摘要:

The inotropic state of the myocardium can be enhanced via an increase in cell Ca2+loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622> EMD 53998>> EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650> EMD 53998> EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Caitransient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+loading and an augmentation in the Caitransient (EMD 54650).

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Collateral vessels that develop after coronary artery occlusion demonstrate perivascular inflammation, subintimal hyperplasia, and endothelial proliferation. This study was performed to test the hypothesis that these abnormalities are associated with evidence for increased production of vasodilator prostaglan-dins. Eight dogs were studied 4–6 months after occlusion of the anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study, the anterior descending coronary artery was cannulated at the site of occlusion to allow measurement of retrograde blood flow as an index of interarterial collateral flow. Injection of radioactive microspheres during the retrograde flow collection allowed determination of continuing tissue flow in the collateral-dependent zone as an index of intramural microvascular collateral flow. Retrograde and tissue flows were measured before and 20 minutes after 5 mg/kg i.v. indomethacin, a dose that caused 95±3% inhibition of the coronary vasodilation in response to a 500 μg intracoronary bolus of arachidonic acid. Heart rate and mean aortic pressure were not significantly altered by indomethacin, and blood flow to the normally perfused myocardial region was not changed by administration of indomethacin. However, indomethacin caused a 40±7% decrease in retrograde flow (p<0.01), and microvascular collateral flow to the dependent myocardium decreased by 20±10% (p<0.05). These data indicate that, unlike the normal coronary circulation, well-developed coronary collateral vessels are under the tonic influence of vasodilator prostaglandins.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effects of four calcium channel blockers (nicardipine, nifedipine, verapamil, and diltiazem) on free radical injury in cultured endothelial cells were studied and compared with those of butylated hydroxytol-uene. When the cultured cells were exposed to a superoxide and hydroxyl radical generating system for up to 60 minutes, lipid peroxidation occurred, and cellular viability decreased by 60% at 30 minutes. Concomitantly, total cellular glutathione decreased by 40%, whereas total protein thiols changed minimally. Preincubation of the cells with each of the calcium blockers (5 and 20 μM) before free radical addition resulted in various degrees of significant protection against cell death, and losses of glutathione correlated significantly (r=0.89,p<0.001). The order of efficacy was nicardipine>nifedipine>verapamil> diltiazem; butylated hydroxytoluene was about fourfold more potent than nicardipine. Because none of the agents affected the level of hydroxyl radicals generated in the aqueous phase, the data suggest that the protective mechanisms were mediated by their lipid antiperoxidative activities, which also prevented the glutathione decrease caused by inhibition of peroxide generation.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effects of electrical field stimulation (EFS) of rabbit middle cerebral arteries were examined using wire-mounted arterial segments. EFS of segments maintained at rest tension caused a tetrodotoxin-sensitive sympathetic contraction. In agonist-contracted segments maintained at approximately 60% of tissue maximum force, EFS caused a relaxation in two thirds of the preparations. Maximum response (mean±SEM) was 33±3.5% of maximal relaxation. The EFS relaxation was tetrodotoxin-sensitive but was not blocked by either chronic surgical sympathectomy or exposure to guanethidine (5 μM). Electron microscopy of chromaffin-fixed arterial sections showed the presence of chromaffin-positive large and small vesicles. Within the same sheath of Schwann were also a smaller number of nerve profiles containing many small clear vesicles. Removal of the vascular endothelium or treatment with atropine (10 nM) eliminated the EFS relaxation in approximately 50% of the segments and reduced the response in another 35–40%; in the remainder, relaxation was unaffected. Combined data for endothelium removal and atropine treatment showed that each caused a significant (p<0.01) reduction in the EFS relaxation. Atropine also significantly reduced EFS relaxation in guanethidine-treated segments. There was no reduction in EFS relaxation after procedures that antagonized ATP- or substance P-mediated relaxations. These results indicate that EFS of precontracted rabbit middle cerebral artery causes a neurogenic nonadrenergic relaxation. The neuroeffector mechanism mediating this response has a predominantly cholinergic endothelium-dependent component as well as a noncholinergic endothelium-independent component.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effect of isovolemic hemodilution on red blood cell flow distribution was studied in complete self-contained microvessel networks of the rat mesentery. Hematocrit, diameter, and length of all vessel segments as well as the topological structure were determined in control networks (systemic hematocrit, 0.54) and after hemodilution (systemic hematocrit, 0.30). Hemodilution was performed by exchanging blood with hydroxyethyl starch (MW 450,000; 6%) or homologous plasma. With hemodilution, the decrease of microvessel hematocrit exceeded that of systemic hematocrit. The average discharge hematocrit in capillaries was 79% of systemic hematocrit in the control group and 73% with hemodilution (p<0.001). The heterogeneity of capillary hematocrit within the network, expressed by the coefficient of variation, increased from 0.4 to 0.7. By using the morphological and topological data of four networks, the distribution of hematocrits was also calculated using a hydrodynamic flow model. The modeling results were found to be in close agreement with the experimental data. This indicates that the observed changes can be deduced from established rheological phenomena, most of all phase separation at arteriolar bifurcations. The changes in hematocrit distribution after hemodilution are accompanied by a redistribution of red blood cell flow within the network: relative to total red blood cell flow, red blood cell flow in the distal capillaries of the network increases by about 40% at the expense of the proximal capillaries that are close to the feeding arteriole and that exhibit the highest red blood cell flow under control conditions. This redistribution leads to a more homogeneous red blood cell flow distribution between proximal and distal regions of vessel networks with hemodilution, which might serve to increase tissue oxygenation in regions endangered by underperfusion.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We explored effects of α1-adrenoreceptor blockade with prazosin on the increased vascular smooth muscle cell (SMC) DNA synthesis induced by angiotensin II (Ang II) in rats. Ang II was infused with or without prazosin or its solvent. Observations were compared with those in rats receiving saline or solvent. In group A, Ang II was infused for 2 weeks by subcutaneously implanted osmotic minipumps at a rate of 35 ng/100 g per minute. Group B received Ang II together with the α1-adrenoreceptor antagonist prazosin (0.35 μg/100 g per minute). Group C received Ang II and 50% dimethyl sulfoxide (DMSO), the solvent of prazosin; group D received 50% DMSO; and group E received 0.9% NaCl (Ang II vehicle). All animals were infused with 5-bromo-2'-deoxyuridine for 2 weeks via separate minipumps to measure DNA synthesis. Ang II significantly increased the fraction of DNA synthesizing SMCs in the media of the thoracic aorta from 0.4±0.1% (mean±SD) in group E (n=6) to 10.8±7.0% in group A (n=8). Addition of prazosin to Ang II reduced the labeling fraction of SMCs to 3.0±2.2% (group B,n=9). The remaining SMC DNA synthesis in the prazosin-treated group was probably due to the effects of the solvent of prazosin, i.e., 50% DMSO, since infusion of 50% DMSO alone increased the labeling fraction to 4.1±2.0% (group D,n=6). Comparable results were obtained in the carotid artery. Both systolic blood pressures and medial cross-sectional areas increased during Ang II infusion, but these parameters were not altered by prazosin or DMSO. We conclude that α1-adrenoreceptors are, either indirectly or by parallel stimulation, involved in the Ang II-induced increase of medial SMC DNA synthesis in the rat. Stimulation α1-adrenoreceptors rather than an elevated blood pressure stimulated vascular SMC DNA synthesis.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Smooth muscle cells (SMCs) in balloon-injured rat carotid artery express tissue-type plasminogen activator (t-PA) at a time when they are migrating from the media to the intima. Since heparin inhibits SMC migration and intimal thickening, we have examined the possibility that heparin might also inhibit t-PA expression. Heparin (nonanticoagulant fraction; molecular weight, ∼6,000) was administered by continuous intravenous infusion (1.0 mg/kg per hour) to Sprague-Dawley rats subjected to balloon injury of the left common carotid artery. At various times up to 14 days after injury, plasminogen activator expression was analyzed by zymography, plasmin generation, enzyme-linked immunosorbent assay, Northern blotting, and in situ hybridization. This dose of heparin inhibited SMC accumulation at 14 days by 60%. Both urokinase plasminogen activator (u-PA) and t-PA activity increased in injured arteries and reached a maximum at 7 days. Heparin treatment decreased t-PA, but not u-PA, activity. Total t-PA protein was decreased by treatment with heparin but not chondroitin sulfate, and the decrease in t-PA protein was associated with decreased t-PA mRNA in the media. These results in the injured rat carotid artery agree with our earlier observations that heparin inhibits t-PA gene expression in cultured baboon aortic SMCs. They also provide support for the hypothesis that heparin interferes with the expression of certain proteases required for SMC migration and proliferation.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Difficulties in studying myocardial metabolism with adequate time resolution have led to contradictory conclusions regarding the mechanisms causing contractile abnormalities during the early stages of ischemia. In acutely instrumented swine, we investigated whether abnormalities in subendocardial ATP, phosphocreatine, or lactate content develop rapidly enough during the first few heart beats after onset of partial myocardial ischemia to contribute to contractile failure. Within the first 15 beats of a 40–50% reduction in left anterior descending coronary artery blood flow, regional myocardial function was significantly reduced but continuing to deteriorate. Rapidly frozen transmural left ventricular biopsies obtained on the 15th heart beat (±1.5 beats) after the onset of ischemia revealed significant decrements in subendocardial phosphocreatine and ATP levels to 77% (p<0.05) and 84% (p<0.005) of control values, respectively, but minimal change in lactate content. Metabolic effects as assessed by transmural averages took longer to become detectable; thus, there was a tendency to underestimate the importance of subendocardial metabolic effects on myocardial function. When left ventricular preload was assessed during this early time period, left ventricular end-diastolic wall thickness only decreased by 3%, and left ventricular end-diastolic pressure did not change significantly despite a large fall in coronary perfusion pressure. Thus, in an in vivo pig model with techniques optimized to detect subendocardial metabolic changes within the period of very early moderate myocardial ischemia, abnormalities in high energy phosphate compounds occurred rapidly enough to contribute to developing myocardial dysfunction, whereas preload-mediated mechanisms related to vascular distending pressure could not explain the functional deterioration under these conditions.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Cardiac adenosine release is thought to depend on the oxygen supply/demand ratio, and this effect may be mediated by changes in high energy phosphate concentrations. Previous studies supporting this hypothesis have been done primarily in isolated hearts. We tested this hypothesis in intact dog hearts. Anesthetized, open-chest dogs were placed in a 4.7-T magnet where31P nuclear magnetic resonance spectra were acquired via a surface coil over the heart at 2-minute intervals (60 scans, 2-second interpulse delay). Coronary sinus flow was shunted through a flow probe and returned via a jugular vein. After a control period, intracoronary norepinephrine was infused (12 μg/min) for 16 minutes and plasma samples were taken every 5 minutes. The phosphocreatine/ATP peak area ratio was used as an index of high energy phosphate changes. During norepinephrine infusion, arterial pressure, heart rate, coronary sinus flow, oxygen consumption, and adenosine release all increased significantly. Adenosine release peaked at 5 minutes but remained elevated after 15 minutes. There was a transient fall in the phosphocreatine/ATP ratio (9.2±3.1%,p<0.05) during the first 7 minutes, but the ratio returned to control levels by 9 minutes. The oxygen supply/consumption ratio increased after 5 minutes of norepinephrine infusion and then returned to control levels. We conclude that during norepinephrine infusion in vivo, persistent adenosine release can occur with only small transient changes in high energy phosphate concentrations and with no decrease in the oxygen supply/demand ratio.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Antistasin is a 119-amino acid protein initially isolated from salivary glands of the Mexican leech,Haementeria officinalis, that exhibits potent anticoagulant properties resulting from selective inhibition of blood coagulation factor Xa. The comparative antithrombotic efficacies of recombinant antistasin (rATS), standard heparin (Hep), and aspirin (ASA) administered adjunctly with recombinant tissue-type plasminogen activator (tPA) on thrombolytic reperfusion and reocclusion were determined in a canine model of femoral arterial thrombosis. An occlusive thrombus was formed by insertion of a thrombogenic copper coil into the femoral artery, and blood flow velocity was monitored directly and continuously by Doppler flowmetry. Sixty minutes after occlusion, dogs received an intravenous infusion of either saline (vehicle) or rATS (0.31, 1.25, or 2.5 μg/kg/min), intravenous boluses of Hep (100 units/kg+50 units/kg/hr or 200 units/kg+150 units/kg/hr), or a single intravenous bolus of ASA (2.0 mg/kg), followed 45 minutes later by tPA (0.8 mg/kg i.v. over 90 minutes). The saline and rATS infusions were discontinued 60 minutes after termination of tPA, and the last Hep boluses were given 105 minutes after termination of tPA. All dogs achieved reperfusion. The time to reperfusion in the ASA group was similar to that in the vehicle group (50±9 versus 50±6 minutes, respectively). Reperfusion times were slightly decreased by the low and high doses of Hep (34±6 and 31±4 minutes, respectively) and the rATS doses of 0.31 and 1.25 μg/kg/min (37±4 and 36±5 minutes, respectively). However, the time to reperfusion was dramatically reduced with the 2.5 μg/kg/min rATS dose (15±3 minutes,p<0.05). After termination of the tPA, the femoral arteries of all vehicle-treated dogs reoccluded within 24±2 minutes. Reocclusion was unaffected by ASA (30±6 minutes) and slightly delayed with low-dose Hep (52±12 minutes). High-dose Hep decreased the incidence of (four of eight) and prolonged the time to (83±24 minutes) reocclusion with an associated elevation in the activated partial thromboplastin time to 8.3-fold control. In stark contrast, reocclusion was prevented in all dogs both during rATS infusions and 2 hours after they were terminated. rATS caused a dose-dependent elevation in the activated partial thromboplastin time, resulting in clotting times 1.8-, 2.9-, and 3.9-fold control at doses of 0.31, 1.25, and 2.5 μg/kg/min, respectively. Slight elevations in bleeding time (≤1.6-fold) were observed with high-dose Hep and rATS at doses of 1.25 and 2.5 μg/kg/min. Thus, in this model of arterial thrombosis, rATS as compared with Hep and ASA significantly accelerated reperfusion and completely prevented acute reocclusion, suggesting that specific factor Xa inhibition represents an effective pharmacological approach to adjunctive thrombolytic therapy.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID