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PubMed1992

Effects of indomethacin on PMA-induced pulmonary endothelial enzyme dysfunction in vivo.

We investigated the effects of phorbol myristate acetate (PMA) on metabolic pulmonary endothelial ectoenzyme dysfunction. Anesthetized rabbits were placed on total heart bypass, and the single-pass transpulmonary metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) by endothelial-bound angiotensin-converting enzyme (ACE) and [14C]adenosine 5'-monophosphate (AMP) by 5'-nucleotidase (NCT) was calculated before and after PMA (10 micrograms/kg iv), a dose that does not produce histologically evident endothelial damage. Under conditions of partial microvascular recruitment (blood flow = 400 ml/min through the entire lung), PMA, but not the vehicle, significantly reduced substrate utilization of both BPAP and adenosine 5'-monophosphate (AMP) and increased the apparent Michaelis constant (Km) values of ACE for BPAP, indicative of metabolic dysfunction. These changes were completely prevented by pretreatment with indomethacin. Under conditions of near full microvascular recruitment (blood flow = 640 ml/min through the left lung only), PMA similarly reduced substrate utilization and increased the apparent Km of ACE for BPAP. In this case, however, indomethacin failed to prevent the observed PMA-induced metabolic dysfunction. We conclude that PMA alters endothelial ectoenzyme substrate metabolism independently from changes in pulmonary blood flow; indomethacin appears to antagonize the effects of PMA under conditions of partial microvascular recruitment only, perhaps by diverting flow to previously unperfused, unexposed to PMA, and hence metabolically healthy vessels.

5'-Nucleotidase↗

PubMed1995

Close relation of endothelial function in the human coronary and peripheral circulations.

OBJECTIVES: The relation between endothelium-dependent vasodilator function in the brachial and coronary arteries was determined in the same subjects. BACKGROUND: Coronary artery endothelial dysfunction precedes the development of overt atherosclerosis and is important in its pathogenesis. A noninvasive assessment of endothelial function in a peripheral conduit vessel, the brachial artery, was recently described, but the relation between brachial artery function and coronary artery vasodilator function has not been explored. METHODS: In 50 patients referred to the catheterization laboratory for the evaluation of coronary artery disease (mean age +/- SD 56 +/- 10 years), the coronary vasomotor response to serial intracoronary infusions of the endothelium-dependent agonist acetylcholine (10(-8) to 10(-6) mol/liter), was studied. Endothelium-dependent vasodilation was also assessed in the brachial artery by measuring the change in brachial artery diameter in response to reactive hyperemia. RESULTS: Patients with coronary artery endothelial dysfunction manifested as vasoconstriction in response to acetylcholine had significantly impaired flow-mediated vasodilation in the brachial artery compared with that of patients with normal coronary endothelial function (4.8 +/- 5.5% vs. 10.8 +/- 7.6%, p < 0.01). Patients with coronary artery disease also had an attenuated brachial artery vasodilator response compared with that of patients with angiographically smooth coronary arteries (4.5 +/- 4.6% vs. 9.7 +/- 8.1%, p < 0.02). By multivariate analysis, the strongest predictors of reduced brachial dilator responses to flow were baseline brachial artery diameter (p < 0.001), coronary endothelial dysfunction (p = 0.003), the presence of coronary artery disease (p = 0.007) and cigarette smoking (p = 0.016). The brachial artery vasodilator response to sublingual nitroglycerin was independent of coronary endothelial responses or the presence of coronary artery disease. The positive predictive value of abnormal brachial dilation ( < 3%) in predicting coronary endothelial dysfunction is 95%. CONCLUSIONS: This study demonstrated a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilation in the brachial artery. This noninvasive method may become a useful surrogate in assessing the predisposition to atherosclerosis in patients with cardiac risk factors.

Acetylcholine↗

PubMed1983

Endothelial cell dysfunction in homocystinuria.

This report describes the isolation and culture of venous endothelial cells from the umbilical cord of an obligate heterozygote for homocystinuria. The effect of different sulphur-containing amino acids on the viability and function of these cells was studied and compared with cultured normal endothelial cells. When endothelial cells were cultured in the presence of methionine (10 mmol/l) or homocystine (10 mmol/l), differences occurred between the viability and function of the heterozygote and normal cells in terms of 51Cr release and ability to prevent platelet adherence. The Cr release corrected for spontaneous release increases for the heterozygote cells after incubation/for 21 h in the presence of methionine to 81.3% (control cells, range: 0-23.3%, n = 5) and in the presence of homocystine to 141% (control cells, range: 13.5-55.2%, n = 5). The total number of platelets that adhere to confluent monolayers increases for heterozygote cells cultured in the presence of methionine to 0.98 X 10(7) platelets cm-2 (normal cells, range: 0.56-0.72 X 10(7) platelets cm-2) and in the presence of homocystine to 1.41 X 10(7) platelets cm-2 (normal cells, range: 0.94-1.06 X 10(7) platelets cm-2). Both normal and control cells were sensitive to homocysteine. This study/indicates for the first time what vascular endothelial cells, derived from an obligate heterozygote, are (partly) deficient in cysthathionine synthase and are more susceptible to methionine- and homocystine-mediated injury than normal endothelial cells. Consequently, in homocystinuria, due to dysfunction of the endothelial cells, toxic sulphur-containing amino acids may accumulate in these cells, causing injury of these cells.

Cells, Cultured↗

PubMed1984

Evidence for an endothelial cell dysfunction in association with Behçet's disease.

Suppression of the fibrinolytic system is a well-known phenomenon in patients with Behcet's disease regardless of whether they present thrombotic complications. This finding has been related to impaired production and/or release of plasminogen activators from the vascular endothelium. In previous studies a diminished release of PF4 upon heparin stimuli was observed in plasma from patients with Behcet's disease and interpreted as an additional indicator for endothelial cell dysfunction. In the present investigations, 12 patients and 10 healthy volunteers received DDAVP infusions and euglobulin clot lysis time, factor VIII activities and 6-keto-PGF1 alpha levels in plasma were repeatedly determined before and after infusions. At different times following DDAVP infusion, euglobulin clot lysis time was significantly longer and levels of F.VIII R:Ag were lower in patients than in normals. F. VIII:C activity increased in both groups, whereas no changes were seen in the plasma levels of 6-Keto-PGF1 alpha either in normals or in patients. It is concluded that the disseminated damage of endothelial tissue associated with Behçet's disease correlates with multiple endothelial cell dysfunctions and subsequent hemostatic abnormalities.

6-Ketoprostaglandin F1 alpha↗

PubMed1991

Cardioprotective and endothelial protective effects of [Ala-IL8]77 in a rabbit model of myocardial ischaemia and reperfusion.

1 We studied the effects of a form of interleukin-8 (i.e., [Ala-IL8]77) on endothelial dysfunction and myocardial injury in rabbits. Pentobarbitone-anaesthetized rabbits were subjected to 1.5 h occlusion of the marginal coronary artery and 3.5 h reperfusion. [Ala-IL8]77 (50 micrograms or its vehicle) was given i.v. as a bolus 10 min prior to reperfusion. [Ala-IL8]77 was also studied in isolated perfused hearts of rabbits. 2 Myocardial ischaemia plus reperfusion in untreated rabbits produced severe endothelial dysfunction and myocardial injury, including marked myocardial necrosis, elevated cardiac myeloperoxidase (MPO) activity in ischaemic cardiac tissue, and loss of response of marginal coronary rings to the endothelium-dependent vasodilators, acetylcholine (ACh) and A23187. 3 Administration of [Ala-IL8]77 10 min prior to reperfusion resulted in significant protective effects in post-ischaemic reperfusion. Compared with untreated rabbits, [Ala-IL8]77 caused a reduced necrotic zone (P less than 0.01), lower MPO activity in the necrotic zone (P less than 0.05), and significantly preserved vasorelaxant responses of marginal coronary artery rings to endothelium-dependent vasodilators, ACh (P less than 0.001) and A23187 (P less than 0.001). 4 These results indicate that myocardial ischaemia and reperfusion result in a severe endothelial dysfunction and myocardial injury which involved the interaction of neutrophils and endothelial cells. However, [Ala-IL8]77 did not appear to exert a direct endothelial protective effect in the absence of neutrophils in rabbit isolated perfused hearts. 5 Inhibition of neutrophil accumulation in the myocardium, perhaps by prevention of endothelial dysfunction resulting from [Ala-IL8]77, leads to significant protective effects in ischaemia and reperfusion in rabbits.

Acetylcholine↗

PubMed1994

Effects of taprostene on neutrophil-endothelial interactions in isolated coronary arteries.

We examined the effects of taprostene (2.5 x 10(-8) M to 1 x 10(-7) M), a stable prostacyclin analog, on PMN-endothelial interaction (i.e., adherence) and subsequent vasocontraction and endothelial dysfunction. Taprostene effectively inhibited the adherence of leukotriene B4-stimulated autologous cat polymorphonuclear (PMN) leukocytes to isolated cat coronary artery endothelium. Taprostene also inhibited coronary artery vasocontraction to leukotriene B4-stimulated PMNs (p < 0.01). In isolated coronary artery rings stimulated with either 2 U/ml of thrombin or 100 microM hydrogen peroxide (H2O2), adherence of unstimulated PMNs to coronary endothelium was significantly increased, resulting in vasocontraction and subsequent endothelial dysfunction. However, taprostene (1 x 10(-7) M) significantly attenuated unstimulated PMN adherence to stimulated coronary endothelium. This antiadherence action effectively attenuated PMN-induced coronary artery vasocontraction (p < 0.01) and significantly blunted the subsequent PMN-induced endothelial dysfunction (p < 0.01) characterized by a loss of endothelium-derived nitric oxide (NO). Thus, taprostene exerts a profound inhibitory effect on PMN-endothelium interaction and subsequent PMN-mediated coronary endothelial dysfunction, which may be beneficial in ischemia-reperfusion and other inflammatory states.

Analysis of Variance↗

PubMedDate not supplied

Effect of verapamil on monocrotaline-induced pulmonary artery hypertension and endothelial cell dysfunction in rats.

Verapamil, a calcium channel blocker has been used with partial success in cases of primary pulmonary hypertension, as well as to reduce hypoxia-induced pulmonary hypertension (PH) in rats. However, its effect on monocrotaline (MCT)-induced PH in rats is not known. We studied the effect of verapamil on MCT-induced PH. Three weeks after a single injection of MCT, significant PH was noted in the MCT-injected rats compared with control (44.35 +/- 3.5 vs. 22 +/- 2.5 mmHg). MCT-injected rats on daily verapamil showed significant reduction in PH (31.5 +/- 3.4 mmHg). The main pulmonary artery of MCT-injected rats revealed subendothelial thickening, thinning and fragmentation of elastic laminae, smooth muscle cell hypertrophy and necrosis or loss of smooth muscle cells, and increased amounts of collagen in media and adventitia. In contrast, the main pulmonary artery of MCT + VP-treated rats showed less intimal thickening, some smooth muscle cell hypertrophy, but little necrosis or loss of cells in addition to disappearance of outer elastic laminae. Smaller pulmonary arteries (less than 150 microns in diameter) in MCT + VP-treated rats showed less medial thickening than MCT groups. However, diminished lung angiotensin-converting enzyme activity suggestive of endothelial cell dysfunction was noted in both MCT and MCT + VP-treated rats. This study indicates that verapamil attenuates MCT-induced PH, but has no effect on pulmonary endothelial cell dysfunction.

Animals↗

PubMed1994

[Abnormal endothelium-mediated regulation of vascular tone in arteriosclerosis].

Knowledge regarding the endothelial-derived relaxing factor (EDRF) has substantially increased over recent years. The chemical identification of EDRF as nitric oxide (NO) and the discovery of the NO-pathway started an exciting research field with new insights into the regulation of many biologic processes. Concerning regulation of the vascular tone, EDRF(NO) is one of the most potent relaxant substances known; in addition, EDRF(NO) is a potent inhibitor of platelet adhesion and aggregation and leukocyte adhesion to the vascular wall; furthermore, EDRF(NO) is probably an inhibitor of smooth muscle cell proliferation. This profile of EDRF(NO) may be an important part of the anti-arteriosclerotic function of intact endothelial cells. In animal models of hypercholesterolemia and in patients with hypercholesterolemia and/or arteriosclerosis, the EDRF(NO) mechanism is impaired or almost abolished (= endothelial dysfunction). The reason for this abnormal endothelial function is not fully understood and may be multifactorial; it has been suggested that this endothelial dysfunction is due to an accelerated breakdown of EDRF(NO) by oxidized low density lipoprotein and/or oxygen derived free radicals. In addition, there may be an increased release of vasoconstrictive substances, e.g., endothelin-1, from endothelial cells which may override the relaxant effects of EDRF (NO). This abnormal function of the endothelium (in terms of the EDRF(NO) mechanism) appears to be reversible in animal models and in patients with hypercholesterolemia, and is accomplished by normalizing plasma cholesterol levels.

Amino Acid Oxidoreductases↗

PubMed1988

Responses of coronary arteries of cardiac transplant patients to acetylcholine.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

Acetylcholine↗

PubMed1992

Free radicals mediate endothelial cell dysfunction caused by elevated glucose.

Impaired endothelium-dependent relaxation occurs in diabetic rabbit aorta and normal aorta exposed to elevated concentrations of glucose and is prevented by cyclooxygenase inhibitors. The role of free radicals in the endothelial cell impairment was examined with free radical scavengers and in aortas from rabbits fed with probucol (1% wt/wt, a lipid-soluble antioxidant). Rings of aorta suspended for measurement of isometric tension were incubated for 6 h in control (5.5 mM) or elevated (44 mM) glucose. Impairment of endothelium-dependent relaxation to acetylcholine caused by exposure to elevated glucose was prevented by superoxide dismutase, catalase, deferoxamine, or allopurinol and did not occur in aortas from probucol-fed rabbits. Similarly, impairment of acetylcholine relaxations in aortas from alloxan-induced diabetic rabbits was restored to normal by superoxide dismutase. Oxygen-derived free radicals generated by xanthine oxidase also caused impaired acetylcholine relaxations. Exposure of aortic segments to elevated glucose or to xanthine oxidase caused a significant increase in release of immunoreactive prostanoids. These data indicate that the endothelial cell dysfunction caused by elevated glucose is mediated by free radicals that are likely generated through the increased cyclooxygenase catalysis occurring in the endothelium. Treatment with antioxidants protects against impaired endothelium-dependent relaxations caused by elevated glucose.

Animals↗

PubMed1992

Endothelial cell dysfunction in HIV infection.

We have investigated plasma levels of endothelial cell products playing a role in hemostasis in 125 HIV-positive patients and 30 controls. Antigenic von Willebrand factor increased significantly with disease progression and was closely correlated with CD4+ cell counts and beta 2-microglobulin levels. Tissue-type plasminogen activator was normal in CDC II/III and CDC IVC2 patients and was slightly increased in AIDS patients, whereas plasminogen activator inhibitor was increased in each group, the stage of the disease not having any effect. Mean total protein S levels were lower in HIV-positive patients and, in 27.2% of the cases, were associated with a decrease in free protein S levels. Such abnormalities could be responsible for a hypercoagulable state in these patients and could be explained by endothelial cell damage during HIV infection. Whether this injury is due to HIV itself remains to be further investigated.

Adult↗

PubMed1991

Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia.

The pregnancy disorder preeclampsia continues as a major cause of maternal and infant mortality and morbidity. Despite intensive research since its recognition 100 years ago, our lack of understanding is evidenced by therapy which remains empiric, early delivery. Part of our failure to more completely understand the syndrome is due to excessive attention to the blood pressure elevation which accompanies the disorder, to the exclusion of a panoply of other physiologic aberrations. Although hypertension, if markedly elevated, can lead to maternal morbidity, it is not usually an important contributor to the pathophysiology of preeclampsia. It is primarily important as a marker for vasoconstriction, which in association with activation of coagulation reduces perfusion to many organs, including the fetal-placental unit. The earliest and likely most important pathophysiologic change is reduced placental perfusion secondary to abnormal implantation and/or a relative increase in placental mass. We propose that reduced placental perfusion results in the production of agent(s) by this organ, which injures or activates endothelial cells. The resulting endothelial cell dysfunction increases sensitivity to normal endogenous pressors, activates the coagulation cascade, and increases vascular permeability. These changes produce the characteristic pathophysiologic changes of the disorder. Evidence supporting this hypothesis includes abnormal endothelial morphology long recognized in glomerular capillaries, increased circulating fibronectin, and increased plasma mitogenic activity that long antedates the clinical disorder. In addition, an agent(s) is present in the blood of these women which activates endothelial cells in vitro as evidenced by increased release of [51Cr] chromium and increased production of PDGF. Preeclampsia is clearly more than "pregnancy induced hypertension."

Endothelium, Vascular↗

PubMed1987

Indications of vascular endothelial cell dysfunction in systemic lupus erythematosus.

Fibrinolytic and other factors have been measured in 73 patients with systemic lupus erythematosus or related conditions to determine whether clinical thrombosis, a common feature of these disorders, is associated with defective fibrinolysis. Twenty five of 72 (35%) patients, compared with two of 22 (9%) controls, showed a low level of plasminogen activator activity in response to venous occlusion, suggesting decreased fibrinolytic potential. In addition, mean plasma levels of von Willebrand factor antigen and fibronectin were markedly raised in the patients (mean (SD) 384.5 (277)% and 727 (436) mg/l respectively) compared with healthy controls (100 (50)% and 306 (65) mg/l). These data suggest a degree of endothelial cell dysfunction. No clear correlation was found between a history of thrombosis and any plasma factor measured, except for prolongation of clotting tests suggestive of the 'lupus anticoagulant'.

Adult↗

PubMed1991

Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion.

We studied the effects of MAbR15.7, an antibody directed against the common beta-chain (CD-18) of a family of neutrophil adherence glycoproteins, on endothelial dysfunction and myocardial injury in a model of myocardial ischemia and reperfusion in cats. Pentobarbital-anesthetized cats were subjected to 1.5 h occlusion of the left anterior descending coronary artery (LAD) and 4.5 h of reperfusion. MI + R resulted in severe myocardial injury and endothelial dysfunction, including significant elevation of plasma creatine kinase (CK) activity, marked myocardial necrosis, high cardiac myeloperoxidase (MPO) activity in ischemic cardiac tissue, and loss of response of LAD coronary rings to the endothelium-dependent vasodilators, acetylcholine (ACh) and A-23187. In contrast, MAbR15.7-treated cats exhibited a lower plasma CK activity at every time point observed after 2 h, a reduced area of cardiac necrosis (2 +/- 1 vs. 30.8 +/- 2.5% of area-at-risk, P less than 0.001), lower MPO activity in the ischemic region (P less than 0.01), and significantly preserved vasorelaxant responses of LAD coronary rings to endothelium-dependent vasodilators, ACh (P less than 0.001), and A-23187 (P less than 0.001). These results indicate that myocardial ischemia and reperfusion induces significant myocardial injury and endothelial dysfunction in the cat involving a CD18-dependent neutrophil adherence mechanism. Inhibition of neutrophil adherence to the endothelium exerts significant protective effects in this model of reperfusion injury.

Acetylcholine↗

PubMed1993

Monoclonal antibody to L-selectin attenuates neutrophil accumulation and protects ischemic reperfused cat myocardium.

BACKGROUND: Interaction of CD11/CD18 located on neutrophil membranes with its endothelial counter-receptor, intercellular adhesion molecule-1, plays a major role in polymorphonuclear leukocyte (PMN)-mediated endothelial dysfunction and myocardial injury associated with ischemia and reperfusion. However, PMN-derived L-selectin, which is thought to play an early role in PMN rolling along the vascular endothelium, has not been studied in a setting of myocardial ischemia and reperfusion. METHODS AND RESULTS: In this study, we evaluated the effects of a monoclonal antibody against L-selectin, DREG-200, in a feline model of myocardial ischemia (1.5 hours) and reperfusion (4.5 hours). DREG-200 (1 mg/kg) or an isotype-matched IgG1 antibody, MAb R3.1, which does not cross-react in cats, was administered as a bolus 10 minutes before reperfusion. In MAb R3.1-treated cats, myocardial ischemia followed by reperfusion resulted in significant coronary vascular endothelial dysfunction, elevated cardiac myeloperoxidase activity indicative of neutrophil accumulation in the ischemic myocardium, and severe myocardial injury. In contrast, administration of DREG-200 at 1 mg/kg significantly attenuated myocardial necrosis (14 +/- 4 versus 32 +/- 3 expressed as percentage of area at risk, P < .001) and attenuated coronary endothelial dysfunction (P < .01) associated with ischemia/reperfusion. Moreover, myeloperoxidase activity in the ischemic myocardium was significantly lower than MAb R3.1-treated cats (0.4 +/- 0.1 versus 0.9 +/- 0.2 U/100 mg tissue, P < .05). CONCLUSIONS: These results demonstrate that blocking L-selectin with DREG-200 exerts a significant cardioprotective effect in a feline model of myocardial ischemia and reperfusion, indicating that L-selectin plays a significant role in mediating PMN accumulation and PMN-induced endothelial and myocardial injury after ischemia and reperfusion.

Animals↗

PubMed1995

Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis.

Vascular endothelium, the single-cell-thick lining of the cardiovascular system, is an important functional component of the blood vessel wall, actively participating in normal vascular physiology as well as the pathogenesis of vascular diseases such as atherosclerosis. The localized modulation of vascular endothelium to a non-adaptive functional state can be termed "endothelial dysfunction." This article provides a brief overview of endothelial dysfunction, especially as it relates to mononuclear leukocyte recruitment during atherosclerotic lesion formation. Potential diagnostic and therapeutic implications are also considered.

Animals↗

PubMed2026

Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices.

OBJECTIVES: Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. METHODS: This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. RESULTS: Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. CONCLUSIONS: Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.

Humans↗

PubMed1987

Early pulmonary endothelial enzyme dysfunction after phorbol ester in conscious rabbits.

We investigated changes in angiotensin converting-enzyme (ACE) activity before and at 5, 15, 60, and 240 min after 20 micrograms phorbol myristate acetate/kg body wt iv in conscious rabbits. ACE activity was estimated in vivo from the single-pass transpulmonary metabolism of the synthetic substrate [3H]benzoyl-Phe-Ala-Pro [( 3H]BPAP) under first-order reaction conditions. Within 5 min after PMA administration, all animals developed profound granulocytopenia (15% of control) and moderate thrombocytopenia (57% of control), both lasting for the duration of the experiment. Concomitantly, there was a significant decrease in the transpulmonary metabolism of [3H]BPAP and the calculated apparent first-order reaction constant Amax/Km of ACE for [3H]BPAP. No histological evidence of lung injury was observed at these times. Since a concomitant fall in the permeability surface area product for urea was also observed, we considered that the apparent decline in ACE activity might have resulted from a reduction in perfused endothelial surface area. To resolve this, we studied the effect of PMA on the Km (a measure of enzyme affinity for its substrate) and Amax (a derivative of Vmax that is dependent upon total enzyme present and thus capillary surface area) of ACE and 5'-nucleotidase for [3H]BPAP and [14C]AMP, respectively. A significant increase in Km for both enzymes was observed at 1 h after PMA, whereas Amax was unaffected, suggesting that low-dose PMA may indeed produce endothelial cell enzyme dysfunction independent of its effect on capillary surface area. These results provide evidence of pulmonary capillary functional injury before or in the absence of structural endothelial damage.

Adenosine Monophosphate↗