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At least 937 records · Page 52Linked to original sources
PubMed2006

Endothelium-dependent vasodilation of cerebral arteries is altered with simulated microgravity through nitric oxide synthase and EDHF mechanisms.

Cephalic elevations in arterial pressure associated with microgravity and prolonged bed rest alter cerebrovascular autoregulation in humans. Using the head-down tail-suspended (HDT) rat to chronically induce headward fluid shifts and elevate cerebral artery pressure, previous work has likewise shown cerebral perfusion to be diminished. The purpose of this study was to test the hypothesis that 2 wk of HDT reduces cerebral artery vasodilation. To test this hypothesis, dose-response relations for endothelium-dependent (2-methylthioadenosine triphosphate and bradykinin) and endothelium-independent (nitroprusside) vasodilation were determined in vitro in middle cerebral arteries (MCAs) from HDT and control rats. All in vitro measurements were done in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (10(-5) M) and cyclooxygenase inhibitor indomethacin (10(-5) M). MCA caveolin-1 protein content was measured by immunoblot analysis. Endothelium-dependent vasodilation to 2-methylthioadenosine triphosphate and bradykinin were both lower in MCAs from HDT rats. These lower vasodilator responses were abolished with N(G)-nitro-L-arginine methyl ester but were unaffected by indomethacin. In addition, HDT was associated with lower levels of MCA caveolin-1 protein. Endothelium-independent vasodilation was not altered by HDT. These results indicate that chronic cephalic fluid shifts diminish endothelium-dependent vasodilation through alterations in the endothelial nitric oxide synthase signaling mechanism. Such decrements in endothelium-dependent vasodilation of cerebral arteries could contribute to the elevations in cerebral vascular resistance and reductions in cerebral perfusion that occur after conditions of simulated microgravity in HDT rats.

Adenosine Triphosphate↗
PubMed1998

Regulation of the cerebral circulation: role of endothelium and potassium channels.

Several new concepts have emerged in relation to mechanisms that contribute to regulation of the cerebral circulation. This review focuses on some physiological mechanisms of cerebral vasodilatation and alteration of these mechanisms by disease states. One mechanism involves release of vasoactive factors by the endothelium that affect underlying vascular muscle. These factors include endothelium-derived relaxing factor (nitric oxide), prostacyclin, and endothelium-derived hyperpolarizing factor(s). The normal vasodilator influence of endothelium is impaired by some disease states. Under pathophysiological conditions, endothelium may produce potent contracting factors such as endothelin. Another major mechanism of regulation of cerebral vascular tone relates to potassium channels. Activation of potassium channels appears to mediate relaxation of cerebral vessels to diverse stimuli including receptor-mediated agonists, intracellular second messenger, and hypoxia. Endothelial- and potassium channel-based mechanisms are related because several endothelium-derived factors produce relaxation by activation of potassium channels. The influence of potassium channels may be altered by disease states including chronic hypertension, subarachnoid hemorrhage, and diabetes.

Aging↗
PubMedDate not supplied

Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats.

OBJECTIVE: The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors. METHODS: Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10(-9)-3 x 10(-5) M)- or sodium-nitroprusside (10(-9)-3 x 10(-4) M)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro-L-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin. RESULTS: Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (E(max)) to acetylcholine was decreased in the insulin resistance group (56 +/- 7%) versus control (93 +/- 3%). LNNA pretreatment further impaired E(max) in the IR group from 56 +/- 7 to 17 +/- 2% (p < 0.01). In control, E(max) was only slightly impaired by LNNA (93 +/- 3 to 63 +/- 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 +/- 3 to 47 +/- 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 +/- 5% with CTX/apamin vs. 56 +/- 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups. CONCLUSIONS: Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.

Acetylcholine↗
PubMed2005

Ultrastructural changes in endothelium during apoptosis indicate low microembolic potential.

BACKGROUND: Apoptotic endothelium has been suggested to have microthrombotic and microembolic potential. While some describe pro-coagulant activities and platelet binding, others demonstrate maintained fibrinolytic protein and anti-platelet aggregatory activity. Canalicular fragmentation is unique to apoptotic endothelium and is suggested to facilitate size reduction of apoptotic cells to reduce microembolic potential. Despite the potential importance of apoptotic microemboli, there are no reports characterizing changes in cell size and shape during endothelial apoptosis. METHODS: Here, we describe transmission and scanning electron microscopic studies of apoptotic endothelium and compare changes seen with apoptotic HL-60 cells incapable of canalicular fragmentation. RESULTS: We demonstrate reduced endothelial size (p<0.05) with progressive apoptosis relative to apoptotic HL-60 cells. Mechanical stress accelerated size reduction of apoptotic endothelium(P< 0.01) but did not affect the size of apoptotic HL-60 cells. Mechanical stress also increased circularity in apoptotic endothelium (p<0.01), suggested to facilitate passage through small vessels. Earlier work indicated that canaliculi form through plasma membrane invagination, but we report fusion of small vesicles contributing to canalicular growth, while canaliculi fuse to form large vacuoles and also dilate at late stages of apoptosis. CONCLUSIONS: These observations are consistent with the suggestion that endothelium is adapted to minimize microembolic potential and that canalicular fragmentation contributes to this.

Apoptosis↗
PubMed1989

Effect of endothelium on phenylephrine-induced contraction in the rat isolated aortic strips.

Phenylephrine tested on the isolated endothelium intact rat aortic strips elicited an enhanced response in the second assay when compared with the response obtained in the first trial. Removal of the endothelium and the pretreatment of the strips in the endothelium with methylene blue almost completely prevented the enhanced response to phenylephrine in the second assay. Pretreatment of the strips with lysine acetyl salicylate failed to abolish the potentiated response to phenylephrine in the second test. These data were taken as an evidence that the basal production or release of endothelium-derived relaxing factor(s) but not cyclooxygenase products of arachidonic acid from the endothelium of the rat aorta can influence the contractile effect of phenylephrine and the enhanced response to this alpha-adrenoceptor agonist in the second assay is probably due to the recuded production or release of these endogenously occurring endothelium-originated substance(s).

Animals↗
PubMed1990

Endothelium-dependent effects of beta-adrenergic blockers.

Nonselective beta-adrenergic blockers have been reported to affect endothelium-dependent responses in isolated blood vessels in the following ways: (a) cause endothelium-augmented direct relaxations; (b) facilitate the endothelium-dependent relaxations evoked by alpha 2-adrenergic activation, or by acetylcholine; (c) augment the intraluminal release of vasodilator prostanoids, and (d) inhibit endothelium-dependent contractions to anoxia. Important species differences exist in terms of the endothelium-dependent effects of the compounds. If they were to occur in the intact organism, the endothelium-dependent effects of the beta-adrenergic blockers could help to explain their vasodilator properties.

Adrenergic beta-Antagonists↗
PubMed1997

Endothelium and high blood pressure.

Due to its strategic anatomical position, the endothelium is constantly exposed to the different risk factors for atherosclerosis. During the last decade it has become clear that hypertension profoundly affects endothelial function. Depending on the form of hypertension, endothelium-dependent relaxation is impaired in most vascular beds. In spontaneous hypertension, the production of nitric oxide, which in endothelial cells is formed from L-arginine via the constitutively expressed enzyme endothelial nitric oxide synthase, represents the main mediator of endothelium-dependent vasodilation and seems to be enhanced. On the other hand, the release of endothelium-dependent contracting factors such as prostaglandin H2 and thromboxane A2 have been demonstrated in this model of hypertension. Similar results have been obtained in the forearm circulation of patients with essential hypertension. In contrast, in models of salt-sensitive hypertension no release of vasoconstrictor prostanoids can be found indicating a decreased production of nitric oxide. Thus, in spontaneous hypertension an increased production of nitric oxide seems to occur, which is ineffective due to either the simultaneous release of endothelium-dependent vasoconstrictors and/or inactivation of nitric oxide, or due to anatomical changes such as hypertension-induced intimal thickness which inhibits its action on vascular smooth muscle cells. In summary, in hypertension, endothelium-dependent vasodilation is blunted and the endothelial L-arginine nitric oxide pathway is altered. These changes seem to represent a consequence rather than a cause of hypertension.

Animals↗
PubMed2002

Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules.

OBJECTIVE: The stimulatory effect of homocysteine (Hcy) on monocyte chemoattractant protein (MCP)-1 expression in vitro has been suggested to play an important role in Hcy-mediated atherosclerosis. We investigated whether such a stimulatory effect occurs in vivo, leading to monocyte adhesion to the endothelium. METHODS AND RESULTS: Sprague-Dawley rats were divided into 4 groups. Hyperhomocysteinemia was induced in 1 group of rats after 4 weeks of a high-methionine diet (serum Hcy levels were 4- to 5-fold higher than levels in control rats). The number of ED-1-positive cells present on the surface of aortic endothelium was significantly elevated in hyperhomocysteinemic rats. There was a significant increase in the expression of MCP-1, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in the endothelium. Antibodies recognizing MCP-1, VCAM-1, or E-selectin could abolish the enhanced monocyte binding to the aortic endothelium of hyperhomocysteinemic rats. Endothelium-dependent aortic relaxation was impaired in hyperhomocysteinemic rats. CONCLUSIONS: These results suggest that in the absence of other known risk factors, hyperhomocysteinemia stimulates the expression of MCP-1, VCAM-1, and E-selectin in vivo, leading to increased monocyte adhesion to the aortic endothelium. Such an effect may contribute significantly to the development of atherosclerosis by facilitating monocyte/macrophage infiltration into the arterial wall.

Animals↗
PubMed2003

Glargine and regular human insulin similarly acutely enhance endothelium-dependent vasodilatation in normal subjects.

OBJECTIVE: Human insulin enhances the vasodilatory effect of acetylcholine (ACh), an endothelium-dependent vasodilator, in normal subjects. Structural changes in a long-acting insulin analog, insulin glargine, may change its binding properties to insulin receptor and structurally homologous receptors, such as the insulin-like growth factor-1 receptor, and thereby alter its vascular effects. In the present study, we compared effects of glargine and regular human insulin on blood flow responses to endothelium-dependent and endothelium-independent vasoactive agents in vivo in normal subjects. METHODS AND RESULTS: Ten healthy men (age: 33+/-9 years [mean+/-SD]; BMI: 23+/-2 kg/m2) were studied on two separate occasions in a double-blind, randomized, crossover fashion. In each study, blood flow responses to intrabrachial artery infusions of ACh and SNP were determined during infusion of saline and intravenously maintained normoglycemic hyperinsulinemia. Hyperinsulinemia (120 minutes; infusion rate: 1 mU/kg per minute) was created by infusing either insulin glargine or human regular insulin. Glargine and human regular insulin similarly stimulated whole-body glucose metabolism and suppressed serum free-fatty acid (FFA) concentrations. Endothelium-independent blood flow responses to low (3 microg/min) and high (10 microg/min) doses of SNP were unaffected by insulin glargine (12.2+/-2.6 versus 13.4+/-4.6 and 19.1+/-4.2 versus 19.6+/-5.1 mL/dL per minute, saline versus insulin, low- and high-dose) and regular human insulin (11.2+/-3.4 versus 12.0+/-5.2 and 16.8+/-5.7 versus 18.4+/-7.7 mL/dL per minute, respectively). In contrast, endothelium-dependent blood flow responses to low (7.5 microg/min) and high (15 microg/min) doses of ACh increased significantly and similarly by insulin glargine, 13.9+/-4.8 versus 19.3+/-6.5 mL/dL per minute (saline versus insulin, +39%, P<0.01) for low-dose ACh and 17.3+/-6.3 versus 23.2+/-9.2 mL/dL per minute (+34%; P<0.02) for high-dose ACh, and regular human insulin, 11.5+/-6.0 versus 15.8+/-8.0 mL/dL per minute (+38%; P<0.05) and 14.0+/-7.5 versus 21.1+/-10.4 mL/dL per minute (+51%; P<0.01). CONCLUSIONS: Insulin glargine and regular human insulin have similar acute stimulatory effects on endothelium-dependent vasodilation in humans.

Acetylcholine↗
PubMed2006

12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-kappaB.

OBJECTIVE: 12/15 lipoxygenase (12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte:endothelial interactions in vivo in apolipoprotein E-deficient mice (apoEKO), a well-characterized mouse model of atherosclerosis. METHODS AND RESULTS: In apoEKO mice that are also deficient in 12/15LO (doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC (Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-kappaB. DoubleKO aorta displayed little nuclear localization of NF-kappaB. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKCalpha significantly reduced NF-kappaB activation, ICAM-1 induction, and monocyte adhesion to aorta. CONCLUSIONS: We conclude that 12/15LO products activate endothelial rhoA and PKCalpha. Activation of rhoA and PKCalpha cause activation and translocation of NF-kappaB to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice.

Animals↗
PubMed1994

Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation.

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.

Animals↗
PubMed1999

A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation.

BACKGROUND: The aim of the study was to determine whether a positive family history of coronary artery disease is related to impaired coronary blood flow regulation. METHODS AND RESULTS: In 150 patients with angiographically normal or minimally diseased coronary vessels, risk factors for coronary artery disease, the extent of atherosclerosis and endothelium-dependent vasomotor responses to acetylcholine, and endothelium-independent blood flow regulation by papaverine or adenosine were assessed. Coronary blood flow responses to acetylcholine were reduced in a dose-dependent manner in patients with a positive family history (P=0.030). By multivariate analysis, hypercholesterolemia (P=0.001), age (P=0.002), and a positive family history (P=0.008) remained predictors of coronary blood flow increase to acetylcholine. The extent of atherosclerotic coronary artery disease was, by multivariate analysis, an additional independent predictor of acetylcholine-induced blood flow (P=0.014), but also of endothelium-independent blood flow regulation (P=0.001). A positive family history had additive effects in addition to the other risk factors, such as hypercholesterolemia or increased age. Angiotensin-converting-enzyme genotype polymorphism had no influence either on endothelium-dependent or endothelium-independent coronary blood flow responses. However, in a subset of 28 patients, homocysteine (which is, in part, genetically determined) was inversely related to maximal acetylcholine-induced blood flow regulation (r=-0.47, P=0.012). CONCLUSIONS: The results of this study demonstrate, for the first time, that a positive family history of coronary artery disease is an important predictor of impaired endothelium-dependent coronary blood flow regulation in humans. The influence of a positive family history is independent of other well known risk factors but instead aggravates endothelial vasodilator dysfunction associated with hypercholesterolemia and increased age, suggesting important interacting effects between genetic and environmental risk factors.

Adult↗
PubMed1990

Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries.

Experiments were designed and performed to determine whether endothelial function remained chronically impaired after coronary artery reperfusion. Canine left anterior descending coronary arteries were exposed to ischemia (60 minutes) followed by reperfusion (12 weeks). Rings (3-4 mm wide) of the reperfused artery and of normal left circumflex (control) coronary artery segments were suspended in organ chambers containing physiological saline solution (37 degrees C, gassed with 95% O2-5% CO2) for isometric force measurement. Endothelium-independent contractions to KCl or prostaglandin F2 alpha and endothelium-independent relaxations to nitric oxide or isoproterenol were comparable in control and chronically reperfused arteries. However, chronically reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to aggregating platelets. In addition, the reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to the platelet-derived compounds adenosine diphosphate, serotonin, and thrombin. However, the endothelium-dependent relaxations to acetylcholine were comparable between control and reperfused arteries. Thus, after 12 weeks of reperfusion, previously occluded coronary arteries exhibited a selective impairment of endothelium-dependent relaxation evoked by aggregating platelets. In vivo, this phenomenon could favor platelet adhesion, aggregation, and platelet-induced contraction of coronary smooth muscle and thus facilitate ischemic events such as vasospasm and coronary thrombosis.

Adenosine Diphosphate↗
PubMed1991

Endothelium-dependent responses in long-term human coronary artery bypass grafts.

In the present study, responses of long-term human coronary artery bypass grafts (CABGs) to known endothelium-dependent vasodilators, acetylcholine, calcium ionophore A23187, thrombin, and histamine, as well as authentic nitric oxide, the putative endothelium-derived relaxing factor, were studied. Sixteen CAGBs were isolated within 1-2 hours from hearts of 14 patients receiving a cardiac transplant. A total of 109 ring segments were prepared from these CABGs and studied in vitro. The duration of the CABGs ranged from 7 months to 12 years. Addition of acetylcholine (0.01-10 microM), calcium ionophore A23187 (0.01-1.0 microM), thrombin (0.01-1.0 unit/ml), and histamine (0.01-1.0 microM) consistently produced a dose- and endothelium-dependent relaxation, reaching a maximum of -35.3 +/- 3.3%, -45.3 +/- 5.5%, -26.9 +/- 4.8%, and -17.8 +/- 2.5% (mean +/- SEM), respectively. No significant difference was observed among the CABGs with different duration of transplantation, whereas the relaxant responses of different segments along the entire length of a CABG were markedly different. These latter differences in the endothelium-dependent responses appear to correlate inversely with the development of intimal proliferative lesions in these CABGs. Addition of nitric oxide (0.01-10 microM) produced a potent dose- and endothelium-independent relaxation, which was also slightly depressed in CABGs with severe intimal proliferation. These results demonstrate that long-term transplanted human saphenous vein grafts retain their endothelium-dependent responses and that development of severe intimal proliferative lesions, rather than the duration of the grafts, result in marked alterations in the reactivity of these transplanted CABGs.

Coronary Artery Bypass↗
PubMed1993

Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels.

BACKGROUND: Patients with hypertension and myocardial hypertrophy may have signs and symptoms of myocardial ischemia in the absence of obstructive coronary disease. Prior investigations have demonstrated impaired coronary flow reserve and have led to speculation that microvascular dysfunction might contribute to ischemia in these patients. Experimental studies have shown that the endothelium, an important regulator of microvascular tone, can be damaged by hypertension and is dysfunctional in cardiomyopathy. We hypothesized that endothelium-dependent vasodilation is impaired in the coronary microvasculature of patients with hypertension and ventricular hypertrophy. METHODS AND RESULTS: We studied coronary microvascular responses in 10 patients with left ventricular hypertrophy secondary to essential hypertension (HTN) (mean arterial pressure at catheterization, 151/94 mm Hg; mean posterior wall thickness, 1.4 +/- 0.1 cm) and nine normal control subjects with no history of hypertension (mean arterial pressure at catheterization, 128/75 mm Hg; mean posterior wall thickness, 1.0 +/- 0.02 cm) using the intracoronary Doppler catheter and quantitative angiography to assess changes in coronary blood flow (CBF). All patients had normal left ventricular systolic function. To assess microvascular endothelial function, we infused the endothelium-dependent vasodilator acetylcholine (10(-8)-10(-6) M) and the endothelium-independent vasodilator adenosine (10(-6)-10(-4) M) into the left anterior descending coronary artery. In response to acetylcholine, CBF increased only 32 +/- 25% in HTN patients, whereas CBF increased 192 +/- 39% in normal control subjects (p = 0.003). CBF increased 465 +/- 93% in HTN patients and 439 +/- 41% in normal control subjects in response to adenosine (p = NS). The proportion of coronary flow reserve attributable to endothelium-dependent dilation (obtained from peak acetylcholine/peak adenosine flow response) was 48 +/- 9% in normal control subjects but only 7 +/- 8% in HTN patients (p = 0.008). CONCLUSIONS: Endothelium-dependent vasodilation is markedly impaired in the coronary microvessels of patients with hypertension and ventricular hypertrophy. Loss of this vasodilator mechanism may contribute to disordered coronary flow regulation and the ischemic manifestations of hypertensive heart disease.

Acetylcholine↗
PubMed1993

Interference of glycosylated human hemoglobin with endothelium-dependent responses.

BACKGROUND: Hypertension and other vascular diseases are more prevalent in diabetic patients than in the general population. In humans and in several animal models of diabetes, a disturbance of endothelium-dependent responses has been shown. Oxyhemoglobin is one of the most known modulators of these endothelium-dependent responses. We postulate that high levels of plasmatic glycosylated hemoglobin, a frequent profile in diabetic patients, may be the cause of the disturbance in endothelium-dependent relaxation and/or contraction. METHODS AND RESULTS: Endothelium-dependent responses to acetylcholine and several alpha-adrenergic agonists (norepinephrine, methoxamine, and clonidine) were tested in segments of rat aorta. Experiments were carried out in control segments and in those preincubated with several concentrations of nonglycosylated, low-glycosylated (7.3%), and high-glycosylated (14%) human hemoglobin. Low concentrations of high-glycosylated human hemoglobin (1 to 100 nmol/L) but not of low- or nonglycosylated hemoglobin, inhibited endothelium-dependent relaxation caused by acetylcholine in intact vessels. The same effect was observed on relaxations caused by nitric oxide in denuded ones. High-glycosylated human hemoglobin (10 nmol/L) induced an increase in norepinephrine-evoked contraction in intact vessels; this latter effect was also shown in vessels contracted with methoxamine but not with clonidine. De-endothelialization of the vascular segments blunted these effects of high-glycosylated human hemoglobin. CONCLUSIONS: High glycosylation of human hemoglobin impairs endothelium-mediated vasoactive responses and may play a pathophysiological role in producing hypertension and vascular diseases in diabetic patients.

Acetylcholine↗
PubMed1995

Circadian variation in coronary tone in patients with stable angina. Protective role of the endothelium.

BACKGROUND: Coronary endothelium plays a key role in the regulation of coronary tone, platelet adhesion, and aggregation, which are important factors in triggering acute cardiovascular events. However, its role in modulating the effects of circadian variations on coronary tone is not known. METHODS AND RESULTS: Responses of 72 nonstenotic coronary segments to acetylcholine and nitroglycerin were measured in 12 patients with chronic stable angina at 6 AM and 1 PM. After baseline angiography, three infusions of acetylcholine (10(-6), 10(-5), and 10(-4) mol/L) were administered selectively into the left coronary artery, followed by nitroglycerin. Diameters (in millimeters) of proximal, middle, and distal segments were measured by quantitative techniques. Forty-seven segments showed a constrictor response to acetylcholine (group 1, dysfunctional endothelium), and 25 other segments showed a dilator response (group 2, normally functioning endothelium). In group 1, the constrictor response to acetylcholine was significantly greater in the morning than in the afternoon (23 +/- 3% and 10 +/- 1%, mean +/- SEM, respectively; P < .001), and the dilator response to nitroglycerin was also significantly greater in the morning than in the afternoon (19 +/- 2% and 11 +/- 2%; P < .01). In group 2, the dilator response to acetylcholine did not differ significantly between the morning and afternoon (22 +/- 3% and 17 +/- 2%, respectively; P = NS), and the dilator response to nitroglycerin was also similar at both times of the day (30 +/- 3% and 28 +/- 4%, respectively; P = NS). CONCLUSIONS: Coronary segments with dysfunctional endothelium exhibit an early morning exaggeration in vasomotor activity, whereas segments with normally functioning endothelium do not show circadian variations. This suggests a potential protective role for the endothelium in modulating variations in coronary tone that may contribute to increased incidence of cardiovascular events in the early morning hours.

Acetylcholine↗
PubMed1995

Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a). Role of oxygen-derived radicals.

BACKGROUND: Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)-mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro. METHODS AND RESULTS: Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 micrograms/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 micrograms/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced dilator responses were unaffected, indicating that smooth muscle dilator capacity was not impaired. Attenuation of dilator responses by oxidized lipoprotein(a) was potentiated in the presence of superoxide dismutase (SOD). The SOD effect was completely blunted by coincubation with catalase (100 U/mL) or deferoxamine. In the absence of SOD, catalase or deferoxamine had no effect on dilator responses. Using a chemiluminescence assay, we could detect increased O2- production by arteries pretreated with oxidized lipoprotein(a), which suggested that enhanced NO inactivation by O2- could be the underlying mechanism for impairment of endothelium-dependent dilations. CONCLUSIONS: These data indicate that oxidized lipoprotein(a) impairs endothelium-dependent dilation and is more potent than oxidized LDL in this effect. The mechanism of the impairment may involve formation of O2- and inactivation of NO.

Animals↗