Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 73 records · Page 4Linked to original sources

PubMed1996

Hypotensive mechanisms of amifostine.

Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.

Adrenergic Agents↗

PubMed1996

Myocardial protection by N,N,N-trimethylsphingosine in ischemia reperfusion injury is mediated by inhibition of P-selectin.

Polymorphonuclear leukocytes (PMNs) play an important role in myocardial ischemia/reperfusion (MI/R) injury. We examined the cardioprotective effects of N,N,N-trimethylsphingosine (TMS) in a murine model of MI (20 min) and R (24 h) injury in vivo, focusing on leukocyte-endothelial interactions. TMS is a synthetic N-methylated sphingosine derivative that has protein kinase C inhibitory activity and has been shown to prevent leukocyte activation. TMS (18 microgram/kg), administered intravenously 1 min prior to reperfusion, significantly attenuated myocardial necrotic injury assessed by myocardial creatine kinase loss compared with MI/R rats receiving only vehicle (P<0.001). Cardiac myeloperoxidase activity, an index of PMN accumulation in the ischemic myocardium, was also significantly attenuated by TMS compared with rats receiving vehicle (P<0.001). We further examined whether TMS can attenuate leukocyte-endothelial interaction by intravital microscopy. TMS significantly attenuated NG-nitro-L-arginine-methyl ester (L-NAME)-stimulated PMN rolling and adherence to the rat microvascular endothelium. This action of TMS appears to be mediated by reduction of P-selectin expression because immunohistochemical analysis demonstrated that TMS significantly attenuated endothelial P-selectin expression in the L-NAME-superfused rat mesenteric microvasculature. Similarly, TMS markedly attenuated rapid P-selectin expression in rat platelets stimulated with either thrombin or L-NAME assessed by flow cytometry. In conclusion, TMS seems to be an effective cardioprotective agent by inhibiting early leukocyte-endothelial interaction, thus preventing leukocyte accumulation in the ischemic reperfused myocardium.

Animals↗

PubMed1996

Protection from myocardial reperfusion injury by acute administration of 17 beta-estradiol.

Although several studies have demonstrated that chronic exposure to estrogen appears to be cardioprotective, acute circulatory effects of estrogen are largely unknown. Therefore, we studied the effects of acute administration of 17 beta-estradiol in myocardial ischemia/reperfusion. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either the estrogenic steroid, 17 beta-estradiol or its non-estrogenic isomer, 17 alpha-estradiol was administered (i.v.) 30 min prior to reperfusion at 1 microgram/kg bolus followed by a constant infusion lasting the remaining duration of the protocol at 1 microgram/kg/h. Control cats were subjected to sham MI/R. Cats treated with 17 beta-estradiol demonstrated a marked reduction in cardiac necrosis following MI/R compared to cats receiving 17 alpha-estradiol or phosphate buffered saline (17 +/- 2% v 33 +/- 1% or 34 +/- 4% area of necrosis indexed to the area-at-risk, P < 0.01). In addition, cats receiving 17 beta-estradiol exhibited reduced myocardial PMN infiltration in necrotic tissue as compared to 17 alpha-estradiol treated cats. Moreover, 17 beta-estradiol administration attenuated neutrophil adherence to ex vivo coronary vascular endothelium compared to the two controls (44 +/- 8 PMNs/mm2 v 79 +/- 7 PMNs/mm2 or 86 +/- 7 PMNs/mm2 P < 0.01). These data indicate that 17 beta-estradiol protects against myocardial ischemia/reperfusion, in part, by attenuating PMN infiltration and subsequent injury due to PMN mediator release.

Animals↗

PubMed1996

Cardioprotective actions of oligotide, a single stranded polydeoxyribonucleotide complex, in myocardial ischaemia and reperfusion injury.

1. The efficacy of oligotide, a single stranded polydeoxyribonucleotide complex, was examined in a feline model of myocardial ischaemia (MI: 90 min) and reperfusion (R: 270 min). Oligotide (15 mg kg-1 bolus) was administered intravenously 80 min after occlusion of the left anterior descending (LAD) coronary artery (i.e., 10 min prior to R) and continued for an additional 280 min (10 mg kg-1 h-1 infusion). 2. Oligotide-treated cats showed significantly smaller myocardial necroses and lower cardiac myeloperoxidase activities (significantly lower neutrophil infiltration) in the necrotic zone as compared to MI+R cats receiving only vehicle. 3. LAD coronary arteries isolated from MI+R cats exhibited a significant endothelial dysfunction (i.e., reduced endothelium-dependent relaxation), and significantly increased adherence of polymorphonuclear neutrophils (PMNs) ex vivo. However, oligotide significantly preserved endothelial function and attenuated PMN adherence in ischaemic LAD coronary arteries. 4. Oligotide attenuated P-selectin expression on thrombin-stimulated platelets as well as PMN adherence to thrombin-stimulated coronary endothelium. Immunohistochemical examination in vivo revealed that oligotide treatment also significantly inhibited coronary endothelial P-selectin expression after 90 min MI and 20 min R. 5. Oligotide exerted a significant cardioprotection in MI+R injury. The mechanism appears to be related to attenuation of PMN-endothelial interaction and eventual infiltration into the ischaemic myocardium.

Acetylcholine↗

PubMed1996

Novel recombinant serpin, LEX-032, attenuates myocardial reperfusion injury in cats.

We studied the potential cardioprotective effects of the novel recombinant serine protease inhibitor (serpin), LEX-032, which inhibits the serine proteases elastase and cathepsin G. LEX-032 is a recombinant construct of human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of human alpha 1-protease inhibitor. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either LEX-032 or its vehicle (i.e., phosphate-buffered saline) was administered intravenously 10 min before reperfusion. Control cats were subjected to sham MI/R. Cats treated with LEX-032 demonstrated a marked reduction in cardiac necrosis after MI/R compared with cats receiving only vehicle (10 +/- 3 vs. 31 +/- 3%, P < 0.01). In addition, relaxation of LAD rings to the endothelium-dependent dilators (e.g., acetylcholine and A23187) was greater in the LEX-032-treated group than in cats receiving vehicle (72 +/- 5 vs. 52 +/- 7%, P < 0.05, and 74 +/- 8 vs. 50 +/- 8%, P < 0.05, respectively), indicating that endothelial function was preserved by LEX-032. Moreover, LEX-032 administration resulted in a marked reduction of polymorphonuclear leukocyte (PMN) adherence to ex vivo coronary vascular endothelium compared with vehicle (33 +/- 4 vs. 86 +/- 7 PMNs/mm2, P < 0.01). These data indicate that LEX-032 is a significant cardioprotective agent exerting its protective effect by inhibition of PMN-mediated cellular injury, and this agent represents a novel means of attenuating PMN-mediated reperfusion injury.

Animals↗

PubMed1996

Direct measurement of nitric oxide release from vascular endothelial cells.

A nitric oxide (NO)-selective electrode was used to directly measure NO release from isolated rat aortic endothelium and cultured rat aortic endothelial cells (RAECs). Basal release of NO was significantly attenuated by a NO synthase inhibitor NG-nitro-L-arginine methyl ester (1 mM) to 42 +/- 14 pmol/1 x 10(5) cells (P < 0.01). The basal release of NO was also significantly inhibited by a calmodulin antagonist W-7 at 15 microM (P < 0.01). L-Arginine (1 mM), significantly stimulated NO release (P < 0.05 vs. control basal release). Stimulation of cultured RAECs with two endothelium-dependent vasodilators, acetylcholine (100 nM) and A-23187 (1 microM), significantly increased NO release [574 +/- 112 pmol/1 x 10(5) cells (n = 5) and 658 +/- 119 pmol/1 x 10(5) cells (n = 5) in acetylcholine- and A-23187-stimulated RAECs, respectively]. Basal release of NO was also detectable in isolated rat aortic rings with intact endothelium. NO release was significantly attenuated by NG-nitro-L-arginine methyl ester and augmented by human superoxide dismutase. These data indicate the physiological usefulness of the amperometric measurement of NO employing a NO-specific electrode in biological systems.

Acetylcholine↗

PubMed1996

Lysophosphatidylcholine promotes P-selectin expression in platelets and endothelial cells. Possible involvement of protein kinase C activation and its inhibition by nitric oxide donors.

Lysophosphatidylcholine (LysoPC), an atherogenic lysophospholipid contained in oxidized low-density lipoprotein (LDL), has been shown to stimulate protein kinase C (PKC). Since PKC activators are suggested to elicit rapid P-selectin expression in platelets and endothelial cells, we examined whether LysoPc promotes P-selectin expression in platelets and P-selectin-mediated leukocyte adherence to endothelial cells via a mechanism involving PKC activation. LysoPc, but not phosphatidylcholine (PC), which is a major phospholipid component in native LDL, significantly upregulated P-selectin on cat platelets by flow cytometric analysis. This P-selectin upregulation by LysoPC was significantly attenuated by two PKC inhibitors, 7-hydroxystaurosporine (UCN-01) and N,N,N-trimethylsphingosine, and by two NO donors, CAS1609 and sodium nitroprusside. Submicellar concentrations of LysoPc significantly activated PKC in platelets, and this was inhibited by either UCN-01 or CAS1609. LysoPC, but not PC, significantly increased adherence of autologous cat polymorphonuclear leukocytes to coronary vascular endothelium, which was also markedly attenuated by UCN-01 and by CAS1609. LysoPC induced P-selectin expression on the surface of cat coronary vascular endothelium as assessed by immunohistochemical analysis. These results suggest that LysoPC, an atherogenic lysophospholipid contained in oxidized LDL, rapidly induces P-selectin expression in both platelets and endothelial cells at least partially via PKC activation. Furthermore, NO-generating agents may inhibit P-selectin upregulation by LysoPC. Since P-selectin may play an important role in initiating atherosclerosis, our data provide further insight into the mechanism of early stages of atherogenesis and of NO-mediated inhibition of atherosclerosis.

Animals↗

PubMed1996

Time course of endothelial dysfunction and neutrophil adherence and infiltration during murine traumatic shock.

Traumatic shock in rats has been shown to induce endothelial dysfunction, and to increase intestinal myeloperoxidase activity (MPO) indicative of neutrophil infiltration. To examine the time course of endothelial dysfunction and neutrophil adherence and infiltration, pentobarbital anesthetized rats, subjected to Noble-Collip drum trauma, were studied prior to and 15, 30, 60, 90, 120, 150, and 180 min following drum trauma. Superior mesenteric artery rings obtained from traumatized rats were tested for responsiveness to acetylcholine (ACh), a receptor-mediated endothelium-dependent vasodilator, and to NaNO2 an endothelium-independent vasodilator. ACh-induced relaxation was not impaired immediately after the induction of trauma (time 0). However, 15-30 min after trauma, responses to ACh were significantly depressed (p < .05) and were further reduced (p < .01) 90-180 min after trauma. No significant changes occurred in response to the direct vasodilator NaNO2 at any of the times studied, indicating no vascular smooth muscle injury. Moreover, the adherence of polymorphonuclear leukocytes (PMNs) to the post-traumatic mesenteric vascular endothelium also showed an increase that peaked 30 min post-trauma. Intestinal MPO activity, indicative of neutrophil infiltration, was characterized by a continuous and sustained increase from 30-180 min. Our findings suggest that endothelial dysfunction resulting in reduced NO release occurs in the early phase of murine traumatic shock, and that this phenomenon is followed by a time-dependent increase in adhesivity of neutrophils to the vascular endothelium leading to a progressive accumulation of PMNs in injured tissues (e.g., intestine).

Animals↗

PubMed1996

The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion.

The microcirculation undergoes a profound degree of endothelial dysfunction within minutes (i.e., 2.5 to 5 min) following reperfusion of ischaemic vasculature. This has been documented in the coronary and mesenteric microcirculation. The endothelial dysfunction is characterized by a loss in basal and agonist-mediated nitric oxide (NO) produced by the vascular endothelium. The loss of NO results in upregulation of cell adhesion molecules (CAMs) particularly P-selectin 10-20 min following reperfusion. Thus, CAM upregulation renders the endothelium sticky, and a marked degree of leukocyte adherence (particularly neutrophils) occurs 20 min following reperfusion. This enhanced involvement of neutrophils leads to neutrophil infiltration into the underlying tissue (e.g., myocardium) within 2-3 h of reperfusion. The infiltration of neutrophils leads to reperfusion injury (i.e., necrosis) which is significant at 3 h but becomes profound at 4.5 h following reperfusion. Cardiac necrosis can be significantly attenuated by treatment with NO, an organic NO donor, L-arginine, or specific blockers of CAMs given just prior to reperfusion. This approach is a promising one for a variety of types of reperfusion injury.

Animals↗

PubMed1996

S-nitrosylated tissue-type plasminogen activator protects against myocardial ischemia/reperfusion injury in cats: role of the endothelium.

S-Nitrosylated tissue plasminogen activator (tPA) is formed by S-nitrosylation of the clinically important agent tPA by nitric oxide, thus conferring nitric oxide donor properties to the molecule. Cats were subjected to 90 min of myocardial ischemia and 270 min of reperfusion and were treated with either tPA or S-nitrosylated tPA 10 min before reperfusion. S-Nitrosylated tPA-treated cats demonstrated marked attenuation of cardiac necrosis after myocardial ischemia/reperfusion, compared with cats receiving only tPA (13 +/- 3% vs. 28 +/- 3%, P < .01). Relaxation of ischemic/reperfused left anterior descending coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in the S-nitrosylated tPA-treated group, compared with the cats receiving only tPA, indicating that coronary vascular endothelial function was preserved by S-nitrosylated tPA. S-Nitrosylated tPA also resulted in markedly reduced adherence of neutrophils to the coronary vascular endothelium, compared with nonnitrosylated tPA (P < .01). Immunohistochemical localization of P-selectin in the ischemic region was also significantly reduced by S-nitrosylated tPA, compared with the control group (P < .01). These data indicate that S-nitrosylated tPA is a cardioprotective agent, likely exerting its effect by site-specific nitric oxide donation resulting in inhibition of neutrophil-endothelium interaction via a P-selectin-dependent mechanism.

Animals↗

PubMed1996

Effects of defibrotide on leukocyte-endothelial cell interaction in the rat mesenteric vascular bed: role of P-selectin.

The effects of defibrotide on leukocyte-endothelial cell interaction and P-selectin surface expression on the microvascular endothelium were investigated. Intravital microscopy was performed in the rat mesenteric microcirculation. The rat mesentery was superfused either with Krebs-Henseleit solution (i.e., control) or 50 microM NG nitro-L-arginine methyl ester (L-NAME). Defibrotide (40 mg/kg) was intravenously infused to control rats and to L-NAME superfused rats. P-selectin expression on mesenteric venules was also investigated by immunohistochemistry. L-NAME caused a significant, time-dependent increase in leukocyte rolling (13 +/- 5 to 101 +/- 18 cells/ min; p < 0.001) and adherence (1.6 +/- 0.7 to 12 +/- 2.5 cells/100 microns length of venule; p < 0.01) compared to control superfused rats. However, intravenous infusion of defibrotide (40 mg/kg) consistently decreased the L-NAME-induced leukocyte rolling (101 +/- 18 to 9.3 +/- 1.3 cells/min; p < 0.001) and adherence (12 +/- 2.5 to 1.9 +/- 1.1 cells/100 microns length of venule; p < 0.01). Exposure of rat mesentery to L-NAME consistently increased P-selectin surface expression (p < 0.01) on the vascular endothelium which was significantly attenuated by defibrotide (p < 0.05). In vivo administration of defibrotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. Since P-selectin was upregulated by the specific nitric oxide synthase inhibitor L-NAME, the present study also confirms the crucial role exerted by nitric oxide in attenuating leukocyte-endothelial cell interaction during various pathophysiological conditions.

Animals↗

PubMed1995

Desmopressin induces endothelial P-selectin expression and leukocyte rolling in postcapillary venules.

Desmopressin, (DDAVP; 1-desamino-8-D-arginine vasopressin) increases the release and activity of von Willebrand factor (vWF); however, its effects on the other major constituent of endothelial Weibel-Palade bodies, P-selectin, has not been investigated. DDAVP-induced P-selectin expression may explain DDAVP's efficacy in bleeding disorders in which vWF levels are normal. Therefore, the objective of this study is to assess the effect of DDAVP on P-selectin expression on endothelial cells of postcapillary venules in vivo and on human umbilical vein endothelium in vitro, and to determine whether DDAVP has direct effects on leukocyte behavior in postcapillary venules. DDAVP (0.1 and 1.0 microgram/mL) induced a significant but transient increase in P-selectin expression on human umbilical vein endothelial cells as well as on rat and human platelets. Immunohistochemical analysis of rat postcapillary venules showed that in contrast to saline, DDAVP injection (1 microgram/kg, intravenous) induced significant endothelial P-selectin expression. DDAVP administration also induced a rapid and significant increase in leukocyte rolling in rat mesenteric venules in vivo. This response was entirely dependent on P-selectin, as an anti-P-selectin antibody rapidly reversed the DDAVP-induced increase in leukocyte rolling. DDAVP induced leukocyte rolling in medium (20 to 40 microns) and large (> 40 microns), but not small (< 20 microns), postcapillary venules. In animals that were treated with DDAVP, there was a steady and significant increase in leukocyte adhesion. This study shows that DDAVP can directly induce P-selectin expression on endothelium in vitro and in vivo and that the latter response is capable of supporting prolonged leukocyte rolling in rat postcapillary venules.

Animals↗

PubMed1995

Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion.

In the present study, the cardioprotective effects of insulin-like growth factor I (IGF-I) were examined in a murine model of myocardial ischemia reperfusion (i.e., 20 min + 24 hr). IGF-I (1-10 micrograms per rat) administered 1 hr prior to ischemia significantly attenuated myocardial injury (i.e., creatine kinase loss) compared to vehicle (P < 0.001). In addition, cardiac myeloperoxidase activity, an index of neutrophil accumulation, in the ischemic area was significantly attenuated by IGF-I (P < 0.001). This protective effect of IGF-I was not observed with des-(1-3)-IGF-I. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated markedly increased DNA fragmentation due to programmed cell death (i.e., apoptosis) compared to nonischemic myocardium. Furthermore, IGF-I significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. Therefore, IGF-I appears to be an effective agent for preserving ischemic myocardium from reperfusion injury and protects via two different mechanisms--inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes.

Animals↗

PubMed1995

Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion.

BACKGROUND: Myocardial injury after ischemia and reperfusion can be attributed largely to the effects of polymorphonuclear leukocytes (PMN). The complement system plays an important role as a chemotactic agent, affecting adhesion molecule expression and neutrophil accumulation. METHODS AND RESULTS: In the present study, the cardioprotective effects of C1 esterase inhibitor (C1 INH) were examined in a feline model of myocardial ischemia and reperfusion (90 minutes of ischemia followed by 270 minutes of reperfusion). C1 INH (15 mg/kg) administered 10 minutes before reperfusion significantly attenuated myocardial necrosis compared with vehicle (10 +/- 2% and 29 +/- 2% necrosis as a proportion of area at risk, respectively; P < .01). Myocardial preservation was also related to reduced plasma accumulation of creatine kinase activity. C1 INH treatment resulted in improved recovery of cardiac contractility and preservation of coronary vascular endothelial function, as assessed by relaxation in response to acetylcholine, compared with contractility and preservation of endothelial function in vehicle-treated animals (69 +/- 6% and 20 +/- 4% relaxation, respectively; P < .01). In addition, cardiac myeloperoxidase activity (an index of PMN accumulation) in the ischemic area was significantly reduced after C1 INH treatment. Furthermore, immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated deposition of the first component of the classic complement pathway, C1q, on cardiac myocytes and coronary vessels. CONCLUSIONS: Blocking of the classic complement pathway by C1 INH appears to be an effective means of preserving ischemic myocardium from reperfusion injury. The mechanism of this cardioprotective effect appears to be inhibition of PMN-endothelium interaction; this inhibition leads to preservation of normal endothelial function, which results in reduced cardiac necrosis.

Animals↗

PubMed1995

Time course of coronary vascular endothelial adhesion molecule expression during reperfusion of the ischemic feline myocardium.

The time course of endothelial P-selectin, ICAM-1, and E-selectin expression was studied in a feline model of myocardial ischemia and reperfusion. Cats were subjected to 90 min of myocardial ischemia followed by 0, 10, 20, 60, 150, or 270 min of reperfusion. At the end of reperfusion, the coronary vasculature was examined immunohistochemically to localize monoclonal antibodies (mAbs) PB1.3, RR1/1, and Cy1787 directed against P-selectin, ICAM-1, and E-selectin, respectively. Immunohistochemical localization for P-selectin, recognized by mAb PB1.3, was maximally expressed 20 min after reperfusion in 60 +/- 6% of coronary venules (P < 0.05 compared to non-reperfused controls), and covered 59 +/- 3% of the endothelial cell perimeter of immunostained coronary venules. Immunolocalization of mAb PB1.3 gradually declined at 60, 150, and 270 min of reperfusion. Immunohistochemical localization of mAb RR1/1 (anti-ICAM-1) in endothelial cells of coronary venules was observed to a modest extent in non-ischemic myocardium and at 10, 20, and 60 min of reperfusion, but was significantly increased following 150 and 270 min of reperfusion (P < 0.05 compared non-reperfused controls). At 270 min post-reperfusion, mAb RR1/1 was seen in 50 +/- 4% of coronary venules. Endothelial immunolocalization of mAb Cy1787 (anti-E-selectin) was only observed in 13 +/- 1 and 14 +/- 3% of coronary venules after 150 and 270 min of reperfusion, respectively, suggesting that pronounced expression of E-selectin does not occur within 270 min after reperfusion. These results demonstrate sequential expression of three major endothelial cell adherence molecules in situ following myocardial ischemia and reperfusion. The timing of endothelial cell expressed P-selectin and ICAM-1 could coordinate neutrophil trafficking during the early stages of reperfusion.

Animals↗

PubMed1995

Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy.

The coronary vascular endothelium produces nitric oxide (NO) during the conversion of L-arginine to L-citrulline. Although NO is a potent vasodilator, at lower concentrations, it also has antineutrophil actions that reduce the inflammatorylike components of ischemia-reperfusion injury. The endothelium is damaged in the early minutes after reperfusion, ie, before neutrophils accumulate and before myocardial necrosis fully develops, and this suggests that endothelial injury is a springboard event in the postischemic inflammatory cascade. Studies of coronary artery occlusion and reperfusion suggest that early damage to the coronary endothelium impairs NO production, which, in turn, abrogates the endogenous antineutrophil effects of NO. However, this impaired endogenous NO-related cardioprotection can be restored either by providing specifically at the onset of reperfusion the precursor to NO (L-arginine) or by providing agents that donate NO. In studies, L-arginine or NO donors reduce infarct size in models of coronary occlusion and reperfusion. The mechanism or mechanisms of this cardioprotection involve preservation of endothelial function and inhibition of neutrophil accumulation in ischemic-reperfused tissue. The cardioprotective potential of NO offers a new therapeutic approach to the reduction of ischemia-reperfusion injury after coronary artery occlusion.

Cell Adhesion↗

PubMed1995

Role of selectins in myocardial ischemia-reperfusion injury.

During reperfusion of ischemic myocardium, there is a well-orchestrated interplay between the coronary vascular endothelium and the circulating neutrophils. This interplay involves the initial slowing or "rolling" of neutrophils along the endothelium during the early moments of reperfusion, followed by firm attachment and amplification of the neutrophil response, and culminating with the diapedesis of neutrophils into the myocardial parenchyma where neutrophil-myocyte interaction contributes to the necrotic process. The selectins are glycoproteins that play a key role in the early phases of neutrophil adherence and activation. There are three members of the selectin family: P-selectin on endothelial cells and platelets, L-selectin on neutrophils, and E-selectin on endothelium. Monoclonal antibodies directed specifically toward these selectins and their associated ligands (eg, Sialyl Lewisx) not only substantiate their role in the dynamic process of neutrophil-mediated reperfusion injury but also offer a unique therapeutic opportunity to interfere with this cascade of inflammatory events.

Cell Adhesion↗

PubMed1995

Comparative pharmacology of nitric oxide and nitric oxide generators on cardiac contractility in mammalian species.

Nitric oxide (NO) is a potent vasorelaxing agent at nanomolar concentrations. At low nanomolar concentrations, NO also inhibits platelet aggregation, attenuates leukocyte adherence to the vascular endothelium, and quenches superoxide radicals. At high nanomolar concentrations, NO attenuates smooth muscle cells growth and stimulates proliferation of vascular endothelial cells. However, even at micromolar concentrations, NO fails to significantly alter cardiac contractility in isolated rat or cat cardiac muscle. Moreover, L-arginine, even at millimolar concentrations, fails to exert a decrease in cardiac contractility significantly greater than that produced by D-arginine.

Animals↗