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PubMed1988

Lysolecithins as endothelium-dependent vascular smooth muscle relaxants that differ from endothelium-derived relaxing factor (nitric oxide)

The effects of lysolecithin (lysophosphatidylcholine) derived from egg yolk as well as of synthetic lysolecithins with different aliphatic chain lengths on tension development of rabbit aortic strips were investigated. Lysolecithins caused slowly progressing, dose-dependent relaxation that was inhibited by hemoglobin, methylene blue, and nordihydroguiaretic acid. Indomethacin caused no inhibition of relaxation. The degree of relaxation was endothelium-dependent and appeared to be related to the activation of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2]. Superoxide dismutase failed to influence relaxation. Lysolecithins with the longest aliphatic chain were the most potent relaxants of aortic strips. The experiments suggest a role of lysolecithins through their weak detergent action on membrane dynamics of endothelial cells, resulting in the production of cyclic GMP and the relaxation of arterial smooth muscle. Lysolecithins differ in several respects from endothelium-derived relaxing factor. Endothelium-derived relaxing factor is an unstable humoral substance released from endothelium and is identical to nitric oxide, itself a labile substance causing vascular relaxation and cyclic GMP accumulation. Lysolecithins may represent a different type of endothelium-dependent muscle relaxant.

Acetylcholine↗
PubMed2000

An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice.

In addition to nitric oxide (NO) and prostacyclin (PGI(2)), the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N(omega)-nitro-l-arginine methyl ester and diclofenac. In the saline-perfused hindlimb of WT and eNOS -/- mice, marked N(omega)-nitro-l-arginine (l-NA, 300 micromol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonist-induced vasodilation in the hindlimb of WT in the absence of l-NA. This endothelium-dependent, NO/PGI(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Gap junction inhibitors (18alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta(9)-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGI(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions.

Acetylcholine↗
PubMed1996

Possible existence of novel endothelium-derived relaxing factor in the endothelium of rat mesenteric arterial bed.

Both acetylcholine (ACh) and cyclopiazonic acid (CPA) caused vasodilation of the mesenteric arterial bed in a concentration-dependent manner. When the mesenteric arterial bed was perfused with 0.1% Triton X-100 for 30 s, ACh- or CPA-induced vasodilation was almost abolished. ACh-induced vasodilation was significantly attenuated in isotonic high K+ (60 mM) solution and significantly decreased by treatment with methylene blue (MB) with NG-nitro-L-arginine (L-NNA) in isotonic high K+ (60 mM) solution, whereas CPA-induced vasodilation of the mesentery was not affected by these treatments. ACh- or CPA-induced vasodilation was not affected by indomethacin. ACh caused significant increase in cyclic GMP levels and cyclic AMP in effluents from the perfused mesentery, whereas CPA could not increase cyclic GMP. CPA caused significant increase in cyclic AMP in a concentration-dependent manner, and CPA-induced increase in cyclic AMP was completely inhibited by removal of the endothelium. These results suggest that one or more endothelium-derived relaxing factor (EDRF) or factors should exist other than endothelium-derived nitric oxide (EDNO) or endothelium-derived hyperpolarizing factor (EDHF) in the endothelium of the rat mesenteric arterial bed. The novel EDRF may relax the mesenteric arterial bed through production of cyclic AMP but not cyclic GMP.

Acetylcholine↗
PubMed1999

Important role of endothelium-derived hyperpolarizing factor in shear stress--induced endothelium-dependent relaxations in the rat mesenteric artery.

Shear stress is one of the most important stimulators for the release of endothelium-derived relaxing factors. Although shear stress-induced release of nitric oxide (NO) has been extensively investigated, it remains to be elucidated whether endothelium-derived hyperpolarizing factor (EDHF) contributes to the endothelium-dependent relaxations to shear stress. This study was designed to address this point in the isolated rat mesenteric artery. Large mesenteric arteries (400-500 microm) and resistance mesenteric arteries (150-250 microm) of the rat were precontracted with phenylephrine (at 80 mm Hg of perfusion pressure), and the changes in vessel diameter in response to variable flow (0-300 microl/min) were continuously examined. The relative contributions of vasodilator prostaglandins, NO, and EDHF were analyzed by the inhibitory effects of indomethacin (10(-5) M), N(G)-nitro-L-arginine (L-NNA, 10(-4) M), and KCl (40 mM), respectively. The shear stress-induced relaxations were totally endothelium dependent in both-sized blood vessels, and the contribution of NO was more prominent in large arteries than in resistance arteries, whereas that of EDHF was noted in both-sized blood vessels. Tetrabutylammonium (a nonselective inhibitor of K channels) almost abolished, whereas the combination of charybdotoxin (an inhibitor of both large- and intermediate-conductance Ca2+ -activated K channels) and apamin (an inhibitor of small-conductance Ca2+ -activated K channels) significantly inhibited the EDHF-mediated component of the shear stress-induced relaxations. These results indicate that EDHF plays an important role in shear stress-induced endothelium-dependent relaxations, where K channels, especially calcium-activated K channels, appear to be involved.

Animals↗
PubMed2006

Effects of angiotensin II receptor antagonist on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats.

BACKGROUND: Diabetes mellitus is an important risk factor for cardiovascular diseases, and vasodilator dysfunction may contribute to vascular complications in diabetes. We previously demonstrated that the angiotensin II receptor blocker (ARB) corrected the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial hyperpolarization and relaxation associated with hypertension or aging, partially independently of blood pressure. OBJECTIVE: To test whether EDHF-mediated, as well as endothelium-independent, relaxations would be altered in arteries from type II diabetic Goto-Kakizaki rats, and whether ARB would correct these alterations. METHODS: Goto-Kakizaki rats were treated with either the ARB candesartan or a combination of hydralazine and hydrochlorothiazide for 8 weeks, beginning at 10 weeks of age. Membrane potentials and contractile responses were recorded from the isolated mesenteric arteries. RESULTS: The two treatments lowered blood pressure comparably. Acetylcholine-induced, EDHF-mediated hyperpolarization and relaxation in mesenteric arteries were markedly impaired in untreated Goto-Kakizaki rats compared with age-matched Wistar rats, and neither ARB nor the combination therapy improved these responses. On the other hand, relaxations to endothelium-derived nitric oxide, assessed in rings precontracted with high potassium solution, were similar among the four groups. Relaxation to the nitric oxide donor sodium nitroprusside and that to levcromakalim, an ATP-sensitive K-channel opener, were also impaired in untreated Goto-Kakizaki rats, and the response to sodium nitroprusside was partially improved in treated Goto-Kakizaki rats. CONCLUSIONS: These findings suggest that EDHF-mediated hyperpolarization and relaxation and endothelium-independent relaxations are both impaired in arteries of type II diabetic rats, and antihypertensive treatment with or without ARB partially corrects endothelium-independent relaxations to the nitric oxide donor but not EDHF-mediated responses.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1995

Effects of chronic treatment with carvedilol on abnormalities of endothelium-dependent relaxation and structure of endothelium in resistance arteries of SHRSP.

1. This study investigated the effects of chronic treatment with carvedilol, a beta-blocking agent with an alpha-blocking activity, on blood pressure, endothelium-dependent relaxation and the endothelial structure of the mesenteric resistance artery in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Chronic treatment with carvedilol at a dose range of 30-120 mg/kg per day lowered systolic blood pressure of SHRSP from 234.9 +/- 3.3 to 198.7 +/- 3.1 mmHg at 16 weeks of age. 3. Acetylcholine-induced endothelium-dependent relaxation was impaired in the mesenteric artery from SHRSP and high concentrations of acetylcholine produced contractions. The impairment of the relaxation was abolished in the presence of indomethacin. Carvedilol treatment improved the impairment in the preparation from SHRSP. The structural abnormality of endothelium was observed in the preparation from SHRSP. The abnormality could be prevented by the antihypertensive treatment. 4. These results suggest that the impairment of endothelium-dependent relaxation in the preparation from SHRSP is due to the corelease of an endothelium-derived contracting factor which is considered to be a product of cyclo-oxygenase pathway of arachidonic acid cascade and that the impairment can be prevented by the antihypertensive treatment with carvedilol.

Acetylcholine↗
PubMed2005

Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin-converting enzyme inhibitor on endothelium-derived hyperpolarizing factor-mediated responses in mice.

UNLABELLED: Background- We have recently identified that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H2O2 accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved. METHODS AND RESULTS: Control and eNOS-/- mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H2O2, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K(Ca) channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS-/- mice (n=6). CONCLUSIONS: These results indicate that endothelium-derived H2O2 accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H2O2 theory.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress.

BACKGROUND: Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans. METHODS AND RESULTS: We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% VO2max; moderate, 50% VO2max; and high, 75% VO2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-induced vasodilation (7.5+/-2.4 to 11.4+/-5.8 mL/min per 100 mL tissue; P<0.05). No intensity of aerobic exercise altered isosorbide dinitrate-induced vasodilation. The administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished the moderate-intensity exercise-induced augmentation of the forearm blood flow response to acetylcholine. High-intensity exercise increases plasma concentrations of 8-hydroxy-2'-deoxyguanosine (from 6.7+/-1.1 to 9.2+/-2.3 ng/mL; P<0.05) and serum concentrations of malondialdehyde-modified low-density lipoprotein (from 69.0+/-19.5 to 82.4+/-21.5 U/L; P<0.05), whereas moderate exercise tended to decrease both indices of oxidative stress. CONCLUSIONS: These findings suggest that moderate-intensity aerobic exercise augments endothelium-dependent vasodilation in humans through the increased production of nitric oxide and that high-intensity exercise possibly increases oxidative stress.

Acetylcholine↗
PubMed1992

Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and hyperpolarizing factors.

Studies were designed to investigate the mechanisms underlying the augmentation by angiotensin I converting enzyme (ACE) inhibitors of the endothelium-dependent relaxations evoked by bradykinin. Isometric tension, tissue levels of cGMP, and transmembrane potential were measured in isolated canine coronary arteries as indications of the respective contribution of nitric oxide and endothelium-derived hyperpolarizing factor. In rings of coronary artery with endothelium, relaxations to bradykinin were potentiated by the ACE inhibitors cilazaprilat and perindoprilat. NG-Nitro-L-arginine (NLA), a nitric oxide synthase inhibitor, impaired relaxations to bradykinin. But the presence of ACE inhibitors partially restored this activity. Bradykinin stimulated the production of cGMP, and this was enhanced significantly by ACE inhibitors, indicating an augmented release of nitric oxide. NLA abolished the increase induced by bradykinin irrespective of the presence of ACE inhibitors. Electrophysiological studies revealed that bradykinin elicited an endothelium-dependent hyperpolarization of vascular smooth muscle that was insensitive to NLA and potentiated by ACE inhibitors. The bradykinin-induced hyperpolarization and NLA-resistant relaxations were transient and impaired by potassium depolarization. Thus, production of endothelium-derived hyperpolarizing factor may account for the NLA-resistant relaxations of canine coronary arteries. The relaxations induced by bradykinin were unaffected by the B1 kinin receptor antagonist des-Arg9,[Leu8]-bradykinin either in the absence or in the presence of NLA but were antagonized by the B2 kinin receptor antagonist D-Arg[Hyp3,D-Phe7]-bradykinin. Molecular exclusion chromatography of 125I-labeled [Tyr8]-bradykinin and its degradation products demonstrated that the breakdown of the kinin by isolated coronary arteries was prevented in the presence of perindoprilat.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1990

Histamine elicits competing endothelium-dependent constriction and endothelium-independent dilation in vivo in mouse cerebral arterioles.

We used television microscopy and an image-splitting technique to monitor the changes in diameter produced by histamine applied locally to mouse pial arterioles in vivo. A high dose (50 micrograms/ml, 3 X 10(-4) M) of histamine constricted the arterioles, whereas lower doses (20 and 10 micrograms/ml) relaxed them. Constriction was blocked and dilation occurred when selective injury of the endothelium was produced by light from a helium-neon laser in the presence of intravascular Evans blue. From this we conclude that the constriction was endothelium-dependent and was caused by the release of an endothelium-derived constricting factor. Constriction was also blocked by each of two antagonists of the H1 histamine receptor and by pretreatment of the arterioles with indomethacin. H1 blockade unmasked a dilating action of 1 micrograms/ml histamine, a dose too low to affect the diameter of arterioles not treated with the H1 blocker. An H2 blocker interfered with the relaxation by low-dose (10 micrograms/ml, 6 X 10(-5) M) histamine. These data indicate that for mouse pial arterioles, histamine can interact with H1 receptors on the endothelium to release an endothelium-derived constricting factor that causes constriction of the underlying muscle while simultaneously interacting with H2 receptors in the muscle that mediate relaxation of the vessel.

Animals↗
PubMed1992

Endothelium-dependent inhibition of Na(+)-K+ ATPase activity in rabbit aorta by hyperglycemia. Possible role of endothelium-derived nitric oxide.

Hyperglycemia has been shown to diminish Na(+)-K+ ATPase activity in rabbit aorta. To examine the basis for this effect, aortic rings were incubated for 3 h in Krebs-Henseleit solution containing 5.5 or 44 mM glucose, and Na(+)-K+ ATPase activity was then quantified on the basis of ouabain-sensitive (OS) 86Rb-uptake. Incubation with 44 mM glucose medium caused a 60% decrease in Na(+)-K+ ATPase activity in rings with intact endothelium (from 0.22 +/- 0.01 to 0.091 +/- 0.006 nmol/min per mg dry wt; P less than 0.01). Similar decreases (45%; P less than 0.01) in Na(+)-K+ ATPase activity were seen when rings incubated with 5.5 mM glucose were exposed to NG-monomethyl L-arginine (300 microM), an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis or when the endothelium was removed (43% decrease). The decrease in Na(+)-K+ ATPase activity induced by hyperglycemia was totally reversed upon adding to the medium either L-arginine, a precursor of EDNO biosynthesis or sodium nitroprusside, which bypasses endothelium and directly activates the soluble guanylate cyclase in vascular smooth muscle. A decrease in Na(+)-K+ ATPase activity (42%; P less than 0.05), only seen in the presence of endothelium, was also observed in aortas taken directly from alloxan-induced diabetic rabbits. These studies suggest that the decrease in vascular Na(+)-K+ ATPase activity induced by hyperglycemia is related, at least in part, to a decrease in the basal release of EDNO. They also suggest that alterations in basal EDNO release and possibly Na(+)-K+ ATPase activity contribute to the impairment in vascular relaxation caused by hyperglycemia and diabetes.

Animals↗
PubMed1992

The endothelium-dependent and the endothelium-independent vasodilators in the isolated, perfused guinea pig heart.

The endothelium-dependent (acetylcholine, bradykinin, substance P) and the endothelium-independent (gliceryl trinirate, 3-morpholinsydnominine, sodium nitroprusside) vasodilators were studied in the Langendorff-perfused heart of the guinea pig. The involvement of prostanoids and EDRF in the endothelium-dependent responses were assessed by using indomethacin, an inhibitor of cyclooxygenase, and NG-nitro-L-Arginine, an inhibitor of NO synthase. The endothelium-independent agents were used as reference compounds. Both indomethacin and NG-nitro-L-Arginine elevated significantly baseline coronary perfusion pressure, indicating that prostanoids (most likely PGI2 and PGE2) and EDRF modulate the resting tone of the guinea pig coronary circulation. NG-nitro-L-Arginine, but not indomethacin, considerably reduced receptor-stimulated responses. It is concluded that acetylcholine, bradykinin or substance P-induced vasodilation is mediated by EDRF. In contrast, prostanoids do not contribute to endothelium-dependent responses. In addition, short-term tachyphylaxis to bolus injection of gliceryl trinitrate but not of sodium nitroprusside was demonstrated, suggesting that this preparation may be of value for studying nitrate tolerance.

Animals↗
PubMed1990

[Vascular endothelium (review). I. General morphology. 2A: histogenesis of the vascular endothelium].

Determination, differentiation, and specialization of vascular endothelium are the main steps of its histogenesis. The source of the first determined endothelioblasts are condensed mesenchymal cells (blood islands) at the yolk sac (extraembryonal) and also in the intraembryonal mesenchyme. The term of determination is not yet known. The marginal cells of the blood islands differentiate into primordial endothelial cells forming primitive vessels by migration, proliferation, fusion, and selection. This "vasculogenesis" is induced by specific matrix components produced by the endothelioblasts themselves and other not known factors. Formation of secondary capillary plexuses is related to organogenesis and takes place by sprouting from preexisting endothelium ("angiogenesis"). Factors which induce and promote angiogenesis were isolated from different embryonic organs. Migration, proliferation, and tube formation are regulated by extracellular matrix components (fibronectin, laminin). Main features of primordial endothelium of protocapillaries are: irregular profile, abundance of synthetic organelles, lack of plasmalemmal vesicles and basement membrane, production of specific matrix components. Specialized endothelium (continuous, fenestrated, discontinuous a.s.o.) develops from secondary plexuses influenced by factors of the specific organ tissue. The probably mechanism by which the endotheliocytes reach their final shape and behavior is discussed; some morphological and functional properties during maturation are documented. The maturation of endothelium is related to establishing of the specific blood-tissue barrier.

Animals↗
PubMed1995

The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18, and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium.

CD11/CD18 and VLA-4 integrins mediate interactions of monocytes with HUVEC cultured on human amniotic tissue. In the present study, the roles of individual CD11/CD18 integrins and endothelial adhesion molecules were examined using blocking mAbs and peptides. After 20 min of incubation, monocyte adhesion to and migration across unstimulated endothelium was dependent primarily on CD11a/CD18. When incubation was extended to 2 h to allow for completion of migration, either CD11a/CD18 or CD11b/CD18 could be used. Similarly, either CD11a/CD18 or CD11b/CD18 could be used by monocytes to bind to and traverse IL-1 beta-stimulated endothelium. Although both CD11a/CD18 and CD11b/CD18 are known to bind to ICAM-1, results of Ab-mixing experiments suggest that alternative ligands on HUVEC for CD11/CD18 integrins also may be used during transendothelial migration of monocytes. Our previous studies indicate that VLA-4 on monocytes interacts primarily with VCAM-1 on unstimulated endothelium. In contrast, migration of monocytes across IL-1 beta-stimulated endothelium was less dependent on VCAM-1. mAbs directed against binding sites for VLA-4 in domain 1 and domain 4 of VCAM-1 did not, by themselves, inhibit interactions of monocytes with stimulated HUVEC. VLA-4-dependent migration across IL-1 beta-stimulated endothelium was markedly inhibited only when mAbs to VCAM-1 were added in combination with peptides of fibronectin. Therefore, VLA-4 can interact with either VCAM-1 or alternative ligands on IL-1 beta-stimulated HUVEC-amnion cultures to mediate transendothelial migration of monocytes.

Amino Acid Sequence↗
PubMed1986

Effect of hypercholesterolemia on vascular reactivity in the rabbit. II. Influence of treatment with dipyridamole on endothelium-dependent and endothelium-independent responses in isolated aortas of control and hypercholesterolemic rabbits.

The effects of cholesterol-feeding in the presence of dipyridamole (0.60 g daily) on contractile responses and on endothelium-dependent and endothelium-independent relaxations in isolated rabbit aortas are described. The investigations were performed simultaneously with those described in Part I (Circ Res 1986; 58:552-564), where the effects of cholesterol feeding on vascular reactivity in rabbit arteries (n = 8 in each group) selected at random from the same group of animals was studied. In the hypercholesterolemic rabbits treated with dipyridamole for 8 or 16 weeks, both the increases in plasma cholesterol and the formation of fatty streaks were significantly less pronounced than in the hypercholesterolemic rabbits not receiving the drug. Segments of the isolated arteries were mounted in organ chambers for isometric tension recording. The contractions caused by acetylcholine, prostaglandin F2 alpha, norepinephrine, clonidine, and serotonin and the endothelium-independent relaxations to nitroglycerin were not significantly altered by the hypercholesterolemia in rabbits treated with dipyridamole, even after 16 weeks of treatment. Thus, the decreased responses to norepinephrine, clonidine, and nitroglycerin and the augmented responses to serotonin noted in aortas of hypercholesterolemic rabbits in Part I were absent in the dipyridamole-treated hypercholesterolemic animals. The endothelium-dependent relaxations to ATP and acetylcholine were not affected after 8 weeks of hypercholesterolemia in presence of dipyridamole, while after 16 weeks the relaxations to ATP and acetylcholine were attenuated only in the more severely affected arteries. The effects of hypercholesterolemia + dipyridamole on endothelium-dependent relaxations were significantly less pronounced than those induced by hypercholesterolemia alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Alteration of vascular endothelium and endothelium smooth muscle interaction after carbogen gas perfusion of isolated rat and guinea pig heart.

The aim of the study was to alter the vascular endothelium of the mammalian myocardium with respect to coronary flow regulation and vascular permeability. For this purpose, carbogen gas perfusion (GP) of Langendorff-type isolated rat and guinea pig heart was chosen. Perfusion of the hearts with carbogen gas was possible, as well as replacement of the GP by fluid perfusion. The energetic and mechanical state, the creatine kinase release, and the electron microscopic examination of the rat heart indicated only a moderate to minimal alteration of the cardiomyocytes after GP. As a result of GP a massive alteration of the vascular endothelium could be demonstrated in the rat heart, based on the release of the cytosolic endothelial marker enzyme, purine nucleoside phosphorylase, the partly altered vascular permeability and the morphologically detected endothelial damage to arterioles, capillaries and venules. Moreover, the reduced coronary flow response to short periods of anoxia (rat, guinea pig) and the inverted flow response to serotonin administration with maintained response to sodium nitroprusside (rat) in the post-gas perfusion period reflected an alteration of endothelial smooth muscular interaction in the rat and guinea pig heart. Furthermore, the distensibility of the coronary vasculature was increased in the rat and guinea pig heart in the post-gas perfusion period, where a relative autoregulatory behavior was maintained (rat) or partly maintained (guinea pig) in passively predilated vessels. In conclusion, carbogen gas perfusion of isolated hearts allows to induce preferred alteration of endothelium and endothelium-smooth muscle interaction.

Animals↗
PubMed2002

Endothelium-dependent and endothelium-independent skin vasoreactivity in the elderly.

BACKGROUND AND AIMS: It was demonstrated that endothelium-dependent vasoreactivity, an aspect of endothelial functioning, is impaired in coronary and brachial arteries, and in skeletal muscle resistance vessels of elderly people. However, little data is available about the influence of aging per se on the endothelial function of the skin microcirculation. The aim of the present study was to evaluate the endothelial function and intrinsic vasodilatory capacity of the skin microcirculation in elderly people with a low atherosclerosis risk profile. METHODS: Using laser Doppler flowmetry, we measured the cutaneous hyperemic responses following local iontophoresis delivery of an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, sodium nitroprusside (SNP), in 15 subjects older than 65 years and in 15 subjects younger than 50 years. Exclusion criteria were diabetes, hyperlipidemia, smoking, arterial hypertension and cardiovascular diseases. RESULTS: Skin maximal hyperemic responses induced both by ACh and by SNP delivery did not differ between the younger and the older groups. Cutaneous blood flow progressively increased in response to the 8 ACh delivery steps, both in the older and younger groups; however, the dose-response curve following ACh delivery was significantly lower in the former (p < 0.001). CONCLUSIONS: While these results should be viewed as preliminary due to the small sample size, they suggest that aging in itself is associated with a mild endothelium dysfunction in the skin microcirculation, whereas its overall vasodilatory capacity is preserved.

Acetylcholine↗
PubMed2000

Altered endothelium-dependent and -independent hyperpolarization and endothelium-dependent relaxation in carotid arteries isolated from streptozotocin-induced diabetic rats.

We examined endothelium-dependent and -independent hyperpolarizations and endothelium-dependent relaxation responses in carotid arteries isolated from streptozotocin-induced diabetic rats and age-matched controls. The resting membrane potentials were not significantly different between control and diabetic carotid arteries. The endothelium-dependent hyperpolarization induced by acetylcholine, which was inhibited by TEA but not by glibenclamide or by treatment with either a high concentration of glucose or pertussis toxin, was significantly weaker in diabetic arteries than in the controls. The relaxation responses to acetylcholine in carotid artery rings were significantly decreased in streptozotocin-diabetic rats. Treatment with NG-nitro-L-arginine (L-NOARG) inhibited the acetylcholine-induced maximal relaxation by 80% and 30% in control and streptozotocin-diabetic rats, respectively, and the simultaneous application of L-NOARG and indomethacin had a more potent inhibitory effect on this relaxation in both groups. The release of 6-keto-prostaglandin F1alpha and that of thromboxane A2 in response to methoxamine or methoxamine plus acetylcholine were both markedly decreased in diabetic rats. The cromakalim-induced hyperpolarization of the carotid artery, which was completely prevented by glibenclamide, was also significantly weaker in diabetic arteries than in the controls. These results suggest that changes in (1) various K+ channels on smooth muscle, (2) the biosynthesis of cyclooxygenase products and (3) endothelium-dependent relaxation may be important factors in the development of diabetic complications in the carotid artery.

6-Ketoprostaglandin F1 alpha↗