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PubMed2000

Endothelial dysfunction, hemodynamic forces, and atherogenesis.

Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NF kappa B and Egr-1, to shear-stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up- and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non-laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL-1 beta). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX-2, and Mn-SOD) support vasoprotective (i.e., anti-inflammatory, anti-thrombotic, anti-oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related "atheroprotective genes" in the endothelial lining of lesion-protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.

Animals↗
PubMed2006

Raloxifene prevents endothelial dysfunction in aging ovariectomized female rats.

Lack of an appropriate animal model has delayed the better understanding of mechanisms related to higher cardiovascular risk in women after menopause. The aging female rat may share some menopausal changes observed in women. However, most studies have attempted to mimic menopause by ovariectomizing young (6-12 weeks old) animals without taking into accounts the influence of aging and of declining ovarian function. Therefore, the present study examined changes in vascular reactivity in the aging (15 months old) female rat after ovariectomy and the effects of chronic raloxifene therapy on vascular reactivity and eNOS protein expression. Aortic rings were prepared from the three experimental groups of rats: sham-operated control, ovariectomized and ovariectomized aging rats receiving daily oral administration of raloxifene for 3 months. Aortic rings were suspended in organ baths for the measurement of isometric tension. Rings with endothelium contracted significantly more to phenylephrine after inhibition of nitric oxide/cyclic GMP-signaling pathway by L-NAME or ODQ (as an index of basal nitric oxide release) in control and raloxifene-treated ovariectomized rats than in ovariectomized rats. This effect was abolished upon mechanical removal of the endothelium. Phenylephrine induced greater contractions only in rings with endothelium from ovariectomized rats as compared with control rats and raloxifene treatment normalized this response. In the presence of L-NAME or ODQ, phenylephrine-induced contraction was similar in rings from the three groups. Rings relaxed more to thapsigargin and acetylcholine in raloxifene-treated ovariectomized rats than in ovariectomized rats. There was no significant difference in aortic eNOS protein contents among the different groups. These results suggest that chronic oral administration of raloxifene to aging ovariectomized female rats augmented the bioavailability of endothelial nitric oxide in isolated aortic rings without altering eNOS protein levels.

Acetylcholine↗
PubMed1993

Effects of nisoldipine upon endothelial dysfunction following ischaemic and peroxidative injury in the perfused rat heart.

OBJECTIVE: Previous studies showed that treatment of hearts with nisoldipine improves recovery of cardiac function following ischaemia, improves reperfusion, and reduces the constrictor sensitivity to endothelin. The aim of the present study was to assess the reduction in vasodilator responses that occurs following ischaemia and reperfusion or after oxidative stress, and to determine whether nisoldipine treatment improves these dilator responses. METHODS: Isolated perfused rat hearts were studied. Coronary vessels were constricted by the addition of U46619 and dilator responses were determined with the addition of acetylcholine (endothelium dependent) or glyceryl trinitrate (endothelium independent). Responses were compared before and after low flow ischaemia (20%, 30 min) and reperfusion (30 min), or treatment with tert-butyl hydroperoxide (tBHP) (0.9 mM, 12 min, 30 min wash). RESULTS: The addition of U46619 caused a prolonged increase in perfusion pressure of 50 to 70 mm Hg which was not significantly different before and after treatment. Dilatation responses to acetylcholine were significantly reduced following ischaemia and reperfusion (34% of preischaemic values) or tBHP (47.6% of pre-tBHP values), while responses to glyceryl trinitrate were not significantly changed. In contrast, when hearts were perfused with nisoldipine, the responses to acetylcholine were significantly improved (88% of preischaemic values with 5 nM nisoldipine, and 68% to 78% of pre-tBHP values with 0.5 nM to 5 nM nisoldipine). Responses to acetylcholine following tBHP were not significantly improved when hearts were perfused with verapamil (5 nM 43.5%, 5 microM 32%, of pre-tBHP values), or diltiazem (5 nM 37%, 5 microM 31%, of pre-tBHP values). CONCLUSIONS: Ischaemia and reperfusion or oxidative stress reduced endothelium dependent responses, but not endothelium independent responses. Nisoldipine reduced the injury to endothelial cell function associated with ischaemia and reperfusion or oxidative stress.

Acetylcholine↗
PubMed1995

Improved survival and reversal of endothelial dysfunction by the 21-aminosteroid, U-74389G in splanchnic ischaemia-reperfusion injury in the rat.

1. Anaesthetized rats subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state (splanchnic artery occlusion, SAO shock) resulting in death within 70-90 min after release of the occlusion. Sham-operated animals were used as controls. 2. Survival rate, survival time, serum tumour necrosis factor (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure (MAP), plasma malonyladehyde (MAL); myeloperoxidase activity (MPO) and the responsiveness to acetylcholine (ACh 10 nM-10 microM) of aortic rings were investigated. 3. SAO shocked rats had a decreased survival rate and survival time (74 +/- 10 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (267 +/- 13 u ml-1) and plasma levels of MAL (57 +/- 7 nmol ml-1), enhanced MPO activity in the ileum (0.23 +/- 0.04 u x 10(-3) g-1 tissue) and in the lung (2.2 +/- 0.8 u x 10(-3) g-1 tissue), leukopenia and reduced responsiveness to ACh of aortic rings. 4. The 21-aminosteroid U-74389G (30 mg kg-1, i.v.) increased survival (survival time = 232 +/- 15 min), lowered the serum levels of TNF-alpha and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 +/- 0.004 u x 10(-3) g-1 tissue) and in the lung (0.23 +/- 0.03 u x 10(-3) g-1 tissue), improved MAP and restored the responsiveness to ACh of aortic rings. 5. Our data suggest that U-74389G is a potent lipid peroxidation inhibitor and that it has antishock and endothelial protective actions.

Acetylcholine↗
PubMed1998

Factors involved in the effects of losartan on endothelial dysfunction induced by aging in SHR.

In the present study we investigated the effects of losartan (10 mg/kg/day; 12 weeks) on acetylcholine (Ach) induced relaxations in isolated mesenteric vascular beds (MVB) from adult and elderly spontaneous hypertensive rats (SHR). Experiments were done in absence or presence of either the NO synthesis inhibitor, L-NAME (10(-5) mol/liter), L-NAME + indomethacin (10(-5) mol/liter) or L-NAME + indomethacin + KCl (10(-5) mol/liter), to evaluate the participation of the factors (NO, PGs and EDHF, respectively) mediating Ach-relaxations. Systolic blood pressure levels were comparable in both groups. However, urinary nitrites excretion and Ach-response was lower in elderly than in adult SHR. The presence of L-NAME and L-NAME + indomethacin only reduced Ach-relaxations in untreated elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of endothelium-derived hyperpolarizing factor (EDHF) in Ach-relaxations was higher than that of nitric oxide (NO) and prostaglandins in both groups, although the EDHF component was lower in elderly when compared to adult SHR. Losartan treatment reduced blood pressure levels and enhanced dose-related Ach-relaxations and urinary nitrites in both groups. Presence of L-NAME and L-NAME + indomethacin blunted the enhancements induced by losartan on Ach-relaxations in both adult and elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of NO in Ach-relaxations was increased by losartan in both groups. Neither EDHF or prostanoids (PGs) components were clearly affected by losartan. In conclusion, (1) diminished EDHF availability accounts for the reduced Ach-relaxations produced by aging in MVB from SHR; (2) the enhancement of Ach-relaxations produced by losartan seems to be dependent on an increased NO availability; and (3) angiotensin II via angiotensin I type 1 receptor (AT1) plays an important role in the deleterious consequences of aging on endothelial function in SHR.

Acetylcholine↗
PubMed2001

Molecular mechanisms of endothelial dysfunction in the diabetic heart.

Our observations show that long term hyperglycaemia by the formation of AGE, but also short term hyperglycaemic periods ("glucose spikes") damage the endothelium of the heart in diabetes. The endothelium is exposed to oxidative stress. The simultaneous generation of NO and superoxide anions enables the reaction of both species to form peroxynitrite which has been identified as an important mediator for the transformation of endothelium from an anticoagulant to a procoagulant state. Together with a functional loss of endothelium these processes are assumed to impair the coronary perfusion and to provoke adaptive processes which finally lead to cardiac dysfunction and remodelling of cardiac structure (Figure 6) as it has been described for the heart in diabetes.

Animals↗
PubMed1996

Reduction in nonparenchymal cell injury and vascular endothelial dysfunction after cold preservation of the liver by gaseous oxygen.

Reintroduction of oxygen to previously anoxic tissue may result in severe cell injury (oxygen paradox) and contribute to the so-called reperfusion damage of ischemic organs. Our study investigated the influence of simple gaseous oxygen supply during ischemia on nonparenchymal cell alterations upon reperfusion of the liver. Livers from male Wistar rats were isolated, rinsed blood-free and stored for 48 h at 4 degrees C in UW-preservation solution (group 1; n = 6). Gaseous oxygen was insufflated into a second group of livers (group 2; n = 6) during the storage period via the inferior caval vein at a pressure limited to 18 mmHg. To simulate the period of slow rewarming of the organ during surgical implantation in vivo, all livers were incubated at 25 degrees C in saline solution for 30 min prior to reperfusion. Reperfusion was carried out in vitro in a recirculating system with Krebs-Henseleit buffer. A control group was perfused immediately after harvest. The technique of aerobic storage (group 2) resulted in normal vascular perfusion characteristics without elevation of portal venous pressure (PVP) above control values, in contrast to group 1 livers which showed a significantly elevated PVP, averaging between 1.5 and 2 times the values of the control. Hepatic efflux of NO (nmol/ml) after 10 min of reperfusion was massively increased in group 1, while only low concentrations were found in group 2 and in control livers. Kupffer cell activation after ischemia was shown by a huge increase in acid phosphate release upon reperfusion compared with the control, with significantly lower values in group 2 after 10 min of reperfusion than in group 1. Thus, aerobic ischemia by gaseous oxygen persufflation seems an appropriate tool for long-term organ preservation, preventing vascular and parenchymal dysfunction upon reperfusion.

Alanine Transaminase↗