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Results for “endothelial dysfunction”

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PubMed1989

Features of endothelial dysfunction in early diabetic nephropathy.

The release of tissue plasminogen activator (tPA) by vascular endothelial cells during exercise was studied in forty men with insulin-dependent diabetes. Three groups, matched for age and diabetes duration, were defined as: group I (n = 19), normal urinary albumin excretion (less than 30 mg/24 h); group II (n = 11), incipient diabetic nephropathy (30-300 mg albumin excreted per 24 h); and group III (n = 10), clinical diabetic nephropathy (more than 300 mg albumin excreted per 24 h). Nine non-diabetic men served as controls. The rise in tPA antigen with exercise was similar in the controls and group I but significantly smaller in groups II and III (p less than 0.01). The albumin transcapillary escape rate was significantly higher in groups II and III than in group I and normal controls (p less than 0.01). The basal plasma level of von Willebrand factor was higher in groups III (p less than 0.01) and II (difference not significant, p = 0.06) than in group I and normal controls. These findings suggest that insulin-dependent diabetic patients with only slightly raised urinary albumin excretion have general endothelial cell dysfunction or damage. It is not yet clear whether these changes are important in the pathogenesis of thrombosis and atherosclerosis in these patients.

Adolescent↗

PubMed1992

Role of platelet-activating factor in the development of endothelial dysfunction in hemorrhagic hypotension and retransfusion.

Platelet-activating factor (PAF), an important mediator of ischemic and shock states, has been shown to prime direct and neutrophil-mediated endothelial cell injury. In the present study we investigated therefore whether PAF is involved in the development of dysfunction of the cerebrovascular endothelium in hemorrhagic hypotension and retransfusion in cats. In vitro responses of middle cerebral arteries prepared from control animals and from animals subjected to hemorrhagic hypotension with or without specific PAF antagonist WEB 2086 treatment (1 mg/kg initial bolus followed by a 0.05 mg/kg/min infusion) were studied by measuring isometric force in organ chambers containing Krebs-Henseleit solution (37 degrees C, gassed with 95% O2-5% CO2). Bleeding was performed in a stepwise fashion by bringing the mean arterial blood pressure to 90, 70 and 50 mmHg and maintained for 20 min at each level followed by a 20-min retransfusion. Hemorrhagic hypotension and retransfusion caused a marked attenuation of the acetylcholine- and ATP-induced endothelium-dependent relaxations of the middle cerebral artery whereas the dilations induced by the nitric oxide donor and direct vasorelaxant SIN-1, remained unaltered. In the vessels, prepared from animals which received WEB 2086 treatment during hemorrhage and retransfusion there were more pronounced cholinergic (but not purinergic) relaxations than in the untreated animals subjected to hemorrhage. SIN-1 induced relaxations remained unaltered after WEB 2086 treatment. Our results suggest that platelet-activating factor is in part involved in the pathophysiological processes leading to the development of the endothelial dysfunction in the present model of hemorrhagic hypotension and retransfusion.

Animals↗

PubMed1990

Plasma free N-terminal fibronectin 30-kDa domain as a marker of endothelial dysfunction in type 1 diabetes mellitus.

The plasma free N-terminal fibronectin 30-kDa domain was measured in 44 type 1 diabetic patients and in 20 healthy subjects. A significantly raised mean concentration of a free N-terminal fibronectin 30-kDa domain was found in plasma of diabetic patients with proliferative retinopathy as compared with healthy persons (P less than 0.001). A positive correlation was observed between free N-terminal fibronectin 30-kDa domain and von Willebrand factor in plasma of all examined subjects (r = 0.62, P less than 0.01). A similar correlation was present between 30-kDa domain and albuminuria (r = 0.56, P less than 0.01). However, no relationship was found between fibronectin 30-kDa domain and control of diabetes as assessed by fructosamine concentration. The free N-terminal fibronectin 30-kDa domain may be used as a marker of actual endothelial cell dysfunction in diabetes.

Adult↗

PubMed1992

Ischaemic endothelial dysfunction after single or multidose cardioplegia.

The effect of ischaemia, either alone or after a single or multidose infusion of St Thomas' Hospital cardioplegia solution (ST), on endothelial function was studied by examining its influence on 5-Hydroxytryptamine- (5-HT-) and nitroglycerine- (GTN-) induced coronary vasodilation in the isolated rat heart. Eighty rat hearts were perfused on a modified Langendorff preparation. Thirty minutes of unprotected ischaemia (N = 16) abolished the vasodilatory response to 5-HT but maintained the response to GTN (expressed as % of the control value 5-HT, pre 45.0 +/- 3.5, post 2.3 +/- 3.2, GTN, pre 42.3 +/- 4.4, post 39.8 +/- 4.0). The increase in coronary flow induced by either agent was unaltered following 30 or 60 min of ischaemia protected by a single dose of ST (N = 16 in each). Ninety minutes of ischaemia preceded by a single infusion of ST (N = 16) markedly reduced the 5-HT response but maintained the vasodilation induced by GTN (5-HT, pre 37 +/- 2.6, post 6.9 +/- 2.6, GTN, pre 40.1 +/- 2.5, post 37 +/- 2.8). During 90 min of ischaemia, infusion of an additional dose of ST after 45 min (N = 8) or two extra doses every 30 min (N = 8) maintained the 5-HT-induced increase in coronary flow (pre 39.5 +/- 3.9, post 36.4 +/- 3.5). It can be concluded that coronary vascular endothelium is more susceptible to ischaemic damage when compared with vascular smooth muscle. This results in early loss of endothelium-dependent vasodilation. Multidose infusion of St Thomas' Hospital cardioplegia solution is superior to a single infusion in protecting endothelial function following prolonged cardiac ischaemia.

Animals↗

PubMed1990

Coronary endothelial dysfunction from ischemia and reperfusion: effect of reactive oxygen metabolite scavengers.

Using anesthetized mongrel dogs exposed to 60 min of ligation of the left anterior descending coronary artery followed by 60 min of reperfusion, we examined the effect of superoxide dismutase (SOD) and dimethylthiourea (DMTU) on evidence of endothelial injury in coronary rings studied in vitro. In 13 dogs treated with saline rings from the normal left circumflex coronary artery (LCF) relaxed by 98 +/- 4% when exposed to 10(-5) M acetylcholine whereas rings from the left anterior descending coronary artery (LAD) relaxed by 79 +/- 7% (p less than 0.05). In the same rings maximum relaxation with the ionophore A23187 was 107 +/- 5% versus 87 +/- 8% (p less than 0.05) for the LCF and the LAD, respectively. Comparisons of concentration-response curves through a range of doses of both acetylcholine and A23187 revealed significant differences for both vasodilators between the LCF and the LAD (p less than 0.01 for each). Nine dogs were treated with bovine SOD infused in the left atrium the last 20 min of ligation and throughout reperfusion (140 units/kg/min) and six other dogs were treated with DMTU 500 mg/kg i.v. given the last 30 min of the ligation period. Neither SOD nor DMTU prevented endothelial injury in the LAD. Despite pretreatment with these agents, there were significant reductions in maximum relaxation and in total concentration-response curves in the LAD as compared with the results in rings from the LCF with both acetylcholine and A23187. There were normal responses to nitroprusside in both the LCF and LAD in all three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1989

Radiation-induced pulmonary endothelial dysfunction and hydroxyproline accumulation in four strains of mice.

C57BL mice exposed to 14 Gy of whole-thorax irradiation develop significant histologic lung fibrosis within 52 weeks, whereas CBA and C3H mice do not exhibit substantial fibrosis during this time. The purpose of the present study was to determine whether this strain-dependent difference in radiation histopathology is associated with genetic differences in pulmonary endothelial metabolic activity or in endothelial radioresponsiveness. C57BL/6J, C57BL/10J, CBA/J, and C3H/HeJ mice were sacrificed 12 weeks after exposure to 0 or 14 Gy of 300-kV X rays to the whole thorax. Lung angiotensin converting enzyme (ACE) activity and plasminogen activator (PLA) activity were measured as indices of pulmonary endothelial function; and lung hydroxyproline (HP) content served as an index of pulmonary fibrosis. Lung ACE and PLA activities in sham-irradiated C57BL/6J and CB57BL/10J mice were only half as high as those in sham-irradiated CBA/J and C3H/HeJ mice. Exposure to 14 Gy of X rays produced a slight but nonsignificant reduction in lung ACE and PLA activity in the C57BL strains, and a significant reduction in the CBA/J and C3H/HeJ mice. Even after 14 Gy, however, lung ACE and PLA activities in CBA/J and C3H/HeJ mice were higher than those in sham-irradiated C57BL/6J and C57BL/10J mice. Lung HP content in all four strains increased significantly after irradiation, but this increase was accompanied by an increase in lung wet weight. As a result, HP concentration (per milligram wet weight) remained constant or increased slightly in both C57BL strains and actually decreased in the CBA/J and C3H/HeJ mice. These data demonstrate significant genetic differences in both intrinsic pulmonary endothelial enzyme activity and endothelial radioresponsiveness among the four strains of mice. Specifically, strains prone to radiation-induced pulmonary fibrosis (C57BL/6J, C57BL/10J) exhibit only half as much lung ACE and PLA activity as do strains resistant to fibrosis (CBA and C3H).

Animals↗

PubMed1992

Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals.

The major objective of the present study was to determine the effect of multiple, brief periods of coronary artery occlusion and reperfusion on postischemic contractile function (sonomicrometry) and endothelium-dependent vasodilator responses in isolated conduit coronary artery rings obtained from anesthetized dogs. The role of oxygen-derived free radicals was also investigated. Dogs were subjected to four 5-min episodes of left anterior descending coronary occlusion interspersed with 5 min of reperfusion followed by a final 60-min reperfusion period. The multiple occlusion-reperfusion protocol resulted in regional segment dysfunction (37 +/- 15% of preocclusion values at 60 min of reperfusion) and attenuated endothelium-dependent responses to acetylcholine, bradykinin, and the calcium ionophore, A23187. Responses to the endothelium-independent vasodilator, sodium nitroprusside, were unaffected. Infusion of superoxide dismutase (5,000 U/kg) and catalase (55,000 U/kg) markedly improved the recovery of myocardial function at 30 and 60 min of reperfusion and completely protected against vascular endothelial damage. These results suggest an important role for oxygen-derived free radicals in the myocardial and endothelial injury that occurs in this model of multiple stunned myocardium.

Animals↗

PubMed1992

Protective effects of benidipine hydrochloride (KW-3049), a calcium antagonist, against experimental arterial calcinosis and endothelial dysfunction in rats.

Protective effects of benidipine hydrochloride (KW-3049) against arterial calcinosis and its possible mechanisms of action have been investigated. Arterial calcinosis was induced in rats by combined administration of vitamin D2 (1050000 IU/kg, s.c.) and nicotine (12.5 mg/kg, p.o., b.i.d.) for 6 successive days. Calcium antagonists, benidipine or nifedipine, were given orally twice a day during the same period. The aortic calcium content in vitamin D2 and nicotine-treated (control) rats increased to about 25 times that in normal rats, accompanying an increase of serum calcium level. Benidipine (10 mg/kg, p.o., b.i.d.) reduced the aortic calcium content to about 18% of control rats without reducing the serum calcium level. Although the presence of aortic endothelial cells was observed under light microscopy in control rats, their surfaces were degenerated under scanning electron microscopy. Benidipine exerted a protective effect against these degenerative changes. Acetylcholine-induced endothelial dependent relaxation was attenuated in control rats, compared with that in normal rats. Benidipine significantly improved this attenuation of the relaxation. These results suggest that the anticalcinotic effect of benidipine is accompanied by its protective effect on endothelial cells.

Acetylcholine↗

PubMed1991

Time course of endothelial dysfunction and myocardial injury during coronary arterial occlusion.

The time course of the effects of permanent myocardial ischemia without reperfusion on the coronary vascular endothelium and myocardium were investigated in anesthetized cats. The left anterior descending (LAD) coronary artery was occluded for 1.5, 3.0, 4.5, or 6.0 h. Coronary rings from the ischemic LAD and the nonischemic left circumflex (LCX) arteries were tested for their responsiveness to the endothelium-dependent vasodilators acetylcholine (ACh, 0.1-100 nM) and the calcium ionophore A23187 (1-1,000 nM), and the endothelium-independent vasodilator sodium nitrite (NaNO2, 0.1-100 microM). Vasorelaxation was not significantly impaired in response to ACh after 1.5 h of ischemia and only moderately impaired after 3.0 h of ischemia (63 +/- 5% of control). However, after 4.5 h of ischemia the ACh-induced response was decreased to 33 +/- 4% of control and further declined to 31 +/- 4% of control after 6.0 h (P less than 0.001 from 1.5 h). There was no significant decrease in LCX ring vasorelaxant responses to vasodilators at all times, and the LAD rings only showed a moderately decreased response to NaNO2 after 6.0 h of ischemia (82 +/- 4% relaxation, P less than 0.05). Transmission electron microscopy revealed very little endothelial damage at 4.5 and 6.0 h, with only some subendothelial swelling noted. Damage to the myocardium did not become significant until after 4.5 h of ischemia, and cardiac myeloperoxidase activity, indicative of neutrophil accumulation, was not significant at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1991

Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms.

This study determines whether an impaired endothelium-mediated vasodilation in coronary resistance vessels exists in patients with microvascular angina. In 23 patients with clinically suspected coronary artery disease and smooth coronary arteries in the angiogram, coronary flow in response to an endothelium-related (acetylcholine) and endothelium-unrelated (dipyridamole) vasodilation was measured. Coronary flow was determined by the gas-chromatographic argon method (1) before, (2) with intracoronary acetylcholine infusion, and (3) after dipyridamole administered intravenously. In 8 patients, acetylcholine did not significantly increase coronary flow (from 91 +/- 28 to 118 +/- 37 ml/min.100 g), whereas flow was greatly increased after administration of dipyridamole (258 +/- 97 ml/min.100 g), indicating an endothelium-related vasodilator defect. In 6 patients, neither acetylcholine nor dipyridamole caused a significant increase in coronary flow, indicating an impaired coronary vasodilation on the vascular site. In 6 patients, coronary flow increased markedly after both administration of both acetylcholine and dipyridamole (from 81 +/- 26 to 191 +/- 68 and 234 +/- 87 ml/min.100 g). In 3 patients given acetylcholine, coronary artery constriction occurred. No significant correlation was found between the response to acetylcholine and that to dipyridamole (r = 0.40, p = not significant). The results indicate that in a subgroup of patients with smooth coronary arteries angina can be caused by an abnormality of the endothelial function in the microcirculation.

Acetylcholine↗

PubMed1989

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease.

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.

Acetylcholine↗

PubMed1991