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D L Lawson

Publications and source records attributed to D L Lawson.

At least 19 recordsLinked to original sources
PubMed1992

Agonist-induced tension determines vascular reactivity during anoxia and reoxygenation.

To determine the influence of pre-existing pharmacologically-induced tension on vascular reactivity during anoxia and reoxygenation, rat aortic rings were contracted with norepinephrine, epinephrine, endothelin or KCl to 1, 2 or 4 g of tension. The rings were then exposed to anoxia (95% N2) for 10 min followed by reoxygenation (95% O2). The degree of anoxia-mediated contraction varied with the magnitude of tension before anoxia and resembled the length-tension relationship in myocardial fibers. The optimal agonist-induced tension for maximal anoxic contraction was approximately 1 to 2 g. This relationship between tension and anoxic contraction was observed in all but KCl-contracted rings. The agonist- as well as KCl-contracted rings showed normal relaxant response to acetylcholine, suggesting that a decrease in endothelium-derived relaxing factor (EDRF) alone cannot be the basis of anoxic contraction and release of endothelium-derived constricting factors (EDCFs) may relate to anoxic contraction in agonist-preconstricted rings. The relationship between the magnitude of agonist-induced tension and the extent of anoxia-mediated contraction may relate to the ability of endothelium to release EDRF and EDCFs as well as to the degree of phosphorylation in vascular smooth muscle cells. The reoxygenation-mediated contraction was noted to progressively increase in all experiments regardless of the pharmacologic agent used. This increase in reoxygenation-mediated contraction correlated with pre-existing pharmacologic tension, and may relate to calcium influx and restoration of ATP and other mediators in the vascular tissues during reoxygenation.

Acetylcholine↗
PubMed1992

Variable effects of human and canine polymorphonuclear leucocytes on vascular smooth muscle tone.

OBJECTIVE: Previous studies have shown variable effects of human and canine polymorphonuclear leucocytes (neutrophils) on vascular tone. The aim of this study was to identify whether these variations in neutrophil function are due to species differences. METHODS: Canine and human arterial rings (with and without endothelium) were contracted with the thromboxane A2 analogue U46619, and then exposed to isolated neutrophils. RESULTS: Human neutrophils caused a significant relaxation of the human mammary arterial rings, and the relaxation was unaffected by the cyclo-oxygenase inhibitor indomethacin, enhanced by superoxide dismutase (SOD), and inhibited by oxyhaemoglobin. The relaxant effect of human neutrophils was also diminished upon pretreatment with NG-monomethyl-l-arginine (L-NMMA), indicating that the vasorelaxant material released by the neutrophils was nitric oxide (NO). Human neutrophils also relaxed canine femoral arterial rings, and the relaxant effect was potentiated by SOD and inhibited by pretreatment with oxyhaemoglobin or L-NMMA, confirming that the vasorelaxation was via release of NO. Canine neutrophils, on the other hand, caused an endothelium dependent contraction of autologous femoral arterial rings. This vasoconstriction was not affected by indomethacin, SOD, oxyhaemoglobin, or L-NMMA. However, treatment of canine neutrophils with the 5-lipoxygenase inhibitor piriprost attenuated (p < 0.02) their contractile effect on vascular rings, suggesting that neutrophil generated 5-lipoxygenase products were probably responsible for smooth muscle contraction. Presence of the leukotriene C4 and D4 receptor antagonist FPL 55,712 totally blocked the contractile effects of canine neutrophils, indicating that femoral arterial ring contraction was mediated by peptido-leukotrienes. CONCLUSIONS: The endothelium dependent nature of the canine neutrophil induced contraction suggests that the 5-lipoxygenase product leukotriene A4 is taken up by endothelial cells for conversion to peptido-leukotrienes. Since SOD had no effect and FPL 55,712 totally blocked the vasoconstrictor effects of canine neutrophils, it appears that the vasoconstrictor effects of the latter are mediated primarily through peptido-leukotrienes. In contrast, the vasorelaxation by human neutrophils is mediated through release of NO.

Animals↗
PubMed1992

Modulation of vascular tone by endothelin-1: role of preload, endothelial integrity and concentration of endothelin-1.

1. Endothelin-1 (ET-1) has been shown to exert both arterial relaxant and constrictor effects. To examine the mechanisms of these divergent effects, rat aortic rings were suspended in an organ bath (baseline preload, 5 g) and exposed to ET-1 (10(-11) to 10(-7) M). ET-1 contracted these rings in a concentration-dependent fashion. 2. When aortic rings were contracted with noradrenaline (NA) to 1 g of tension, ET-1 caused further contraction of these rings. In rings precontracted to 2 to 4 g of tension, low concentrations of ET-1 (10(-11) to 10(-9) M) caused a significant relaxation, but high concentrations (greater than or equal to 5 x 10(-9) M) caused a marked contraction, indicating both relaxant and contractile effects of ET-1 depending on the preload and ET-1 concentration. 3. To determine the mechanism of ET-1-induced relaxation, aortic rings were pretreated with the cyclo-oxygenase inhibitor indomethacin, NG-monomethyl-L-arginine (L-NMMA) an inhibitor of synthesis of endothelium-derived relaxing factor (EDRF), or oxyhaemoglobin (Hb) which decreases the activity of EDRF, prior to their exposure to ET-1. Both indomethacin and L-NMMA markedly (P less than 0.01) attenuated ET-1-induced relaxation, whereas Hb totally abolished it. Removal of the endothelium from aortic rings also abolished ET-1-mediated relaxation. 4. The relaxant effect of ET-1 in NA-precontracted rings was associated with marked accumulation of guanosine 3':5'-cyclic monophosphate (cyclic GMP), whereas ET-1-induced contraction of quiescent rings was not. 5.In manually stretched rings (4 g of tension), ET-l caused only concentration-dependent contraction, but no cyclic GMP accumulation.6. Thus, ET-1 contracts rat aortic rings with intact endothelium and those which are passively stretched. However, stimulation of rat aortic rings with NA to modest tension alters the contractile effect of ET-1 to a potent relaxant effect. The ET-l-mediated relaxation in this setting appears to be endothelium-dependent and is related to release of both cyclo-oxygenase products and EDRF.

Animals↗
PubMed1992

5-Hydroxytryptamine potentiates vasoconstrictor effect of endothelin-1.

Interactions between 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) relative to contraction of rat aortic rings were examined in this study. Pretreatment of rings with threshold concentration of 5-HT potentiated the subsequent contractile response to ET-1. However, pretreatment with threshold concentration of ET-1 did not potentiate the contractile response to 5-HT. The 5-HT receptor antagonist LY 53857 blocked the synergistic contractile effects of 5-HT and ET-1 on rat aortic rings. Indomethacin and the thromboxane A2/endoperoxide receptor antagonist SQ 29548 also attenuated (P less than 0.05) the synergistic contractile effects of 5-HT and ET-1, suggesting release of thromboxane A2 or expression of thromboxane A2 receptors during this interaction. The calcium channel blocker verapamil also decreased the synergistic contractile effects of 5-HT and ET-1. Contraction of aortic rings by 5-HT alone was abolished by LY 53857 and attenuated by verapamil, diltiazem, and SQ 29548. Decrease in the force of contraction by verapamil as well as diltiazem indicates activation of voltage-dependent calcium channels during 5-HT-mediated contraction and perhaps during amplification of the vasoconstrictor activity of ET-1 by 5-HT.

Animals↗
PubMed1992

Slow channel calcium blockers attenuate reoxygenation-mediated vascular contraction, but augment anoxia-mediated vascular contraction.

Anoxia and reoxygenation modulate vasomotor tone. To determine the effect of the slow channel calcium blockers verapamil and diltiazem in vascular smooth muscle contraction during states of altered oxygenation, rat aortic rings with intact endothelium were contracted with norepinephrine (NE) or the thromboxane A2 mimic U46,619 and then exposed abruptly to anoxia (switch from 95% O2 to 95% N2) for 30 min and then reoxygenated (switch from 95% N2 to 95% O2). Anoxia caused a transient 40 +/- 9% (mean +/- SE, n = 15) increase in contraction, whereas reoxygenation resulted in an initial decrease followed by a large (83 +/- 21%) increase in contraction. Treatment of vascular rings with verapamil or diltiazem (1 microgram/ml or 2 microM) decreased contractile response to the agonists (p less than 0.01). Both these agents consistently augmented the magnitude and duration of anoxia-induced contraction (p less than 0.01). In other experiments, pretreatment of vascular rings with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of endothelium-derived relaxing factor (EDRF) synthesis, or with oxyhemoglobin, an inhibitor of EDRF activity, or de-endothelialization resulted in marked (p less than 0.01) decrease in anoxic contraction, indicating that anoxia-induced contraction is caused by modulation of EDRF. Treatment of aortic rings with verapamil also reduced acetylcholine-mediated relaxation (from 86 +/- 6% to 45 +/- 5%, p less than 0.02) and cyclic GMP accumulation (from 192 +/- 53 to 111 +/- 35 fmol/mg, p less than 0.02), indicating reduction in EDRF synthesis or activity by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Recovery of vascular smooth muscle relaxation from nitroglycerin-induced tolerance following a drug-free interval. A time-course in vitro study.

Hemodynamic tolerance occurs upon continuous exposure of vascular tissues to nitroglycerin (NTG). This phenomenon is believed to be due to the depletion of the tissue sulfhydryl (SH) group, which is essential for NTG-induced increase in tissue cyclic GMP and vasorelaxation. To determine the effect of an NTG-free interval on recovery of tissue cyclic GMP accumulation and vasorelaxation following development of NTG tolerance, isolated rat aortic rings were kept in Krebs physiologic buffer at 37 degrees, precontracted with epinephrine, and exposed to NTG. The mean concentration of NTG, which relaxed the rings by 50% (EC50) upon first exposure, was 1.1 x 10(-7) M (N = 20), and vascular cyclic GMP levels after NTG increased from 21 to 46 fmol/mg (P less than 0.02). A second exposure to NTG 15 min later increased the EC50 to 1.3 x 10(-4) M and cyclic GMP levels did not change (P less than 0.001 vs first NTG exposure), indicating tolerance to NTG. However, acetylcholine-mediated relaxation of aortic rings was preserved even in NTG-tolerant rings. A second exposure of tissues to NTG separated by 30, 60, and 120 min from the first exposure progressively decreased the EC50, such that at 120 min the EC50 of NTG was 0.4 x 10(-7) M (P = NS vs first NTG exposure). Tissue cyclic GMP levels increased from 14 to 71 fmol/mg (P = NS vs first NTG exposure). These data confirm development of tolerance to the vasorelaxant effects of NTG following initial exposure. An interval of 2 hr between multiple exposures of tissues to NTG results in preservation of the smooth muscle relaxation and an increase in tissue cyclic GMP in response to NTG.

Acetylcholine↗
PubMed1991

Role of superoxide radicals in anoxia reoxygenation-mediated vascular contraction.

To determine the mechanism of anoxic vasoconstriction, precontracted rat aortic rings were exposed to 95% N2, which caused additional contraction. Reoxygenation (95% O2) resulted in initial relaxation followed by contraction. Indomethacin did not affect anoxic contraction or reoxygenation-mediated events, but NG-monomethyl-1-arginine, which inhibits EDRF synthesis, and oxyhemoglobin, which reduces EDRF activity, markedly decreased anoxic contraction and reoxygenation relaxation, and potentiated subsequent contraction. Superoxide dismutase did not affect anoxic contraction, but potentiated reoxygenation relaxation and attenuated subsequent contraction. Endothelin concentrations remained unchanged throughout anoxia and reoxygenation. Thus, anoxic contraction and reoxygenation-mediated early relaxation appear to be due to changes in EDRF. On the other hand, reoxygenation-induced contraction appears related to release of superoxide radicals.

Animals↗
PubMed1991

Captopril-induced reversal of nitroglycerin tolerance: role of sulfhydryl group vs. ACE-inhibitory activity.

The angiotensin-converting enzyme (ACE) inhibitor captopril has been shown to reverse vascular tolerance to nitroglycerin (NTG). Whether captopril reverses NTG tolerance by providing sulfhydryl (SH) groups or by inhibiting ACE is not clear. To examine this issue, we treated rat aortic rings with buffer, captopril (SH +, ACE inhibitory activity +), enalaprilat (SH-, ACE inhibitory activity +), or N-acetylcysteine (NAC, SH+, ACE inhibitory activity-) prior to their contraction with epinephrine and subsequent relaxation with NTG. Previous exposure of NTG-treated rings resulted in marked resistance to the vasorelaxant effect of a subsequent exposure to NTG in buffer-treated rings. Both NAC and captopril, but not enalaprilat, potentiated the vasorelaxant effects of NTG during the first exposure of vascular rings to NTG and also prevented the development of tolerance to NTG during a second exposure. Buffer-treated rings showed an inability to accumulate cyclic guanosine monophosphate (GMP) in response to a second exposure to NTG. In contrast, both NAC and captopril-pretreated rings demonstrated a persistence of cyclic GMP accumulation during the second NTG exposure. The endothelium-dependent vasodilator acetylcholine (ACh) caused relaxation of the NTG-tolerant rings and also induced cyclic GMP accumulation in these rings. In other experiments, we found that prior exposure of vascular rings to ACh did not cause resistance to the subsequent vasorelaxant effects of ACh. NAC, captopril, and enalaprilat did not modulate the effects of ACh during either the first or subsequent exposures to ACh. In addition, indomethacin did not influence the "protective" effects of NAC or captopril against NTG tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation.

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.

Animals↗
PubMed1991

Effects of activated polymorphonuclear leukocytes on vascular smooth muscle tone.

Unstimulated polymorphonuclear leukocytes (PMNLs) release nitric oxide or a like material that relaxes vascular tissues. To determine the effects of activated PMNLs on vascular tone, precontracted rat aortic rings were exposed to ionophore A23187-treated PMNLs. Whereas "unstimulated" PMNLs caused 29 +/- 4% relaxation, "stimulated" PMNLs caused initial contraction followed by 90 +/- 7% relaxation of aortic rings. Indomethacin or the 5-lipoxygenase blocker piriprost had no effect on PMNL-induced initial contraction or subsequent relaxation. However, initial contraction was abolished and the subsequent vasorelaxation attenuated (22 +/- 5%) by the superoxide radical scavenger superoxide dismutase (SOD), suggesting that release of superoxide radicals may have induced vascular contraction and caused endothelial damage that would permit unopposed vasorelaxant effect of PMNLs. To examine this hypothesis, aortic rings were exposed to superoxide radicals (generated by xanthine plus xanthine oxidase, X + XO) or manually deendothelialized. These rings revealed marked relaxation (78 +/- 6 and 85 +/- 6%, respectively) in response to unstimulated PMNLs. These observations suggest that stimulated PMNLs exert an initial vasoconstrictor effect and a subsequent vasorelaxant effect in response to release of superoxide radicals and nitric oxide, respectively. Arachidonate metabolites or 5-lipoxygenase products do not appear to be important in the actions of PMNLs on vascular smooth muscle.

Animals↗
PubMed1991

Omega-3 polyunsaturated fatty acids augment endothelium-dependent vasorelaxation by enhanced release of EDRF and vasodilator prostaglandins.

Dietary supplementation with fish oil results in augmentation of endothelium-dependent vasorelaxation in experimental animals. The present study was designed to evaluate the direct in vitro effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) on vascular reactivity in isolated rat aortic rings. Aortic rings were incubated with the omega-6PUFA arachidonic acid (AA, 10(-7) M) or the omega-3 PUFAs eicosapentaenoic acid (EPA, 10(-7) M) and docosahexaenoic acid (DHA, 10(-7) M) in an organ bath at 37 degrees C. Following contraction with norepinephrine, changes in isometric force were measured in response to the endothelium-dependent vasodilators acetylcholine (ACh, 10(-10) to 10(-5) M) or the calcium ionophore A23187 (10(-10) to 10(-5) M). Parallel sets of vascular rings were pretreated with the cyclooxygenase inhibitor indomethacin (10(-5) M) or the inhibitor of nitric oxide synthesis NG-monomethyl L-arginine (L-NMMA 5 x 10(-5) M) prior to treatment with AA or EPA. Treatment of rings with EPA resulted in an increase (P less than 0.05) in ACh-mediated vasorelaxation compared both to AA-treated and buffer-treated rings (maximum relaxation 83 +/- 5% vs 46 +/- 5% and 63 +/- 4%, respectively). A similar augmentation was observed in DHA-treated rings. Pretreatment of rings with indomethacin or I-NMMA decreased (P less than 0.05) the ACh-mediated vasorelaxation, although EPA-treated rings showed less (P less than 0.05) attenuation of ACh response compared to AA-treated or untreated control rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Evidence for generation of a large amount of nitric oxide-like vascular smooth muscle relaxant by cholesterol-rich neutrophils.

To determine the effect of cholesterol incorporation on the ability of neutrophils to generate superoxide radicals and nitric oxide-like vasorelaxant material, isolated human neutrophils were incubated with cholesterol-rich liposomes, which increased total cholesterol content by 141% and esterified cholesterol content by 523%. Cholesterol loading resulted in 5 to 7 fold increase in cytosolic calcium in resting as well as in PMA or f-MLP-stimulated cells, but a marked (P less than 0.01) reduction in both PMA- and f-MLP-stimulated superoxide radical generation by these cells. Nitric oxide-like activity measured as relaxation of rat aortic rings was more pronounced (P less than 0.02) in cholesterol-rich than in cholesterol-poor cells. The greater relaxation of aortic rings in response to cholesterol-rich neutrophils was observed in rings with or without intact endothelium, and was potentiated by superoxide dismutase and inhibited by oxyhemoglobin as well as L-NMMA, thus suggesting that the vasorelaxant material was nitric oxide. The greater generation of nitric oxide by cholesterol-rich neutrophils occurs perhaps in response to increased cytosolic calcium.

Animals↗
PubMed1990

Coronary reperfusion in dogs inhibits endothelium-dependent relaxation: role of superoxide radicals.

Previous studies indicate that release of superoxide radicals during coronary reperfusion following occlusion may relate to the loss of endothelium-dependent coronary arterial relaxation. We examined coronary arterial ring relaxation in dogs subjected to temporary circumflex (Cx) coronary artery occlusion and treated with saline or the superoxide radical scavenger superoxide dismutase (SOD). In dogs treated with saline, Cx coronary ring relaxation in response to leukotriene D4 (LTD4) and acetylcholine (ACh) was attenuated (p less than 0.01), but coronary relaxation in response to nitroglycerin was preserved, suggesting loss of endothelium-dependent relaxation following coronary reperfusion. In contrast, Cx coronary relaxation in response to LTD4 and ACh was preserved in the SOD-treated dogs (p less than 0.01 compared to saline-treated dogs). To further examine the role of superoxide radicals in the loss of endothelium-dependent relaxation, normal nonischemic canine coronary artery and rat aortic rings were exposed to a superoxide radical generating system of xanthine and xanthine oxidase in vitro. Xanthine plus xanthine oxidase treatment caused a significant (p less than 0.01) decrease in the relaxant effects of ACh. Pretreatment of rat aortic rings with SOD protected against the loss of ACh-induced relaxation. These observations suggest that release of superoxide radicals during reperfusion is the basis of loss of endothelium-dependent coronary arterial relaxation. Treatment with superoxide radical scavengers prior to coronary reperfusion protects against this loss.

Acetylcholine↗
PubMed1990

Superoxide dismutase decreases reperfusion arrhythmias and preserves myocardial function during thrombolysis with tissue plasminogen activator.

Release of superoxide radicals during the early phase of coronary reperfusion may result in degradation of endothelium-derived relaxing factor (EDRF), extension of myocardial injury, precipitation of arrhythmias, and stimulation of platelet aggregation. These factors may relate to the occurrence of ventricular fibrillation during reperfusion and coronary reocclusion following initial thrombolysis. This study was designed to examine the effects of concomitant administration of superoxide radical scavenger superoxide dismutase (SOD) with tissue plasminogen activator (tPA) compared to tPA alone (without SOD) in acute coronary thrombosis in anesthetized dogs. Dogs with a stable electrically induced coronary thrombus were randomly given intravenously tPA (0.75 mg/kg) alone or SOD bolus (2 mg/kg) followed by SOD (4 mg/kg) + tPA (0.75 mg/kg) over 20 min. tPA alone restored coronary blood flow in six of nine dogs (reperfusion rate of 67%) with time to reflow of 18.5 +/- 6.7 (mean +/- SD) min. Coronary reocclusion occurred spontaneously in four of six dogs with initial reperfusion (reocclusion rate of 67%). In contrast, SOD + tPA restored coronary blood flow in 9 of 12 dogs (reperfusion rate of 75%, not significant vs. tPA alone) with time to reflow of 11.3 +/- 4.8 min and coronary reocclusion occurred in only 3 of 9 dogs with reperfusion (reocclusion rate of 33%, not significant vs. tPA alone). Reperfusion arrhythmias were more frequent in dogs who received tPA alone compared to those who received SOD in addition to tPA (mean Holter-monitored PVC count of 730 vs. 12 beats/h, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Sulfhydryl group in angiotensin converting enzyme inhibitors and superoxide radical formation.

The superoxide radical scavenging effects of the SH group in the captopril molecule has been proposed to be the basis of the "cadioprotective" effect of this angiotensin converting enzyme (ACE) inhibitor in animal models of myocardial injury. We determined the effects of captopril, another ACE inhibitor with an SH group (SQ 26,703), its stereoisomer without ACE inhibitory effect but with an SH group (SQ 14,534), another ACE inhibitor without a SH group (enalaprilat), and N-acetylcysteine on superoxide radical generation by human neutrophils and by the purine-xanthine oxidase reaction. None of the compounds examined decreased superoxide radicals in therapeutic concentrations; however, SH-containing agents directly reduced spectrophotometric absorbance of ferricytochrome C. Thus, SH-containing agents with or without ACE inhibitory effects do not scavenge superoxide radicals.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Superoxide radical-mediated endothelial injury and vasoconstriction of rat thoracic aortic rings.

Endothelium regulates smooth muscle tone in response to various agonists and antagonists by release of vasorelaxing and vasoconstricting factors. It also has been postulated that superoxide radicals, which degrade endothelium-derived relaxing factor, exert smooth muscle-constrictor effects. To determine the role of superoxide radicals on vasomotor tone, we exposed rat thoracic aortic rings in vitro to a superoxide radical-generating system of xanthine and xanthine oxidase (X + XO). In rings with intact endothelium, X + XO caused modest smooth muscle contraction and increased vascular sensitivity to both l-epinephrine and thromboxane A2 (TxA2) "mimic" U46619. These vascular contractile effects were more pronounced in rings without intact endothelium. In the supernates of vascular rings with intact endothelium, TxA2 and prostacyclin metabolites were identified on exposure of vascular rings to X + XO, indicating stimulation of the cyclooxygenase pathway. Although both superoxide radical scavenger superoxide dismutase and cyclooxygenase inhibitor indomethacin blocked release of TxA2 and prostacyclin, only superoxide dismutase blocked the contractile effects of superoxide radicals (p less than 0.05). Neither catalase nor mannitol had any effect on X + XO mediated vasoconstriction, suggesting that hydrogen peroxide and hydroxyl radicals did not participate in the observed effects of X + XO. Exposure of vascular rings to X + XO revealed extensive endothelial disruption as determined by scanning electron microscopy. Thus superoxide radicals exert procontractile effects on vascular smooth muscle and enhance its response to l-epinephrine and TxA2 mimic. These effects are probably exerted by injury to the endothelial barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Tissue plasminogen activator and plasmin independently decrease human neutrophil activation.

Tissue-plasminogen activator (t-PA) and plasmin both decrease platelet aggregation, which may contribute to thrombolysis and tissue salvage. Since neutrophils may contribute to reperfusion injury, we examined the effects of t-PA and plasmin on human neutrophil function. t-PA (1 to 100 micrograms/ml) decreased f-MLP-induced chemotaxis and ionophore A23187-induced superoxide and LTB4 release in isolated neutrophils, and these effects were not blocked by the plasmin-inhibitor epsilon-aminocaproic acid (epsilon-ACA). On the other hand, plasmin (0.05 to 0.5 units/ml) also decreased these neutrophil functions but its effects were blocked in the presence of epsilon-ACA. Thus, while both t-PA and plasmin decrease neutrophil functions, effects of t-PA are independent of plasmin generation. Cumulative effects of t-PA and plasmin on neutrophil functions may relate to the overall efficacy of t-PA in thrombotic disorders.

Calcimycin↗