylisopropylamiloride prevented the veratri-dine- induced rise in [Ca2+]iwithout affecting Na+-Ca2+exchange, suggesting that amiloride derivatives can reduce Ca2+loading by blocking Na+entry through Na+channels, an action that may in part underlie their ability to prevent hypoxic Na+and Ca2+loading.ConclusionsNa+influx through the voltage-gated Na+channel is an important route of hypoxic Na+loading, Na+−dependent Ca2+loading, and reoxygenation hypercontracture in isolated rat cardiac myocytes. Importantly, the Na+channel appears to serve as a route for hypoxic Na+influx after myocytes become inexcitable.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The different vulnerabilities of heart and brain to hypotension and hypoxia have been discussed. Hemorrhagic or cardiogenic hypotension appears to cause greater cerebral lesions than drug-induced hypotension. The present model was established to evaluate myocardial blood flow (MBF) and function of the heart and cerebral blood flow (CBF) during tachyarrhythmias and to characterize the capacity of blood flow regulation in the heart and brain during tachycardia-induced borderline hypotension.Methods and ResultsMBF and CBF were determined with radiolabeled microspheres. Coronary and central venous oxygen tensions were measured to estimate myocardial and cerebral oxygen consumption (M&OV0622;o2and C&OV0622;o2. Measurements were performed in 62 Sprague-Dawley rats during sinus rhythm and high-rate left ventricular pacing and after hemorrhage. In control rats, MBF and CBF were 5.08±1.07 and 1.09±0.29 mL · g−1· min−1· MBF increased (7.21±1.98 mL · g−1· min−1,P< .05), whereas CBF decreased (0.99±0.29 mL · g−1· min−1,P=NS) during normotensive high-rate pacing. MBF and CBF dropped to 4.27±2.24 mL · g−1· min−1(P< =NS) and 0.68±0.29 mL · g−1· min−1(P< .05) during pacing-induced borderline hypotension and decreased further during severe hypotension (1.77±0.81 mL · g−1· min−1,P< .01; 0.45±0.18 mL · g−1· min−1,P< .01). During borderline hypotension due to hemorrhage, MBF and CBF were 4.05±0.95 mL · g−1· min−1(P=NS) and 0.71±0.23 mL · g−1· min−1(P< .05). MVo2and CVo2were 72.7±15.4 and 12.7plusmn;3.3 mL · 100 g−1· min−1in control rats. MVo2increased during normotensive pacing (100.3plusmn;27.4 mL · 100 g−1· min−1,P=NS). Mean M&OV0622;o2was reduced during pacing-induced borderline hypotension (64.1±35.6 mL · 100 g−1· min−1,P=NS) and severe hypotension (29.8±15.4 mL · 100 g−1· min−1,P< .05). CVo2decreased in correlation to CBF. Coronary and cerebrovascular resistance and autoregulation indexes indicated a maintenance of MBF regulation and a failure of CBF regulation during borderline hypotensive tachycardias. These results show a dissociation of MBF and CBF after onset of hypotensive tachycardias. Thus, brain tissue appears to be jeopardized at an earlier stage than myocardial muscle during tachyarrhythmias.ConclusionsThe proposed hypotension model is suitable to analyze tachyarrhythmia-induced hemodynamic changes and end-organ perfusion in the presence of myocardial dysfunction. It has the potential to test therapeutic strategies in the treatment of tachycardias.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Changes in stress and tissue material properties have been proposed as important mechanical factors that may influence infarct expansion and subsequent healing. Because such changes will be reflected by alterations in the finite deformation of the tissue, we examined the direction and magnitude of myocardial deformation after coronary ligation in the pig.Methods and ResultsGold beads were implanted in the left ventricular free wall of five pigs. After ligation of the coronary supply to the region containing the markers, we used biplane cineradiography to reconstruct the three-dimensional deformations of the myocardium during single cardiac cycles as well as the remodeling deformations that occurred over time. Deformations were studied at 1 and 3 weeks after infarction. The analysis of single cardiac cycles revealed permanent loss of systolic shortening immediately after ligation. However, significant passive systolic wall thickening (P< .001) and large shears were observed at 3 weeks in regions composed almost entirely of collagen. The analysis of remodeling deformations at 1 week revealed infarct expansion with a predominant axis that varied widely. At 3 weeks, a 30% to 60% reduction in local tissue volume was measured in the infarct region, with the principal direction of scar shrinkage nearly circumferential in all animals (range, −2° to 35°).ConclusionsWe conclude that infarct expansion and scar shrinkage may be controlled by different factors. In addition, we conclude that measurement of systolic wall thickening alone is not always adequate to assess postinfarction regional contractile function.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

DSPA (Desmodussalivary plasminogen activator) is a new thrombolytic agent corresponding to a natural plasminogen activator discovered in the saliva of the vampire batDesmodus rotundus. Compared with tissue plasminogen activator (TPA), DSPA, produced in a recombinant cell line, is more fibrin cofactor dependent than TPA.Methods and ResultsThe thrombolytic properties of DSPA and TPA were compared in a canine model of copper coilinduced coronary thrombosis. All dogs received heparin 200 IU/kg IV and SC. Whereas controls did not reperfuse within 180 minutes (none of six), intravenous bolus administration of DSPA at 25, 50, and 100 μg/kg resulted in a 100% incidence (6 of 6) of recanalization within 37, 23, and 18 minutes, respectively. TPA at 63 and 125 mu;g/kg reopened the coronaries in 33% (two of six) and 50% (three of six) of cases within 40 minutes. Eighty-three percent (5 of 6) of the arteries were still patent 3 hours after 50 and 100 mu;/kg DSPA, whereas only 20% (one of five) of all coronaries originally recanalized with both doses of TPA were still open at 3 hours. Plasma levels of α2-antiplasmin decreased significantly only with 125 mu;g/kg TPA. The clearance of DSPA (2.3 to 3.5 mL · min−1· kg−1) was lower compared with TPA (11.4 to 20 mL · min−1· kg−1) due to a prolonged terminal half- life.ConclusionsIn a canine coronary thrombosis model, DSPA exhibited higher potency and recanalized coronary arteries faster and with a lower incidence of reocclusion than TPA. Its properties may translate into a higher efficacy in patients compared with available thrombolytic agents. The long halflife of DSPA may allow for single bolus administration in the treatment of acute myocardial infarction.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Reocclusion of recanalized coronary arteries often limits the efficacy of coronary thrombolytic therapy in patients with acute myocardial infarction. Activated protein C (APC) is an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the effect of APC on thrombolysis with recombinant tissue-type plasminogen activator (rTPA) was studied in a canine model of coronary artery thrombosis.Methods and ResultsContinuous artery flow monitoring in the left anterior descending coronary artery of 30 anesthetized adult beagles was performed by a magnetic flowmeter. Localized thrombosis was produced in the left anterior descending coronary artery and administration of rTPA (alteplase, 0.45 mg/kg IV) was done for 30 minutes. The dogs were randomly assigned to receive one of the following intravenous adjunctive therapies: (1) control group (n= 10): human albumin at a rate of 0.83 mL/min; (2) APC group (n=10): human plasmaderived APC (0.6 mg/kg) with human albumin as a vehicle at a rate of 0.83 mL/min; and (3) heparin group (n= 10): heparin (200 U/kg) with saline at a rate of 0.83 mL/min. Each adjunctive therapy was started simultaneously with rTPA and lasted for 60 minutes. Coronary recanalization occurred in all dogs of each adjunctive treatment group in 19.1±1.9 minutes (mean±SEM). In a 120-minute observation after the termination of rTPA, reocclusion developed in all the dogs in the control and heparin groups but in only 3 of the 10 dogs in the APC group (P< .002 versus control and heparin). Time from recanalization to reocclusion (minutes, mean±SEM) was prolonged in the APC group (103.2±14.2) as compared with the control (10.2±2.3,P< .001) and heparin (30.3±11.8,P< .002) groups. Activated partial thromboplastin time was prolonged similarly in each group after thrombolytic therapy. On the other hand, bleeding time was prolonged in only the heparin group after the treatment. Serious hemorrhagic side effects were not observed in all three groups.ConclusionsAPC prevents coronary artery reocclusion after recanalization with rTPA in a canine model of coronary artery thrombosis. This finding suggests that APC may be useful as an adjunctive treatment to enhance the effects of thrombolytic therapy in patients with acute myocardial infarction.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In vitro and in vivo studies have demonstrated both anticoagulant and antiproliferative effects of heparin. The purpose of this study was to assess the effect of local intramural delivery of heparin, using heparin-coated hydrogel balloons, on platelet deposition and early smooth muscle cell proliferation after in vivo balloon angioplasty.Methods and ResultsThe effects of local heparin delivery were assessed during balloon angioplasty of porcine peripheral arteries. All balloon dilatations were performed with oversized hydrogel balloons coated with a known quantity of heparin. Balloon dilatations in contralateral vessels with uncoated hydrogel balloons served as study controls. The pharmacokinetics of heparin delivery were assessed using3H-heparin to quantitate heparin wash-off from the balloon surface, heparin delivery to the arterial wall, and intramural persistence of drug. Platelet deposition at 1 hour after balloon injury was quantified using111In-labeled platelets. Smooth muscle cell proliferation was assessed 6 to 7 days after angioplasty with immunohistochemical staining for proliferating cell nuclear antigen.3H-heparin wash-off from the hydrogel balloon surface occurred rapidly, with approximately 95% of the heparin coating disappearing within 10 seconds in the intact circulation. Approximately 2% of heparin on the balloon surface was delivered intramurally at the time of angioplasty. Intramural heparin dissipated rapidly, although small amounts of intramural heparin could still be detected for at least 48 hours. In comparison to control vessels, there was less111In-platelet deposition (P= .002) and less medial smooth muscle cell proliferation (P= .03) in heparin-treated vessels.ConclusionsLocal intraluminal delivery of heparin at the time of balloon angioplasty with heparin-coated hydrogel balloons results in intramural deposition of drug that persists for at least 48 hours. This in vivo technique significantly decreases platelet deposition and early smooth muscle cell proliferation after angioplasty injury.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Long-term maintenance of arterial duct patency by a catheter technique would be a valuable nonsurgical method of palliation for duct-dependent circulations. We used a new method: percutaneous radiofrequency thermal balloon angioplasty of neonatal lamb arterial ducts.Methods and ResultsRadiofrequency balloons 5 or 6 mm in diameter were introduced via the femoral vein of 32 neonatal lambs and inflated to 4 atm. In 28, a radiofrequency generator was used to heat the saline/contrast mixture in the balloon to 65°C (n=2), 75°C (n=2), 85°C (n=10), 100°C (n=8), and 120°C (n=6). In 4 lambs, angioplasty alone was performed. Lambs were recatheterized to assess patency at intervals up to 78 weeks. Immediate results showed the arterial duct to be patent in all cases, with a mean rise in systolic pulmonary artery pressure of 13±8 mm Hg and a mean rise in pulmonary artery oxygen saturation of 12±15%. With a mean follow-up of 45.7±28 weeks, 3 of the 4 (75%) angioplasty alone ducts closed, but only 5 of the 28 (18%) radiofrequency-treated ducts (P< .05). The mean rise in oxygen saturation between the superior vena cava and the pulmonary artery was 7.6±7% at last follow-up. Follow-up angiography of the arterial ducts showed the development of stenoses in all patent ducts.ConclusionsRadiofrequency thermal balloon angioplasty leads to long-term arterial duct patency in lambs in >80% of the treated group and is significantly more effective than balloon angioplasty alone.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Angiotensin II (Ang II) induces vascular smooth muscle cell migration and growth in vitro and induces DNA synthesis in vascular smooth muscle in vivo. Angiotensinconverting enzyme (ACE) inhibitors and angiotensin II receptor antagonists inhibit neointimal hyperplasia in many experimental models of restenosis. However, recent clinical trials (MERCATOR and MARCATOR) reported that treatment with low (antihypertensive) doses of an ACE inhibitor (cilazapril) failed to prevent restenosis. Because ACE activity is induced in the neointima after injury, we hypothesize that the inhibition of neointimal development may be dependent on the suppression of tissue ACE activity, which in turn is dependent on the dose of the ACE inhibitor.Methods and ResultsTo test this hypothesis, we treated rats with increasing doses of an ACE inhibitor, quinapril, before injury of the carotid artery. Blood pressure, serum and tissue ACE activity, and neointimal area were measured. The results demonstrated a dose-dependent inhibition by quinapril of serum and tissue ACE activities and neointima formation. However, the IC50s for blood pressure reduction and serum ACE inhibition were significantly lower than that observed for the suppression of neointima formation. The degree of neointimal formation showed a better correlation with residual tissue ACE than with serum ACE or blood pressure.ConclusionsThese results demonstrate a dissociation of the ability of an ACE inhibitor to decrease blood pressure and inhibit circulating ACE activity from its ability to inhibit tissue ACE activity. These results suggest that the need for a higher dose of an ACE inhibitor for the inhibition of neointima formation may be due to the relative difficulty in inhibiting tissue ACE activity.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Impulse propagation in the ventricle depends on both sodium channel availability and cell-to-cell coupling through gap junctions. Sodium channel block has been shown to depress conduction velocity (&thetas;) more longitudinal (LONG) to than transverse (TRANS) to fiber orientation. Because exposure to CO2produces intracellular acidosis and decreased gap junction conductance in vitro, we tested the hypothesis that increased Pco2would result in preferential depression of transverse conduction in vivo.Methods and ResultsIn anesthetized dogs, when arterial pH was reduced to 6.70±0.04 by increasing the fraction of inhaled CO2to 40%,&thetas;TRANSfell from 0.23±0.04 to 0.19±0.02 m/s (−16±8%,P< .03), while &thetas;LONGwas unchanged (-3±7%,P=NS). In contrast, with the same degree of acidemia produced by HCI infusion, only &thetas;LONGfell (−8±7%), coincident with a rise in serum K+.ConclusionsThe observed effect of CO2on propagation in the intact heart is consistent with its previously described in vitro actions to uncouple cell-to-cell communication and may provide a model to study the role of cell-to-cell coupling in normal and abnormal propagation.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID