Biomedical subjects

X L Ma

Publications and source records attributed to X L Ma.

At least 55 records · Page 3Linked to original sources

PubMed1998

Effects of a hydroxylated metabolite of the beta-andrenoreceptor antagonist, carvedilol, on post-ischaemic splachnic tissue injury.

1 Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new beta-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury. 2 Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg(-1) and 1.0 mg kg(-1), SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation. 3 Administration of 1 mg kg(-1) carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg(-1) carvedilol had no protective effects on post-ischaemic tissue injury. 4 Previous studies have shown that SB 211475 has virtually no beta-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.

Adrenergic beta-Antagonists↗

PubMed1998

L-propionyl carnitine, an endogenous ester in fatty acid metabolism, exerts anti-shock and endothelial protective effects in rat splanchnic ischemia-reperfusion injury.

Splanchnic artery occlusion (SAO) results in a severe form of circulatory shock in which oxygen-derived free radicals play an important role. L-Propionyl carnitine (LPC), an endogenous ester that plays a crucial role in cellular fatty acid oxidation and metabolism, has been shown to exert a protective effect in myocardial ischemia/reperfusion injury. Our purpose was to investigate the effects of LPC in an SAO model of ischemia/reperfusion injury. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. An intravenous bolus of LPC (200 microg/kg) administered 2 min before reperfusion prolonged survival time (116+/-4 vs. 81+/-3 min in 1 mL/kg .9% NaCl vehicle, p < .01), increased survival rate (88 vs. 13.6%, p < .01), and attenuated the percent increase in hematocrits (27+/4% vs. 43+/-3%, p < .05), and the increases in tissue myeloperoxidase activity (1.76+/-.4 U/100 mg vs. 3.79+/-.2 U/100 mg, p < .05). In addition, LPC increased mean arterial blood pressures at 60 min (p < .05), 80 min (p < .05), 100 min (p < .05), and 120 min (p < .05) postreperfusion. Moreover, LPC markedly attenuated splanchnic artery endothelial dysfunction induced by SAO ischemia/reperfusion injury (maximal vasorelaxation to ACh, 74+/-2.7% vs. 57+/-1.9% in vehicle, p < .01). In this murine SAO model of ischemia/reperfusion injury, LPC affords significant protection that may be achieved through inhibiting leukocyte infiltration into intestinal tissue and preserving endothelial function, thereby decreasing microvascular permeability and maintaining tissue perfusion.

Animals↗

PubMed1998

Cloricromene reduces infarct size and alters postischaemic blood flow defects in dog myocardium.

1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia-reperfusion. 2. Dogs were instrumented to measure blood pressure, left anterior descending (LAD) coronary flow (flow probe) and regional myocardial blood flow (coloured microspheres). Two groups were studied: (i) CLO (n = 8) received an infusion of cloricromene (15 micrograms/kg per min); and (ii) VEH (n = 8) received saline. Infusions began at the onset of ischaemia (60 min) and continued through reperfusion (180 min). 3. Haemodynamic responses were not different between groups. Cloricromene reduced the area of necrosis expressed as a percentage of the area at risk from 35 +/- 3% in the VEH group to 23 +/- 4% in the CLO group (P < 0.05). Regional myocardial blood flow in the ischaemic region was different between groups; VEH dogs showed an early reperfusion hyperaemia followed by a progressive reduction in flow, while CLO dogs exhibited a gradual increase in reflow in the absence of an early hyperaemic response (P < 0.05). Left anterior descending flow was enhanced during the reperfusion period in the CLO group compared with VEH (P < 0.05). Cloricromene reduced polymorphonuclear neutrophil (PMN) infiltration (myeloperuxidase activity) in all myocardial regions when compared with VEH (non-ischaemic zone, 0.34 +/- 0.54 vs 0.05 +/- 0.01 IU/100 mg; ischaemic zone, 2.03 +/- 0.80 vs 0.24 +/- 0.08 IU/100 mg; and necrotic zone, 0.56 +/- 0.04 vs 3.59 +/- 1.09 IU/100 mg for VEH vs CLO groups, respectively; P < 0.01). In a separate in vitro preparation, cloricromene reduced adherence of platelet-activating factor (PAF)-stimulated PMN to canine coronary endothelium. Stimulation of PMN by 100 nmol/L PAF resulted in adherence of 176 +/- 36 compared with 48 +/- 12 cells/mm2 in PAF-stimulated PMN treated with 100 mumol cloricromene (P < 0.001). 4. These data indicate that cloricromene reduces myocardial infarct size in a canine model of ischaemia-reperfusion injury. Postischaemic blood flow patterns are significantly different in cloricromene-treated dogs. Cloricromene-mediated reductions in infarct size, neutrophil accumulation and adherence may play a role in this effect.

Animals↗

PubMed1998

SP/W-5186, A cysteine-containing nitric oxide donor, attenuates postischemic myocardial injury.

The effects of SP/W-5186, a cysteine-containing nitric oxide (.NO) donor, on myocardial reperfusion injury were studied in a rabbit ischemia (45 min) and reperfusion (180 min) model. Five min before reperfusion, either low-dose (0.3 micromol/kg) or high-dose (1 micromol/kg) SP/W-5186 was given intravenously as a bolus. Administration of 0.3 micromol/kg SP/W-5186 did not change mean arterial blood pressure, heart rate or pressure-rate index. However, administration of low-dose SP/W-5186 exerted marked cardioprotective effects as evidenced by improved cardiac functional recovery (P <.05 vs. vehicle), decreased plasma creatine kinase concentration (P <. 01) and reduced infarct size (P <.01). Moreover, administration of SP/W-5186 significantly decreased platelet aggregation (P <.01 vs. vehicle), attenuated polymorphonuclear leukocyte (PMN) accumulation in myocardial tissue, inhibited PMN adhesion to endothelial cells and preserved endothelial function. Administration of high-dose SP/W-5186 resulted in a transient but significant decrease in mean arterial blood pressure and exerted more cardiac protection compared with low-dose treatment. However, the effects on platelet aggregation, PMN accumulation and PMN adhesion did not differ significantly between the two SP/W-5186 groups. Furthermore, administration of SP/W-6373, an analogue of SP/W-5186 that lacks the NO moiety, failed to exert any protective effects. These results demonstrate that NO released from SP/W-5186 significantly protected myocardial tissue from reperfusion injury. The primary mechanisms of the observed cardioprotection by SP/W-5186 involve inhibition of platelet aggregation, attenuation of PMN-endothelium interaction and preservation of endothelial function.

Animals↗

PubMed1997

Peroxynitrite aggravates myocardial reperfusion injury in the isolated perfused rat heart.

OBJECTIVE: This study examined the effects of peroxynitrite (ONOO-) on cardiac function and cellular injury following ischemia (30 min) and reperfusion (60 min) in isolated perfused rat hearts. METHODS: 3-Morpholinosydnonimine (SIN-1, 0.1 mM), an ONOO- donor, was administered alone or combined with superoxide dismutase (SOD, 300 U/ml) or glutathione (GSH, 1 mM) at the time of reperfusion. RESULTS: Administration of SIN-1 alone significantly aggravated post-ischemic myocardial injury characterized by depressed cardiac function recovery (p < 0.05 vs. vehicle), increased lactic dehydrogenase (LDH) and creatine kinase (CK) release (p < 0.01 vs. vehicle), and enlarged necrotic size (p < 0.01 vs. vehicle). The co-administration of either SOD to decrease the formation of ONOO-, or GSH to increase the detoxification of ONOO-, completely blocked the detrimental effects of SIN-1 and exerted significant cardioprotective effects against reperfusion injury. CONCLUSION: These results suggest that ONOO- may play a significant role in postischemic myocardial injury.

Animals↗

PubMed1997

Endothelial stunning and myocyte recovery after reperfusion of jeopardized muscle: a role of L-arginine blood cardioplegia.

Ischemia and reperfusion may damage myocytes and endothelium in jeopardized hearts. This study tested whether (1) endothelial dysfunction (reduced nitric oxide release) exists despite good contractile performance and (2) supplementation of blood cardioplegic solution with nitric oxide precursor L-arginine augments nitric oxide and restores endothelial function. Among 30 Yorkshire-Duroc pigs, 6 received standard glutamate/aspartate blood cardioplegic solution without global ischemia. Twenty-four underwent 20 minutes of 37 degrees C global ischemia. Six received normal blood reperfusion. In 18, the aortic clamp remained in place 30 more minutes and all received 3 infusions of blood cardioplegic solution. In 6, the blood cardioplegic solution was unaltered; in 6, the blood cardioplegic solution contained L-arginine (a nitric oxide precursor) at 2 mmol/L; in 6, the blood cardioplegic solution contained the nitric oxide synthase inhibitor L-nitro arginine methyl ester (L-NAME) at 1 mmol/L. Complete contractile and endothelial recovery occurred without ischemia. In jeopardized hearts, complete systolic recovery followed infusion of blood cardioplegic solution and of blood cardioplegic solution plus L-arginine. Conversely, contractility recovered approximately 40% after infusion of normal blood and blood cardioplegic solution plus L-NAME. Postischemic nitric oxide production fell 50% in the groups that received blood cardioplegic solution and blood cardioplegic solution plus L-NAME but was increased in the group that received blood cardioplegic solution L-arginine. In vivo endothelium-dependent vasodilator responses to acetylcholine recovered 75% +/- 5% of baseline in the blood cardioplegic solution plus L-arginine group, but less than 20% of baseline in other jeopardized hearts. Endothelium-independent smooth muscle responses to sodium nitroprusside were relatively unaltered. Myeloperoxidase activity (neutrophil accumulation) was similar in the blood cardioplegic solution (without ischemia) and blood cardioplegic solution plus L-arginine groups (0.01 +/- 0.002 vs 0.013 +/- 0.003 microgram/gm tissue). Myeloperoxidase activity was raised substantially to 0.033 +/- 0.002 microgram/gm after exposure to normal blood and to 0.025 +/- 0.003 microgram/gm after infusion of blood cardioplegic solution and was highest at 0.053 +/- 0.01 microgram/gm with exposure to blood cardioplegic solution plus L-NAME in jeopardized hearts. The discrepancy between contractile recovery and endothelial dysfunction in jeopardized muscle can be reversed by adding L-arginine to blood cardioplegic solution.

Animals↗

PubMed1997

Adenosine inhibition of neutrophil damage during reperfusion does not involve K(ATP)-channel activation.

This study tests the hypothesis that cardioprotection exerted by adenosine A2-receptor activation and neutrophil-related events involves stimulation of ATP-sensitive potassium (K(ATP)) channels on neutrophils during reperfusion. The adenosine A2 agonist CGS-21680 (CGS) inhibited superoxide radical generation from isolated rabbit polymorphonuclear neutrophils (PMNs) in a dose-dependent manner from 17.7 +/- 2.1 to 7.4 +/- 1.3 nmol/5 x 10(6) PMNs (P < 0.05). Pinacidil, a K(ATP)-channel opener, partially inhibited superoxide radical production, which was completely reversed by glibenclamide (Glib). Incremental doses of Glib in combination with CGS (1 microM) did not alter CGS-induced inhibition of superoxide radical generation. CGS significantly reduced PMN adherence to the endothelial surface of aortic segments in a dose-dependent manner from 189 +/- 8 to 50 +/- 6 PMNs/mm2 (P < 0.05), which was also not altered by incremental doses of Glib. Infusion of CGS (0.025 mg/kg) before reperfusion reduced infarct size from 29 +/- 2% in the Vehicle group to 15 +/- 1% in rabbits undergoing 30 min of ischemia and 120 min of reperfusion (P < 0.05). Glib (0.3 mg/kg) did not change the infarct size (28 +/- 2%) vs. the Vehicle group and did not attenuate infarct size reduction by CGS (16 +/- 1%). Glib did not change blood glucose levels. Cardiac myeloperoxidase activity was decreased in the ischemic tissue of the CGS group (0.15 +/- 0.03 U/100 mg tissue) compared with the Vehicle group (0.37 +/- 0.05 U/100 mg tissue; P < 0.05). We conclude that adenosine A2 activation before reperfusion partially reduces infarct size by inhibiting neutrophil activity and that this effect does not involve K(ATP)-channel stimulation.

Adenosine↗

PubMed1997

Hypercholesterolemia impairs a detoxification mechanism against peroxynitrite and renders the vascular tissue more susceptible to oxidative injury.

Previous studies have shown that glutathione (GSH) plays a central role in the protection against peroxynitrite (ONOO-) toxicity. The present study evaluated the changes of the GSH cytoprotective system against ONOO- in hypercholesterolemia and determined the effects of carvedilol, a beta-blocker with free radical-scavenging activity, on these hypercholesterol-induced changes. New Zealand White rabbits were fed either a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with either carvedilol or propranolol. Eight weeks later, the rabbits were killed, and the thoracic aortas were isolated. Total GSH content of aortic tissue, vasorelaxation response of aortic rings to exogenous ONOO-, No regeneration from ONOO- by aortic homogenate, and ONOO(-)-induced aortic tissue injury were examined. Hypercholesterolemia decreased tissue GSH content (0.52 +/- 0.08 versus 0.86 +/- 0.04 mumol/g in control, P < .01), attenuated the vasorelaxation response to ONOO- (40 +/- 4.1% versus 76 +/- 3.2%, P < .01), reduced NO regeneration from ONOO- (387 +/- 40 versus 662 +/- 51 pmol, P < .01), and potentiated ONOO(-)-induced vascular tissue injury (37 +/- 4.4% versus 14 +/- 2.6% of increase in lactate dehydrogenase release after 3-morpholinosydnonimine exposure, P < .01). Treatment of the hypercholesterolemic rabbits with carvedilol, but not propranolol, significantly preserved tissue GSH content (0.79 +/- 0.05 mumol/g, P < .01 versus nontreated hypercholesterolemic rabbits), restored the vasorelaxation to ONOO- (61 +/- 2%, P < .01), increased NO regeneration from ONOO- (583 +/- 39 pmol, P < .01), and attenuated ONOO(-)-induced tissue injury (19 +/- 1.8%, P < .01). These results suggest that hypercholesterolemia impairs the GSH-mediated detoxification mechanism against ONOO- and renders the vascular tissue more susceptible to oxidative injury. Carvedilol, a novel vasodilating beta-blocker with antioxidant activity, significantly preserved this self-defense system and protected tissue from oxidant injury.

Animals↗

PubMed1996

Exogenous NO inhibits basal NO release from vascular endothelium in vitro and in vivo.

This study tested the hypothesis that exogenous nitric oxide (NO) inhibits basal release of NO in isolated rat aortic rings and in vivo. Thoracic aortic rings were suspended in organ chambers with Krebs-Henseleit solution. In untreated rings, the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) markedly increased basal vascular tone by 34.6 +/- 5.2% of maximal force produced by 100 nM thromboxane A2 mimetic U-46619, indicating a basal release of NO. Other rings were pretreated with the exogenous NO donor S-nitroso-N-acetylpenicillamine (SNAP) for 20 min and then washed free of drug. In these rings, L-NAME-induced vasoconstriction was significantly attenuated in a concentration-dependent manner (from 34.6 +/- 5.2 to 25.7 +/- 2.9% at SNAP = 0.5 microM, 15.2 +/- 3.1% at 1 microM, and 11.9 +/- 2.5% at 5 microM), while having no effect on NO-independent phenylephrine-induced vasoconstriction (35.4 +/- 4.7 untreated vs. 41.3 +/- 4.3% SNAP pretreated, not significant). In addition, the nonnitrosylated parent molecule of SNAP, acetylpenicillamine, had no effect on the vasoconstriction induced by L-NAME. In the in vivo studies in anesthetized rats, L-NAME caused significant hypertensive responses (34 +/- 4-mmHg increase in mean arterial blood pressure). Subvasoactive doses of SNAP attenuated these hypertensive responses in a dose-dependent manner (20 +/- 3-mmHg increase with 10 micrograms/kg SNAP pretreatment and 16 +/- 4-mmHg increase with 20 micrograms/kg SNAP pretreatment), but any dose of acetylpenicillamine studied had no effect. Coadministration of superoxide dismutase and SNAP significantly potentiated the inhibitory effect of the NO donor on vasocontraction responses to L-NAME. Furthermore, SNAP did not attenuate the hypertensive responses to phenylephrine. These results indicate that exogenous NO significantly inhibits basal NO release both in vitro and in vivo, suggesting that NO plays an important negative-feedback regulatory role under physiological conditions.

Animals↗

PubMed1996

Carvedilol, a new beta adrenoreceptor blocker and free radical scavenger, attenuates myocardial ischemia-reperfusion injury in hypercholesterolemic rabbits.

Oxygen-derived free radicals play a critical role in atherogenesis and reperfusion injury. The present experiment evaluated the effects of carvedilol, a new beta adrenoreceptor blocker with potent free radical-scavenging activity, on myocardial ischemia and reperfusion injury in a hypercholesterolemic rabbit model. New Zealand rabbits were fed a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with 1200 ppm carvedilol or propranolol. Eight weeks later, the rabbits were subjected to 60 min of myocardial ischemia followed by 60 min of reperfusion. The nontreated cholesterol-fed animals experienced greater cardiac damage after ischemia and reperfusion than rabbits fed a normal diet (necrosis 51% +/- 4% vs. 28% +/- 3% in the normal-diet group, P < .01). In addition, nontreated cholesterol-fed rabbits showed a significantly decreased vasorelaxant response to ACh in U-46619-precontracted aortic rings (56% +/- 5% vs 90% +/- 3% in the control group, P < .001). Treatment with propranolol neither preserved endothelial function after cholesterol feeding nor reduced neutrophil accumulation in ischemic-reperfused myocardial tissue. Propranolol treatment did significantly decrease HR, pressure-rate index and infarct size (necrosis 33% +/- 4%). Despite their having essentially identical effects on HR and pressure-rate index, carvedilol exerted more profound cardiac protective effects than propranolol (necrosis 19% +/- 3%). Moreover, carvedilol treatment significantly preserved aortic endothelial function and markedly reduced neutrophil accumulation in ischemic-reperfused myocardial tissue. These results indicate that in addition to its beta blocking activity, the antioxidant and endothelial protective activities of carvedilol contributed significantly to its cardiac protective effects after ischemia and reperfusion.

Adrenergic beta-Antagonists↗

PubMed1996

Heme oxygenase inhibitor zinc protoporphyrin IX causes an activation of nitric oxide synthase in the rabbit internal anal sphincter.

The studies were performed in the rabbit internal anal sphincter (IAS) smooth muscle strips to examine the influence of the heme oxygenase inhibitor, [zinc protporphyrin (ZnPP IX)], on basal tone. ZnPP IX produced a concentration-dependent fall in the basal tone and was the focus of our investigation. To examine the mechanism of the fall in IAS tone by ZnPP IX, the effect of different concentrations of ZnPP IX on basal IAS tone and the release of nitric oxide were examined before and after the neurotoxin tetrodotoxin and various nitric oxide synthase (NOS) inhibitors. The inhibitory effect of ZnPP IX was blocked by the NOS inhibitors L-NG-nitroarginine, NG-monomethyl-L- arginine and L-N5-(1-iminoethyl)ornithine and the neurotoxin TTX. The fall in IAS tension by ZnPP IX was accompanied by a release of NO. ZnPP IX(1 x 10(-3)M) caused a fall in IAS tension of 43.7% which was reduced to 16.5% in the presence of L-NG-nitroarginine (1 x 10(-4)M). Furthermore, the fall in IAS tone in the presence of ZnPP IX was restored both by the NOS inhibitors and tetrodotoxin. The basal release of nitric oxide in these experiments was 0.50 +/- 0.07 nmol and in the presence of ZnPP IX (1 x 10(-3)M), it increased to 1.72 +/- 0.28 nmol (more than a 3-fold increase). Thus the fall in the basal IAS tone by ZnPP IX was associated with a release of NO from the myenteric neurons as these effects were significantly blocked by the NOS inhibitors and tetrodotoxin. We conclude that in the rabbit IAS, ZnPP IX causes a fall in the basal IAS tension by the activation of NOS in myenteric neurons. We speculate that in the resting state, the heme oxygenase pathway exerts important counter-regulatory effects on the NOS pathway and when blocked (e.g., by ZnPP IX), the underlying NOS pathway is unmasked leading to a massive and prolonged release of NO. The exact significance of this mechanism remains to be determined.

Anal Canal↗

PubMed1995

In vivo release of interleukin-1 beta into hypothalamic extracellular fluid in rats: effects of repeated sampling.

Interleukin-1 beta (Il-1 beta) concentrations in extracellular fluid (ECF) withdrawn at 10-min intervals through a push-pull cannula (PPC) located in the hypothalamus were studied in freely behaving male rats for 1 h at 24 and 72 h and again at 7 days after PPC implantation. Il-1 beta concentrations in ECF were similar in the latter. However, when ECF was sampled at 3 h and again 7 days after PPC implantation, Il-1 beta concentrations were greatly elevated at 7 days when compared to all other intervals. These results demonstrate how the relationships between Il-1 beta measured in ECF and the conditions of measurement appear to be integral parts of a whole intracerebral system: cytokine concentrations appear to be inextricably bound to intrahypothalamic conditions created by the sampling device presence and frequency of use.

Animals↗

PubMed1995

Carvedilol, a new beta-adrenoreceptor blocker antihypertensive drug, protects against free-radical-induced endothelial dysfunction.

We tested the ability of carvedilol, an antihypertensive beta-adrenoreceptor antagonist with antioxidant properties, to protect rat aorta rings from free-radical-induced endothelial cell (EC) dysfunction. Rings were exposed to the superoxide generator pyrogallol. Vascular function of intact rings was assessed by observing acetylcholine (ACh)-induced vasorelaxation following submaximal contraction by U-46619. Function of rings denuded of ECs was assessed by observing S-nitroso-N-acetylpenicillamine (SNAP)-induced vasorelaxation following submaximal contraction by U-46619. Carvedilol exerted a significant protective effect against pyrogallol-induced vasoconstriction (17.1 +/- 4.8 vs. 31.9 +/- 5.4% for vehicle, p < 0.05). Carvedilol also demonstrated significant protection against pyrogallol-induced endothelium dysfunction, enhancing vasorelaxation to 1,000 nmol/l ACh (73 +/- 3.9 vs. 48 +/- 3.0% vehicle, p < 0.01). These protective effects were not seen with propanolol, a pure beta-receptor antagonist. Carvedilol mixed with pyrogallol and SNAP preserved SNAP-induced vasorelaxation in rings denuded of ECs (80.4 +/- 5.3 vs. 63.7 +/- 4.8% control, p < 0.05). Carvedilol appears to protect vascular function by scavenging free radicals and enhancing the effects of NO.

Acetylcholine↗

PubMed1995

Carvedilol, a new beta-adrenoreceptor blocker, vasodilator and free-radical scavenger, exerts an anti-shock and endothelial protective effect in rat splanchnic ischemia and reperfusion.

Splanchnic artery occlusion (SAO) followed by reperfusion results in circulatory shock in which oxygen-derived free radicals play an important role. Carvedilol, a novel beta adrenoceptor antagonist and a vasodilator, has been recently shown to exert potent antioxidant effects in multiple cell model systems. In the present experiment, we investigated the effect of carvedilol on SAO shock. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. Administration of 1 mg/kg carvedilol 10 min before reperfusion prolonged survival time (P < .05) and attenuated the increases in tissue myeloperoxidase activities (P < .01) and hematocrits (P < .001). Moreover, carvedilol significantly preserved superior mesenteric artery endothelial function (P < .01). Similar protection was seen in SAO shock rats treated with the superoxide free-radical scavenger superoxide dismutase. Except for a moderate attenuation of an increase in hematocrits, protective effects were not seen in SAO shock rats treated with the prototypic beta blocker propranolol. These results indicate that in murine SAO shock, carvedilol affords significant protection, which may be achieved through maintenance of tissue blood perfusion, quenching of oxygen free radicals, preservation of vascular endothelial function, and inhibition of neutrophil-endothelial interaction and its resultant increased microvascular permeability.

Adrenergic beta-Antagonists↗

PubMed1994

Quantification of neutrophil migration following myocardial ischemia and reperfusion in cats and dogs.

Endothelial cell dysfunction and cardiac myocyte injury resulting from ischemia and reperfusion have been associated with accumulation of neutrophils in the myocardium. To determine whether the accumulation is related primarily to intravascular sequestration or extravascular infiltration of neutrophils during the early period of reperfusion, we morphometrically quantified the tissue distribution of neutrophils in cats and dogs. At the end of the reperfusion period, the base of the heart was cross-clamped to preserve neutrophil location at the moment of death. Point-counting methods were used to determine the distribution of neutrophils inside and outside coronary arterioles and venules (< or = 100 microns in diameter) as well as coronary capillaries 5-10 microns in diameter in 0.5-microns-thick, plastic-embedded sections. Ischemia-reperfusion resulted in a threefold increase in neutrophil number in the lumen of arterioles and venules at 60 min of reperfusion and up to a sevenfold increase at 270 min of reperfusion (P < .05) compared to time-matched control nonischemic hearts. The ratio of intravascular neutrophils in venules to arterioles was 2:1. Intracapillary neutrophils increased, but not significantly, at 60 min of reperfusion. At 270 min of reperfusion, intracapillary neutrophils increased 11-fold (P < .05). The percentage of total neutrophils that accumulated outside arterioles and venules in cat hearts was 8% at 60 min of reperfusion (not significant, NS) and 28% at 270 min of reperfusion (P < .05). In dog hearts, the percentages were 26% (NS) and 44% (P < .05), respectively. The percentage of total neutrophils that accumulated outside capillaries was < 6% in both cat and dog hearts (NS). The combination of rapid intravascular sequestration, delayed extravascular infiltration, and low incidence of neutrophil-cardiac myocyte contact in situ in these two species suggests that neutrophil-mediated cardiac myocyte injury during early reperfusion may initially depend on diffusion of inflammatory mediators and subsequently require direct contact between neutrophils and cardiac myocytes.

Animals↗

PubMed1994

Beneficial actions of S-nitroso-N-acetylpenicillamine, a nitric oxide donor, in murine traumatic shock.

We studied the effects of the nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP), in rat traumatic shock characterized by hypotension, increases in plasma free amino-nitrogen (5.3 +/- 0.5 U/ml vs. 2.5 +/- 0.3 U/ml controls) and intestinal myeloperoxidase activities (2.7 +/- 1.0 U/100 mg vs. 0.2 +/- 0.1 U/100 mg controls), and a survival time of 143 +/- 20 min. Moreover, superior mesenteric artery rings isolated from rats in traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine only 21 +/- 6% of U-46619 induced contraction. Administration of 100 micrograms/kg SNAP 10 min post-trauma followed by 10 micrograms/kg/h infusion prolonged survival time to 273 +/- 18 min (p < .05), attenuated the increases in plasma free amino-nitrogen (3.1 +/- 0.4 U/ml, p < .05) and tissue myeloperoxidase activities (0.6 +/- 0.3 U/100 mg, p < .05). Moreover, SNAP significantly preserved superior mesenteric artery endothelial function; the vasorelaxation to acetylcholine was 54 +/- 4% (p < .01). Protective effects were not seen in traumatic shock rats treated with the non-NO-donating parent compound N-acetylpenicillamine. These results indicate that SNAP affords significant protection in murine traumatic shock which may be achieved through maintenance of systemic blood pressure, preservation of vascular endothelial integrity, and inhibition of neutrophil-endothelial interaction and the resultant reduced microvascular leakiness.

Acetylcholine↗

PubMed1994

Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock.

We studied the effects of CP-0127, a novel bradykinin receptor antagonist, in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma-free amino-nitrogen (8.6 +/- 0.97 vs. 2.3 +/- 0.15 U/ml in control rats) and intestinal myeloperoxidase (MPO) activity (2.7 +/- 0.33 vs. 0.08 +/- 0.03 U/100 mg control rats, intestinal tissue), and a survival time of only 110 +/- 9 min. Moreover, superior mesenteric artery (SMA) rings isolated from rats subjected to traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine (ACh) significantly less than rings isolated from control rats (21 +/- 4 vs. 92 +/- 4%, P < 0.001). Administration of CP-0127 at a dose of 10 mg/kg subcutaneously completely blocked the hypotensive response to 2.5 micrograms/kg bradykinin injected intravenously in sham traumatic shock rats. CP-0127 given immediately posttrauma prolonged survival time to 219 +/- 27 min (P < 0.01) and attenuated the increases in plasma-free amino-nitrogen (3.7 +/- 0.41 U/ml, P < 0.01) and tissue MPO activities (1.2 +/- 0.71 U/100 mg intestinal tissue, P < 0.05). Furthermore, SMA endothelial function was significantly preserved (relaxation to ACh: 57 +/- 6%, P < 0.01) in CP-0127-treated traumatic shock rats. These results indicate that bradykinin plays an important role in tissue injury associated with traumatic shock and that CP-0127 affords significant protection, which may be achieved through inhibition of neutrophil-endothelial interaction and protection of vascular endothelial function.

Animals↗

PubMed1994

PMN adherence to cat ischemic-reperfused mesenteric vascular endothelium under flow: role of P-selectin.

We studied polymorphonuclear leukocyte (PMN) adherence to cat ischemic-reperfused mesenteric artery and vein endothelia under conditions of flow in vitro. Under physiological shear rates, only a few PMNs adhered to non-ischemic-reperfused arterial and venous endothelia (11 +/- 2 and 20 +/- 3 PMN/mm2, respectively). However, after 60 min of ischemia and 20 or 120 min of reperfusion, a significant increase in PMN adherence to arterial endothelium was observed. At 20 min of reperfusion, 44 +/- 4 PMN/mm2 adhered, and at 120 min postreperfusion, 63 +/- 12 PMN/mm2 adhered (P < 0.01 from control). Moreover, a greater degree of PMN adherence occurred on the venous than on the arterial endothelium. Thus, 159 +/- 10 and 198 +/- 12 PMN/mm2 adhered to mesenteric venous endothelium isolated after 20 and 120 min reperfusion, respectively (P < 0.01 vs. arteries). Furthermore, addition of PB 1.3 (20 micrograms/ml), a monoclonal antibody against P-selectin, 5 min before perfusion with PMNs significantly attenuated the increase in PMN adherence to both arterial and venous endothelia (P < 0.01). These results indicate that PMN-endothelial interaction also occurs in conduit vessels after ischemia and reperfusion, although a more profound PMN adherence occurs in veins.

Animals↗