Dietary intake of unsaturated fatty acid of eicosapentaenoic acid (EPA) is thought to reduce the size and incidence of myocardial infarction. These beneficial effects are postulated to be due to chronic antithrombotic properties of EPA itself. We studied the possible direct effects of EPA on vascular smooth muscle as well as the ability of EPA to modify the vasoactivity of constrictor mediators in rabbit and cat aortic rings and isolated cat coronary arteries. EPA concentration-dependently (30 to 300 microM) relaxed rabbit and cat aortic rings having an intact endothelium, while EPA did not show any significant vasodilator effects on rings without an endothelium. This EPA-induced vasorelaxation was not altered by the cyclooxygenase inhibitor ibuprofen, but was totally abolished by the guanylate cyclase inhibitor methylene blue, indicating an endothelium-dependent smooth muscle relaxation mechanism. In isolated perfused cat coronary arteries, EPA (3 to 300 microM) exerted a dilator effect which was endothelium-independent and not affected by ibuprofen. The response was attenuated by propyl gallate, a lipoxygenase inhibitor. EPA also inhibited leukotriene (LT) C4, (50 nM) and LTD4 (50 nM)-induced vasoconstriction of isolated cat coronary arteries ranging from a blockade of 10% to 15% (P less than 0.05) at 3 microM of EPA to a blockade of 89% to 93% (P less than 0.01) at 300 microM. In contrast, the thromboxane analog, CTA2, induced coronary constriction was not significantly altered by EPA. Thus, EPA produces endothelium-dependent relaxation in rabbit and cat aorta and endothelium-independent vasodilation in cat coronary arteries (i.e., intact vessels or helical strips). Moreover, EPA exerts acute anti-leukotriene actions in coronary arteries. In the case of long-term dietary intake of EPA, these actions may contribute to the protective action of EPA in myocardial ischemia.

Animals↗

PubMedDate not supplied

Mechanism of the beneficial effect of dexamethasone on myocardial cell integrity in acure myocardial ischemia.

Dexamethasone (6 mg/kg) given intravenously to anesthetized cats exerted no significant hemodynamic effect on control open-chest cats or in cats subjected to acute myocardial ischemia by coronary artery ligature. However, dexamethasone normalized elevated S-T segments toward preischemic values, and prevented much of the increase in plasma CPK activity following coronary artery ligation. Moreover, dexamethasone prevented loss of CK activity within ischemic myocardial tissue five hours after the onset of ischemia. Dexamethasone also reduced the extent of ischemic damage as assessed by a nitro-blue tetrazolium staining technique, providing anatomic verification of the reduced ischemic damage. Moreover, dexamethasone prvented the swelling and vacuolization of myocardial lysosomes in the ischemic region, indicating a stabilization of lysosomal membranes within the heart. These data indicate that lysosomal disruption is an important consequence of myocardial ischemia and that early treatment with dexamethasone prevents the loss of myocardial lysosomal and cellular enzymes as reflected in normalization of the ECG and plasma CK activity of ischemic cats. In this way, dexamethasone may act to retard the spread of the developing infarct within the ischemic myocardium.

Acute Disease↗

PubMedDate not supplied

Influence of verapamil on cellular integrity and electrolyte concentrations of ischemic myocardial tissue in the cat.

Verapamil, at a dose of 1 mg/kg, was given intravenously to anesthetized cats one hour after coronary artery occlusion. Verapamil significantly reduced mean arterial blood pressure, but produced an increase in heart rate, partially offsetting the reduction in myocardial oxygen demand resulting from the reduction in pressure. Verapamil failed to prevent the elevations in the S-T segment of the electrocardiogram observed in cats subjected to myocardial ischemia (MI) and given only the vehicle for verapamil (i.e., 0.9% NaCl). Moreover, verapamil also did not prevent the accumulation of creatine phosphokinase (CPK) activity in the circulating blood after MI. Nevertheless, verapamil significantly prevented the loss in CPK and in amino-nitrogen observed in the ischemic region of the myocardium, indicating some protective effect on myocardial integrity. The major effects of verapamil on electrolyte content of ischemic myocardial tissue were a decrease in sodium and an increase in potassium. However, calcium gain by the heart was not prevented by verapamil. Verapamil, therefore, exerts a partial degree of protection of the ischemic myocardium but exerts some other effects which do not help prevent the spread of ischemic damage in the myocardium.

Animals↗

PubMedDate not supplied

Ischemia aggravating effects of platelet-activating factor in acute myocardial ischemia.

The effect of platelet-activating factor (PAF) was studied during the acute phase of myocardial ischemia in cats. PAF infusion (0.75 micrograms/kg/h for 4.5h) in anesthetized, open-chest cat decreased arterial blood pressure, but did not influence heart rate or biochemical indices of cell integrity. The same dose of PAF, however, started 30 min after coronary ligation, resulted in a significantly higher elevation of plasma creatine phosphokinase (CK) activity and a reduced CK content in the region of the ischemic myocardium. Treatment with the thromboxane A2 synthetase inhibitor, CGS-13080, significantly attenuated the PAF-aggravated ischemic cellular damage. These experiments suggest that hypoxia-generated PAF may contribute to the aggravation of myocardial ischemia, part of which appears to be due to PAF-induced release of thromboxane A2.

Animals↗

PubMedDate not supplied

Lack of thromboxane A2 involvement in the arrhythmias occurring during acute myocardial ischemia in dogs.

Coronary artery occlusion (CAO) followed by reperfusion of the ischemic myocardium has been associated with the onset of ventricular arrhythmias. It has been suggested that platelet aggregates in the ischemic area may release thromboxane A2 (TxA2) which may then be responsible for the arrhythmias that occur during reperfusion. To study this possibility, the effect of TxA2 synthetase inhibition on arrhythmias was examined in anesthetized dogs during occlusion and for 60 minutes following release. Imidazole (30 mg/kg) was infused intravenously for 10 minutes, followed by continuous infusion of 100 mg/kg/hr for 125 minutes. The left anterior descending coronary artery was occluded, 5 minutes after the initial dose, for 60 minutes. Three minutes after release of CAO, TxB2 concentrations were significantly higher in the arterial blood of vehicle-treated animals (2.06 +/- 0.53 pmoles/ml) than in either CAO + imidazole (0.66 +/- 0.16 pmoles/ml) or sham-CAO animals receiving imidazole (0.66 +/- 0.09 pmoles/l). However, CAO dogs whether receiving imidazole or 0.9% NaCl generated a significantly greater number of ectopic beats during and after occlusion than sham-CAO animals. Therefore, release of TxA2 does not appear to be a major causative factor in the generation of reperfusion arrhythmias in dogs following coronary artery occlusion.

Animals↗

PubMedDate not supplied

Lack of effect of thyrotropin releasing hormone (TRH) in circulatory shock.

Thyrotropin releasing hormone (TRH) has been reported to reverse hypotension induced by a variety of agents and thus it has been suggested to be of therapeutic value in circulatory shock. We have investigated TRH (2 mg/kg bolus plus 2 mg/kg/hr infusion) in both hemorrhagic (cats) and traumatic shock (rats). TRH induced a pressor effect of 23 +/- 8 mm Hg (p less than 0.05) in cats and 19 +/- 3 mm Hg (p less than 0.01) in rats during hypotension. However, this transient (10-15 min) response did not result in any sustained improvement in the cardiovascular status of the animals in either shock model when compared to the vehicle. In addition, TRH did not attenuate any of the biochemical indices of the severity of the shock state (i.e., plasma amino-nitrogen concentrations, or plasma cathepsin D and MDF activities) nor did it improve survival time in traumatic shock (2.8 +/- 0.4 vs. 2.0 +/- 0.2 hours). Furthermore, TRH resulted in a significant blunting of the maximum post-reinfusion superior mesenteric artery flow and enhanced beta-glucuronidase release from liver lysosomal preparations in vitro. These potentially detrimental effects in conjunction with the lack of any overt protective effect under the conditions existing in these two shock models, do not provide evidence that TRH is beneficial as a therapeutic agent in circulatory shock.

Animals↗

PubMedDate not supplied

Antagonism of thromboxane analog-induced vasoconstriction by non-steroidal anti-inflammatory agents.

The ability of six non-steroidal anti-inflammatory agents--meclofenamate, indomethacin, flurbiprofen, naproxen, ibuprofen, and acetylsalicylic acid--to inhibit coronary constriction induced by the thromboxane agonist carbocyclic thromboxane A2 (CTA2) was studied in isolated perfused cat coronary arteries. At constant flow, 7.5 nM CTA2 increased coronary artery perfusion pressure by 33 +/- 3 mm Hg (n = 20). Sodium meclofenamate reduced 7.5 nM CTA2-induced vasoconstriction by 2% at 0.34 microM (ns), 38% at 3.4 microM (ns), and 99% at 34 microM (p less than 0.025). The IC50 for meclofenamate was 5.4 microM; the IC50 for indomethacin, flurbiprofen, naproxen, ibuprofen, and acetylsalicylic acid was 42, 150, 250, 485, and 610 microM, respectively. Increasing the external calcium concentration to 10 mM completely reversed the inhibition of CTA2-induced coronary vasoconstriction. Furthermore, the data suggest that inhibition of CTA2-induced coronary vasoconstriction by anti-inflammatory agents may be explained either by thromboxane receptor antagonism or calcium channel blockade.

Animals↗

PubMedDate not supplied

Protection of ischemic cat myocardium by CGS-13080, a selective potent thromboxane A2 synthesis inhibitor.

A specific inhibitor of thromboxane A2 (TxA2) synthesis, CGS-13080, was studied during acute myocardial ischemia (MI) in cats. To define more clearly the mechanism of action of CGS-13080, we also studied it effects on isolated cat coronary arteries, in vitro aggregation of cat platelets, and production of thromboxane B2 (TxB2) from cat platelet-rich plasma (PRP). MI cats that received the vehicle for CGS-13080 exhibited a significant increase in plasma concentration of TxB2. This was accompanied by increases in the ST segment of the electrocardiogram, specific activity of plasma creatine kinase (CK), and loss of CK activity and amino-nitrogen from the ischemic myocardium. In contrast, TxB2 concentrations, plasma and tissue CK activities, and myocardial amino-nitrogen concentration of MI cats treated with CGS-13080 were not significantly different from those in sham MI cats that had received the drug. In vitro, CGS-13080 did not inhibit contraction of cat coronary arteries produced by a stable TxA2 analog and did not inhibit aggregation of cat PRP indiced by arachidonic acid (AA). However, production of TxB2 by cat platelets treated with AA was completely inhibited by this agent. Thus, specific inhibition of TxA2 synthesis without thromboxane receptor antagonism can exert a protective effect on the myocardium during ischemia in cats.

Animals↗

PubMedDate not supplied

Pulmonary artery endothelial dysfunction following ischemia and reperfusion of the rabbit lung.

We studied endothelial dysfunction of the rabbit pulmonary artery following in vivo ischemia and reperfusion of the lung, and also investigated the mechanisms of endothelium-dependent relaxation in these arteries. Intrapulmonary arteries were isolated from rabbits subjected to ischemia and reperfusion of one lung. Percent relaxation values of sham-operated (i.e. nonischemic) pulmonary arteries to endothelium-dependent vasodilators acetylcholine (ACh) and A23187 were 72 +/- 4 and 65 +/- 4%, respectively, while relaxation to the endothelium-independent dilator NaNO2 was 97 +/- 1%. The relaxation of control artery rings to ACh and A23187 were significantly decreased to 2 +/- 1 and 5 +/- 4%, respectively, following addition of N omega-nitro-L-arginine methyl ester, while relaxation following treatment with indomethacin or glybenclamide remained normal. Relaxation to NaNO2 was not altered by pretreatment with any of the above compounds. Thus, pulmonary artery relaxation to the endothelium-dependent dilators ACh and A23187 appears to be mediated by the release of EDRF. Endothelium-dependent relaxation of pulmonary arteries from lungs exposed to 90 min of ischemia and 30 min of reperfusion remained essentially normal, while 90 min of ischemia followed by 60 min of reperfusion resulted in a significant decrease in endothelium-dependent relaxation to A23187 to 37 +/- 7% (p < 0.05), whereas the response to ACh was reduced only to 57 +/- 3% (not significant). 90 min of ischemia followed by 90 min of reperfusion resulted in significant attenuation of endothelium-dependent relaxation to both ACh (36 +/- 4%) and A23187 (33 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Effect of recombinant soluble P-selectin glycoprotein ligand-1 on leukocyte-endothelium interaction in vivo. Role in rat traumatic shock.

-Traumatic shock induces profound pathophysiological alterations and initiates inflammatory reactions in many tissues, thus resulting in acute multiple organ damage (eg, intestine, pancreas, and liver). In the rat, Noble-Collip drum trauma increases P-selectin expression on the vascular endothelium as a result of loss of endothelium-derived NO. Here we postulated that blockade of the earliest steps in leukocyte adhesion (ie, leukocyte rolling) via administration of a recombinant soluble form of P-selectin glycoprotein ligand-1 (PSGL-1; the recombinant soluble form is rsPSGL.Ig) would attenuate selectin-mediated events observed in the rat during traumatic shock. Using intravital microscopy of the rat mesenteric microvasculature, we found that intravenous infusion of rsPSGL.Ig significantly inhibited leukocyte-endothelium interaction (ie, leukocyte rolling, adherence, and transmigration) induced by traumatic shock as well as by activation of the microvascular endothelium with 50 micromol/L NG-nitro-L-arginine methyl ester. Immunohistochemical detection of P-selectin on the mesenteric venular endothelial surface demonstrated that rsPSGL.Ig functionally neutralizes effects of P-selectin on the endothelial cell surface rather than attenuating P-selectin expression. Systemic administration of rsPSGL.Ig to traumatized rats prolonged survival time and survival rate, significantly attenuating ileal myeloperoxidase activity and significantly preserving mesenteric endothelial function. Furthermore, PSGL-1 mRNA levels were significantly increased in the blood of traumatized rats and were reduced after systemic administration of rsPSGL.Ig. Thus, soluble recombinant forms of PSGL-1 are able to ameliorate acute shock states by suppressing selectin-mediated leukocyte-endothelium interaction at both the functional and molecular levels.

Acetylcholine↗

PubMedDate not supplied

Novel beneficial effects of defibrotide, an endothelium protecting agent, following ischemia and reperfusion in the isolated perfused rat heart.

Infiltrating polymorphonuclear leukocytes (PMNs) have been implicated as key mediators of ischemia/reperfusion injury of the heart. These toxic effects are due to PMN and endothelial cell interactions. This microvascular dysfunction results in an impairment of the coronary circulation which enhances myocardial damage. The effect of defibrotide was examined in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of defibrotide (200 micrograms/kg) to I/R hearts in the presence of PMNs preserved coronary flow and protected against cardiac contractile dysfunction (p < 0.001) in comparison to those I/R hearts perfused with PMNs but receiving only vehicle. Defibrotide also significantly decreased PMN accumulation in the ischemic myocardium as evidenced by an attenuation in myeloperoxidase activity (p < 0.001). Defibrotide exerted a significant cardioprotection in PMN mediated I/R injury of rat heart. The mechanism appears to be related to inhibition of PMN-endothelium interaction and eventual PMN infiltration into the ischemic myocardium.

Animals↗

PubMedDate not supplied

Administration of polymerized bovine hemoglobin improves survival in a rat model of traumatic shock.

The ability of purified and modified hemoglobin solutions to expand blood volume and act as oxygen and carbon dioxide transporters with no apparent toxic side effects has lead to an increased interest in their utilization in shock conditions. Although hemoglobin solutions have been shown to provide beneficial effects in endotoxic and hemorrhagic shock, they have not been studied in whole body traumatic injury. We investigated the effects of a polymerized bovine hemoglobin solution (HBOC-201) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, a survival time of 102 +/- 20 min, significant increases in intestinal myeloperoxidase (MPO) activity and splanchnic vascular endothelial dysfunction characterized by an impaired vasorelaxation of the superior mesenteric artery (SMA) to endothelium-dependent vasodilators. Traumatized rats were treated with HBOC-201 or an equal volume of vehicle corresponding to 5, 10 or 15% of the calculated blood volume. Treatment with HBOC-201 10 min posttrauma prolonged survival, normalized mean arterial blood pressure and attenuated endothelial dysfunction of the SMA. However, administration of HBOC-201 failed to significantly attenuate increases in intestinal MPO activity following trauma. No beneficial effects were observed with the administration the vehicle. These data indicate that HBOC-201 exerts significant beneficial effects in traumatic shock states by normalizing systemic blood pressure and attenuating vascular endothelial dysfunction. HBOC-201 may serve as a useful adjunctive agent in the early treatment of trauma.

Animals↗

PubMedDate not supplied

Preservation of myocardial membrane integrity in the early phase of acute myocardial ischemia.

Myocardial uptake of dexamethasone (Dex) or methylprednisolone (MP) was studied using tritiated tracers in isolated perfused cat hearts during acute myocardial ischemia. Considerable amounts of Dex and MP were incorported into the plasma membranes in control, border-zone, and ischemic myocardium. Lesser amounts were bound to the remaining subcellular organelles. A gradient of the glucocorticoid uptake was observed decreasing from control myocardium to ischemic myocardium in all subcellular fractions. By the first hour of ischemia, the myocardial plasma membranes underwent marked depletion of activity of 5'-nucleotidase, a plasma membrane marker enzyme, indicating early loss of plasma membrane integrity in acute myocardial ischemia. The incorporation of Dex or MP into the plasma membranes resulted in a significant decrease in loww of 5'-nucleotidase activity of the plasma membranes in the border-zone and ischemic myocardium. The data provide direct evidence 1) to support a membrane stabilizing action of glucocorticoids, and 2) to focus on the plasma membranes as a potentially important site of protection during the early phase of acute myocardial ischemia.

Acute Disease↗

PubMedDate not supplied

Mechanisms of inhibition of nitric oxide production in a murine model of splanchnic artery occlusion shock.

Nitric oxide has been thought to be a major endothelium-derived relaxing factor which is synthesized from L-arginine and can be selectively inhibited by L-NG-monomethyl arginine. On the other hand, another endothelium-derived vasorelaxant, defined as endothelium-derived hyperpolarizing factor, has been reported. We compared their role in regulating the splanchnic vascular tone in splanchnic artery occlusion shock in the rat. Administration of L-NG-monomethyl arginine (100 mg/kg) given 5 min prior to reperfusion of splanchnic arteries which were occluded for 45 min, produced a significant increase in mean arterial blood pressure. However, the indices of the severity of shock status, including survival time, survival rate and increases in hematocrit, plasma cathepsin D and myocardial depressant factor activity following splanchnic artery occlusion shock were not exacerbated by administration of L-NG-monomethyl arginine. Addition of L-NG-monomethyl arginine (1 mg/ml) induced a small but significant increase in basal vascular tone of superior mesenteric artery rings, but it failed to totally block acetylcholine-induced vasorelaxation (48 +/- 4% relaxation). Although there were no significant changes in basal vascular tone after administration of glibenclamide (30 micrograms/ml), acetylcholine-induced vasorelaxation was significantly attenuated (58 +/- 4% relaxation). When L-NG-monomethyl arginine and glibenclamide were added together, acetylcholine-induced vasorelaxation was almost totally abolished (18 +/- 2% relaxation). Our results indicate that rat splanchnic artery endothelial cells may produce both endothelium-derived relaxing and hyperpolarizing factor. Endothelium-derived relaxing factor plays an important role in the regulation of basal vascular tone of the splanchnic circulation, while endothelium-derived hyperpolarizing factor may be important in modulating the mesenteric blood flow following splanchnic artery occlusion shock.

Acetylcholine↗