Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 199 records · Page 11Linked to original sources

PubMed1988

Cardioprotective actions of nisoldipine in postreperfusion myocardial ischemia.

Nisoldipine, a dihydropyridine with calcium channel-blocking activity, was studied in myocardial ischemia and reperfusion in cats. At an infusion rate of 3 micrograms/kg/hr, nisoldipine did not significantly alter the product of mean arterial blood pressure and heart rate, the pressure-rate index. When infusion of nisoldipine was started 30 minutes after occlusion and continued for 5 1/2 hours, nisoldipine exerted a marked antiischemic effect. This effect was manifested as a significant reduction in necrotic myocardial tissue expressed either as a percentage of area at risk (p less than 0.01) or as a percentage of total left ventricle (p less than 0.01). The washout of creatine kinase into the circulation was also reduced in nisoldipine-treated cats. When nisoldipine infusion started at 60 minutes after ischemia, the effects were still significant (p less than 0.05) but less striking, and when nisoldipine infusion was delayed until 90 minutes after ischemia, no significant cardioprotection was observed. Nisoldipine also blunted the washout of creatine kinase into the peripheral circulation on reperfusion. Thus nisoldipine exerts a cardioprotective effect in cats during myocardial ischemia independent of reducing myocardial oxygen demand. The effect is optimal when nisoldipine is given during the first 30 minutes of ischemia and declines thereafter, reaching insignificant effects at 90 minutes.

Animals↗

PubMed1988

Studies on the mechanism of the vasodilator action of nicorandil.

Nicorandil, a compound having structural similarities to some of the organic nitrates, was studied for its mechanism of vasodilation. Nicorandil is thought to be a K+ channel opening agent. However, little is known about its receptor activation profile, its endothelial dependence, and its effects in atherosclerotic vessels. Nicorandil, at 0.2 to 5 x 10(-6) M, relaxed norepinephrine precontracted rabbit aortic rings in a concentration-dependent manner. Moreover, nicorandil relaxed aortic rings to the same extent in the presence and absence of an intact endothelium. However, nicorandil's effect was diminished in aortic rings from atherosclerotic rabbits. The vasorelaxation action of nicorandil was unaffected by the cyclooxygenase inhibitor ibuprofen or the lipoxygenase inhibitor propyl gallate, suggesting that nicorandil does not act via the release of a vasodilator eicosanoid. Although the nicorandil effect was not influenced by atropine, a muscarinic receptor antagonist, it was significantly attenuated by methylene blue, a guanyl cyclase inhibitor. Thus, nicorandil has some properties in common with organic nitrates and with K+ channel activators but appears to be a unique type of vasodilator.

Acetylcholine↗

PubMed1988

Protective effects of CG-4203, a novel stable prostacyclin analog, in traumatic shock.

We studied the effects of CG-4203, a novel stable prostacyclin analog, in a severe model of traumatic shock in rats. Traumatic shock was produced by Noble Collip drum trauma and was characterized by marked hypotension, a 4- to 5-fold increase in plasma cathepsin D and myocardial depressant factor activities, and survival time of 95 +/- 15 minutes. Treatment with CG-4203 (100 ng/kg/min) significantly prolonged survival time to 194 +/- 20 min (p less than 0.002). Traumatized rats treated with CG-4203 exhibited significantly lower plasma activities of the lysosomal hydrolase cathepsin D (p less than 0.05). Furthermore, the plasma accumulation of myocardial depressant factor (MDF) activity was also significantly blunted in traumatized CG-4203 treated rats when compared with traumatized rats receiving only the vehicle (p less than 0.01). Our results suggest that a combination of membrane stabilizing and anti-proteolytic effects and inhibition of platelet aggregation may mediate the protective effects of CG-4203 in traumatic shock.

Animals↗

PubMed1988

Efficacy of a combination thromboxane receptor antagonist and lipoxygenase inhibitor in traumatic shock.

The effects of a thromboxane receptor antagonist having lipoxygenase inhibitory activity, L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) (1 mg/kg per h) were studied in a standardized model of traumatic shock. Pentobarbital (35 mg/kg) anesthetized rats subjected to Noble-Collip drum trauma were characterized by a 82 +/- 12 min survival time, a 20-fold increase in plasma cathepsin D activity, and a 6-fold increase in plasma myocardial depressant factor (MDF) activity. L-655,240 significantly attenuated the accumulation of MDF activity in the plasma (74 +/- 3 vs. 46 +/- 4 units/ml), vehicle vs. drug, respectively, and significantly (P less than 0.01) prolonged survival time to 206 +/- 26 min. However, plasma cathepsin D was not significantly altered with L-655,240 administration during traumatic shock. L-655,240 at 20 micrograms/ml markedly attenuated minced rat lung fragments from producing LTC4 and LTD4.L-655,240 exhibited significant anti-proteolytic activity in pancreatic homogenates. Therefore, L-655,2340 does not stabilize lysosomal membranes directly, but exerts an anti-proteolytic action which appears to curtail the production of a myocardial depressant factor by the ischemic pancreas, thus protecting during traumatic shock. A combination anti-eicosanoid drug such as L-655,240 may therefore prove to be an important therapeutic agent in acute ischemic disorders including traumatic shock.

Animals↗

PubMed1988

Use of a novel peptide leukotriene receptor antagonist, Ly-163443, in splanchnic artery occlusion shock.

We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗

PubMed1988

Mechanisms of action of PGE1 in hemorrhagic shock in rats.

We studied the effects of prostaglandin E1 (PGE1) in a severe model of hemorrhagic shock in rats. PGE1 was administered as a continuous IV infusion of either 0.1 microgram/kg/min or 1.0 microgram/kg/min starting 30 minutes after the onset of bleeding and continuing until one hour after reinfusion. Hemorrhaged rats treated with PGE1 (1 microgram/kg/min) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (ie, 0.9% NaCl) (final MABP 84 +/- 3 vs 57 +/- 4 mm Hg, P less than .01). PGE1 at 1 microgram/kg/min also attenuated the increase in plasma activities of cathepsin D (P less than .01), and at both doses blunted the plasma accumulation of free amino-nitrogen compounds (P less than .02 at 0.1 microgram/kg/min and P less than .01 at 1.0 microgram/kg/min). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with PGE1 (1 microgram/kg/min) than in rats receiving the vehicle (35 +/- 4 U/mL vs 74 +/- 12 U/mL, P less than .01). Rats receiving PGE1 (1.0 microgram/kg/min) also exhibited a significantly increased survival rate (P less than .01) and post-reinfusion survival time (P less than .01) compared with rats receiving only the vehicle. Our data suggest that antiproteolytic and membrane-stabilizing actions of PGE1 are important and may contribute to its beneficial effects in hemorrhagic shock. Other mechanisms (eg, inhibition of platelet aggregation and vasodilation) may also be involved.

Alprostadil↗

PubMed1988

Lipoxins A4 and B4: comparison of icosanoids having bronchoconstrictor and vasodilator actions but lacking platelet aggregatory activity.

Lipoxins A4 (LxA4) and B4 (LxB4), two lipoxygenase-generated icosanoids of arachidonic acid metabolism, were found to have a distinct biological profile. Both LxA4 and LxB4 slowly contracted pulmonary parenchymal strips isolated from guinea pigs, rabbits, and rats in a concentration-dependent manner over the range 0.1-1 microM. This bronchoconstrictor effect was not associated with release of peptide leukotrienes or thromboxane A2, nor was it blocked by lipoxygenase inhibitors or thromboxane receptor antagonists, suggesting it is a direct effect of lipoxins. However, the leukotriene D4 (LTD4) receptor antagonist LY-171883 reduced the LxA4 response, indicating that LTD4 and LxA4 may share the same receptor. LxA4 and LxB4 also exerted an endothelium-dependent vasorelaxation in guinea pig, rat, and, to a lesser extent, rabbit aortic vascular smooth muscle. In contrast to other vasoactive icosanoids, LxA4 and LxB4 failed to aggregate rat, rabbit, or guinea pig platelets or to inhibit ADP-induced aggregation. LxA4 also enhanced the release of liver lysosomal hydrolases in a liver large granule fraction, indicating a lysosomal labilizing action of LxA4. LxA4 and LxB4 share a similar biological profile. It is not clear yet whether the lipoxins could be mediators of circulatory or pulmonary disease states.

Animals↗

PubMed1988

Prostacyclin mediation of vasodilation following mesenteric traction.

Eight untreated patients (group I) and four patients who received ibuprofen preoperatively (group II) scheduled for elective abdominal aortic aneurysm repair were studied. Heart rate (HR); systolic, diastolic, and mean arterial pressure (MAP); systolic and diastolic pulmonary artery pressure; pulmonary capillary wedge pressure (PCWP); cardiac output (CO); and central venous pressure (CVP) were recorded pre-induction, before mesenteric traction, and 5, 15, and 30 min post-mesenteric traction. Plasma samples were obtained at these times for analysis of six-keto-prostaglandin F1 alpha (PGF1 alpha) concentration by radioimmunoassay. Group II patients received ibuprofen 12 mg/kg orally 1 1/2 h before surgery. Plasma samples from six group I patients and all group II patients taken 5 min after mesenteric traction were added to isolated helical strips of cat superior mesenteric arteries precontracted with norepinephrine (200 ng/ml) for analysis of reduction in developed force. In group I, abdominal mesenteric traction resulted in a significant decrease in MAP (P less than 0.03) and SVR (P less than 0.005) with an increase in CO (P less than 0.05) at 5 min post-mesenteric traction, which returned to mean pre-mesenteric traction values by 30 min and a significant increase in PGF1 alpha concentrations. There was a significant positive correlation between PGF1 alpha and CO (P less than 0.001) and a significant negative correlation between PGF1 alpha and SVR (P less than 0.01) at 5 min post-mesenteric traction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1988

Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock.

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane-stabilizing agent that has been shown to exert beneficial effects in a variety of models of ischemia and circulatory shock. However, the use of PGI2 is limited by its instability and rapid biodegradation. We studied the effects of a novel, stable prostacyclin analog, CG-4203, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CG-4203 maintained postreinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (final MABP 101 +/- 3 vs. 75 +/- 5 mm Hg, p less than 0.01). CG-4203 was also found to attenuate the increase in plasma cathepsin D activity (p less than 0.01), as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in CG-4203-treated hemorrhaged rats than in rats receiving the vehicle (25 +/- 2 vs. 54 +/- 7 U/ml, p less than 0.01). In addition, CG-4203 exerted an anti-proteolytic action in pancreatic homogenates and inhibited platelet aggregation in platelet-rich plasma. However, CG-4203, at concentrations expected during treatment of shock, failed to have an immediate or delayed vasodilator effect in rat aortic rings, and thus vasodilation is not an important aspect of the antishock effects of CG-4203. Our results suggest that inhibition of platelet aggregation, as well as the antiproteolytic and membrane-stabilizing actions, could mediate the beneficial effects of CG-4203 in hemorrhagic shock.

Animals↗

PubMed1988

Protective effects of a platelet activating factor (PAF) antagonist and its combined treatment with prostaglandin (PG) E1 in traumatic shock.

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using CV-6209, a specific antagonist of PAF. CV-6209, at a dose of 1 mg/kg (i.v.) given after trauma, significantly improved survival rate at 150 min and overall survival time. Furthermore, the plasma accumulation of the lysosomal hydrolase, cathepsin D, and a cardiotoxic peptide, myocardial depressant factor (MDF), were also attenuated by CV-6209 in traumatic shock. Combined treatment employing low doses of CV-6209 [0.2 mg/kg, i.v. and prostaglandin (PG) E1, 0.8 microgram/kg/min] in this shock model was also examined. CV-6209 (0.2 mg/kg) or PGE1 (0.8 microgram/kg/min) alone at these doses showed only minimal effects on survival, or plasma cathepsin D or MDF activities. However, combined treatment with CV-6209 (0.2 mg/kg, i.v.) and PGE1 (0.8 microgram/kg/min) significantly improved survival rate at 150 min, overall survival time, and decreased the accumulation of plasma MDF. These results suggest that PAF may play an important pathophysiologic role in traumatic shock in rats. Moreover, combination therapy using a PAF antagonist and PGE1 may be useful for the treatment of traumatic shock.

Alprostadil↗

PubMed1988

Cardioprotective actions of human superoxide dismutase in two reperfusion models of myocardial ischaemia in the rat.

1. In rats under ether anaesthesia, the left coronary artery was ligated and reperfused after 10 min of ischaemia. Forty-eight hours later the myocardium was analyzed for creatine kinase (CK) activity. 2. Human superoxide dismutase (h-SOD) given 1 min after occlusion and again 6 h later significantly improved survival and retarded the loss of myocardial CK. 3. In rat isolated hearts perfused at 15% of normal flow for 30 min followed by re-establishment of normal flow for 20 min, perfusion pressure increased by 72% and myocardial CK decreased by 44%. No significant changes occurred in wet-to-dry heart weight ratio. 4. Administration of h-SOD at 2.5 or 5.0 mg, significantly attenuated the elevated post-ischaemic perfusion pressure and the loss of myocardial CK activity in rat perfused hearts. 5. h-SOD appears to be an effective anti-ischaemic agent in the intact animal as well as the isolated perfused heart of the rat subjected to low flow followed by reperfusion at normal flow. The mechanism of this cardioprotective effect is not totally dependent upon the formed elements of the blood, but may be partially due to a direct cytoprotective effect.

Animals↗

PubMed1988

Cardioprotective actions of thromboxane receptor antagonism in ischemic atherosclerotic rabbits.

Atherosclerosis was induced in New Zealand White rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 10-12 wk. Half of the cholesterol-fed rabbits were given BM 13505, a specific thromboxane A2/endoperoxide (TxA2/PGH2) receptor antagonist, and the other half were given its vehicle (i.e., 2% Na2CO3). At the end of 10-12 wk, the rabbits underwent experimental myocardial ischemia or an identical sham operation, except that the coronary artery was not occluded. BM 13505 was shown to protect the ischemic rabbit myocardium by three different methods: 1) maintenance of myocardial tissue creatine kinase (CK) activity in the ischemic myocardium; 2) reduced loss of free amino nitrogen-containing compounds from the myocardium; and 3) blunting the rise of plasma CK activity. Part of the mechanism for these effects may be due to inhibition of platelet aggregation and blockade of the vasoconstrictor effect of TxA2. However, these protective effects were not due to differences in myocardial oxygen demand among the groups. Finally, BM 13505 exhibited an antiatherogenic effect by reducing the deposition of cholesterol in the aortic wall and by retarding plaque formation in coronary arteries. However, it does not achieve this antiatherogenic effect by lowering plasma cholesterol concentrations or by scavenging superoxide free radicals. Thus blockade of TxA2 receptors exerts a variety of beneficial effects that reduce the severity of ischemic damage resulting from myocardial ischemia.

Animals↗

PubMed1988

Potentiation of myocardial salvage by tissue type plasminogen activator in combination with a thromboxane synthetase inhibitor in ischemic cat myocardium.

We studied the effects of a thrombolytic agent (t-PA) and a thromboxane synthetase inhibitor (CGS-13080) in a model of myocardial ischemia and reperfusion. Occlusion of the left anterior descending coronary artery for 2 hours followed by 4 hours of reperfusion in anesthetized cats results in a large washout of creatine kinase into the blood (32 +/- 7 IU/mg protein) and an area of necrotic tissue comprising 52 +/- 5% of the area at risk and 9 +/- 0.6% of the left ventricle. Intravenous administration of t-PA (500 IU/kg.min) for 30 minutes alone at reperfusion or infusion of CGS-13080 (500 micrograms/kg.hr) had no effect on washout of creatine kinase or extent of necrotic tissue development. Administration of the same doses of both t-PA and CGS-13080 together markedly attenuated creatine kinase release to 10 +/- 2 IU/mg protein (p less than 0.01) and reduced the area of necrotic tissue to 9 +/- 2% of the area at risk and only 1.3 +/- 0.3% of the left ventricle (p less than 0.001). No significant sustained effects of these agents were observed on mean arterial blood pressure, heart rate, or the pressure rate index in these experiments. Thus, t-PA and CGS-13080 exert synergistic effects in preserving myocardial integrity in cats subjected to acute myocardial ischemia followed by reperfusion. The mechanism of this beneficial effect does not appear to be via reduced myocardial oxygen demand, increased myocardial oxygen supply, or enhanced inhibition of thromboxane A2 formation. The mechanism of this anti-ischemic effect is not clear but may involve a metabolic or a cytoprotective effect.

Animals↗

PubMed1988

Pharmacological actions of synthetic atrial natriuretic factor on coronary vascular smooth muscle.

The pharmacological activities of synthetic atrial natriuretic factor (ANF) on cat coronary artery were studied in vitro. In the preparation of isolated cat coronary artery perfused at a constant flow, ANF (3-300 nM) decreased perfusion pressure in a concentration dependent manner, indicating coronary vasodilating activity. ANF also relaxed feline coronary strips when contracted by U-46,619, CTA2, angiotensin II, serotonin, leukotriene C4 and D4. This relaxant effect was independent in the presence of endothelial cells and occurred in the presence of guanylate cyclase inhibitor, methylene blue. ANF had no direct effect on electrically driven isolated cat papillary muscles signifying a lack of direct inotropic activity. It can be concluded that ANF may potentiate coronary vasodilation and therefore contribute to coronary regulation, without directly altering myocardial performance.

Animals↗

PubMed1988

Anti-shock effects of human superoxide dismutase in splanchnic artery occlusion (SAO) shock.

We studied the effects of human superoxide dismutase (h-SOD) in splanchnic artery occlusion (SAO) shock. Pentobarbital anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state usually resulting in a fatal outcome within 20 min after the release of the occlusion. h-SOD (10 mg/kg) was infused intravenously starting at reperfusion and lasting for 10 min. SAO shock rats treated with h-SOD maintained postreperfusion MABP at significantly higher values compared to rats receiving the vehicle (final MABP 84 +/- 6 vs 46 +/- 1 mm Hg, P less than 0.01, respectively). Treatment with h-SOD attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.01 from vehicle) as well as the activity of the lysosomal protease cathepsin D (P less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in h-SOD-treated rats than in SAO rats receiving only the vehicle (27 +/- 1 vs 64 +/- 3 U/ml, P less than 0.01). SAO shock rats treated with h-SOD also exhibited a significantly higher survival rate than the SAO shock +/- vehicle group (88% vs 11%, P less than 0.01, respectively). These results support the role of oxygen-derived radicals in the pathophysiology of SAO shock, and indicate that h-SOD effectively ameliorates the deleterious effects of oxygen radicals in this severe model of ischemia and reperfusion.

Animals↗

PubMed1988

Thromboxane A2 and leukotrienes are eicosanoid mediators of shock and ischemic disorders.

Several important eicosanoids are produced during ischemic and shock states that may mediate much of the pathogenesis of these disorders. The primary substances of interest are the thromboxanes (e.g., TxA2), and the peptide leukotrienes (e.g., LTC4 and LTD4). TxA2 and the peptide leukotrienes fulfill all the criteria for a mediator in ischemia and shock. They are potent agents that exhibit a multiplicity of serious pathogenic actions. Moreover, inhibition of the formation or actions of TxA2 and the LTs is salutary in shock. TxA2 and the peptide leukotrienes therefore should be considered as important mediators of ischemia and shock, and probably as potent mediators as any known humoral substances in shock.

Animals↗

PubMed1988

Beneficial mechanisms of action of a prostacyclin enhancing agent in splanchnic artery occlusion shock.

Defibrotide stimulates PGI2 production and exerts significant antithrombotic, fibrinolytic and plasminogen-activating activities. We studied its effects in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion usually resulting in death 90-120 minutes after releasing the clamps. Defibrotide 910 mg/kg +25 mg/kg/h) treated SAO shock rats maintained higher post-reperfusion mean arterial blood pressure compared to those receiving only the vehicle (0.9% NaCl). SAO shock rats treated with defibrotide exhibited lower plasma activities of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and myocardial depressant factor (p less than 0.02 from vehicle) as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). All SAO shock rats treated with defibrotide survived the entire 120 post-release period compared with only a 42% survival rate for rats receiving only the vehicle (p less than 0.02). These results suggest a remarkable protective effect of defibrotide in SAO shock.

Animals↗

PubMed1988

Use of the novel cardiotonic and vasodilator agent pimobendan in traumatic shock.

The effect of 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone (pimobendan, UD-CG 115 BS), a novel positive inotropic and vasodilator agent, was studied in a severe model of murine traumatic shock. Noble-Collip drum trauma produced a shock state characterized by a significantly reduced mean arterial blood pressure (MABP), a 5-fold increase in plasma cathepsin D and myocardial depressant factor (MDF) activities, and a survival time of 80 +/- 12 min. Administration of pimobendan (100 micrograms/kg, i.v. bolus) significantly prolonged the survival time to 175 +/- 24 min (p less than 0.01). Although plasma cathepsin D was not affected by pimobendan, this agent significantly attenuated the accumulation of MDF activity in the plasma when compared to animals receiving only its vehicle (37 +/- 6 vs 61 +/- 9 U/ml, p less than 0.05). Additionally, pimobendan inhibited platelet aggregation in cat platelet rich plasma, but failed to have an antiproteolytic effect in cat pancreatic homogenates. These results suggest that cardiotonic and vasodilator activities combined with inhibition of platelet aggregation could mediate the beneficial effects of pimobendan in traumatic shock.

Animals↗