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PubMed1992

Endothelium-dependent and -independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery.

1. The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline-precontracted endothelium-intact and endothelium-denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5'-triphosphate (ATP) and adenosine. 2. GTP (10 microM-1 mM) dose-dependently relaxed endothelium-intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed endothelium-denuded artery rings. The acetylcholine- and GTP-induced relaxations of endothelium-intact rings were attenuated by NG-nitro L-arginine methyl ester (L-NAME, 330 microM) which attenuation was reversed with L-arginine (1 mM). 3. Guanosine (10 microM-1 mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The relaxations were more pronounced in endothelium-intact preparations and were only slightly attenuated by L-NAME (330 microM). 4. ATP (1 microM-1 mM) and adenosine (10 microM-1 mM) dose-dependently relaxed endothelium-intact and -denuded artery rings. The responses were more pronounced in endothelium-intact vascular preparations. 5. GTP (100 microM) and guanosine (100 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in both endothelium-intact and -denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were not affected. 6. ATP (100 microM) increased cyclic GMP concentration of endothelium-intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 microM) and adenosine (100 microM) in endothelium-intact and -denuded vascular preparations.7. These results provide evidence that exogenous GTP and guanosine relax precontracted endothelium-intact and -denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of endothelium-intact rings can mainly be explained by the release of endothelium-derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of endothelium-dependent and -independent effects. The endothelium-independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.

Acetylcholine↗
PubMed1995

Effect of the vascular endothelium on noradrenaline-induced contractions in non-pregnant and pregnant guinea-pig uterine arteries.

1. The effect of pregnancy on noradrenaline-mediated contraction of guinea-pig uterine artery rings with both intact and denuded endothelium was investigated. 2. Noradrenaline (25 nM-100 microM) induced concentration-dependent contraction of non-pregnant and pregnant guinea-pig uterine arterial rings with intact endothelium with similar pD2 and maximal response values (non-pregnant: pD2 = 5.85 +/- 0.02, maximal response = 121 +/- 8.2%; pregnant: pD2 = 5.81 +/- 0.04, maximal response = 122 +/- 9.1%). Removal of endothelium did not affect noradrenaline-induced contractions in non-pregnant guinea-pig uterine artery (pD2 = 5.97 +/- 0.02, maximal response = 119 +/- 8.6%). In contrast, in arteries from pregnant guinea-pigs, removal of endothelium shifted concentration-response curve for noradrenaline to the left, without affecting maximal response value (pD2 = 6.36 +/- 0.03, maximal response = 120 +/- 9.0%). 3. The pKA values for noradrenaline were: 5.76 +/- 0.09 and 5.82 +/- 0.10 for non-pregnant guinea-pig uterine artery with intact and denuded endothelium, respectively and 5.74 +/- 0.09 and 5.72 +/- 0.07 for pregnant guinea-pig uterine artery with intact and denuded endothelium, respectively. 4. The receptor occupancy-response relationship for noradrenaline was linear for all types of vessels, except for pregnant guinea-pig uterine artery with denuded endothelium, since half-maximal response to noradrenaline was obtained with 44.8 +/- 6.9% (non-pregnant guinea-pig uterine artery with intact endothelium), 43.3 +/- 6.1% (non-pregnant guinea-pig uterine artery with denuded endothelium) and 44.3 +/- 6.3% (pregnant guinea-pig uterine artery with intact endothelium) receptor occupancy. In pregnant guinea-pig uterine artery with denuded endothelium, occupancy-response relationship for noradrenaline was non-linear since half-maximal response to noradrenaline was obtained with 19.7 +/- 3.3% receptor occupancy. 5. NG-monomethyl-L-arginine (100 microM) and indomethacin (10 microM) did not affect concentration-response curve for noradrenaline in guinea-pig uterine arteries, regardless of pregnancy status or endothelial condition. 6. In quiescent preparations, the alpha-adrenoceptor antagonists, prazosin (5-50 nM) and yohimbine (1-10 microM) produced parallel rightward shifts of the curves for noradrenaline and the slopes of the Schild plots were not significantly different from unity. The plots constrained to a slope of unity gave the following - log Kb values: prazosin vs. yohimbine 8.78 +/- 0.03 vs. 6.41 +/- 0.02 for non-pregnant guinea pig uterine artery with intact endothelium, 8.95 +/- 0.03 vs. 6.34 +/- 0.02 for non-pregnant guinea-pig uterine artery with denuded endothelium, 8.91 +/- 0.01 vs. 6.44 +/- 0.03 for pregnant guinea-pig uterine artery with intact endothelium and 9.07 +/- 0.01 vs. 6.52 +/- 0.03 for pregnant guinea-pig uterine artery with denuded endothelium.7. It is concluded that initially there is no difference in noradrenaline action between uterine arteries from non-pregnant and pregnant guinea-pigs, but after removal of the endothelium the pregnant guinea-pig uterine artery is more sensitive to noradrenaline, which is related to increased receptor reserve for noradrenaline in this tissue. It is probable that relaxing factor derived from the endothelium mediates this effect, but it is unlikely to be nitric oxide or prostacyclin. Antagonist affinities and affinity of noradrenaline itself suggests that an identical subtype of alpha-adrenoceptor, probably the alpha 1 subtype, is involved in the noradrenaline-induced contraction of non-pregnant and pregnant guinea-pig uterine artery with or without endothelium.

Animals↗
PubMed1994

Endocardial endothelium in the rat: junctional organization and permeability.

Selective permeability of endocardial endothelium has been suggested as a mechanism underlying the modulation of the performance of subjacent myocardium. In this study, we characterized the organization and permeability of junctional complexes in ventricular endocardial endothelium in rat heart. The length of intercellular clefts viewed en face per unit endothelial cell surface area was lower, and intercellular clefts were deeper in endocardial endothelium than in myocardial vascular endothelium, whereas tight junctions had a similar structure in both endothelia. On this basis, endocardial endothelium might be less permeable than capillary endothelium. However, confocal scanning laser microscopy showed that intravenously injected dextran 10,000 coupled to Lucifer Yellow penetrated first the endocardial endothelium and later the myocardial capillary endothelium. Penetration of dextran 10,000 in myocardium occurred earlier through subepicardial capillary endothelium than through subendocardial capillary endothelium. Penetration of tracer might thus be influenced by hydrostatic pressure. Dextran of MW 40,000 did not diffuse through either endocardial endothelium or capillary endothelium. The ultrastructure of endocardial endothelium may constitute an adaptation to limit diffusion driven by high hydrostatic pressure in the heart. Differences in paracellular diffusion of dextran 10,000, between endocardial endothelium and myocardial vessels, may result from differing permeability properties of the endocardium and underlying myocardium.

Animals↗
PubMed1992

Removal of venous endothelium with air.

Much research on the activity and half-life of endothelium-derived substances has entailed the removal of endothelium from arteries by mechanical or enzymatic processes. It has been observed that the technique used for the removal of arterial endothelium may profoundly affect smooth muscle function and release of prostanoids by the vessel wall. The function and patterns of regeneration of arterial endothelium have been extensively described, but there is a relative paucity of information about the venous endothelium, due in part to the difficulty of its removal. We developed a technique for removal of the endothelium of rabbit femoral veins by passing a stream of air through the lumen of the vessel to dry and remove the endothelium. The effectiveness of endothelium removal was verified by the lack of in vitro reactivity to endothelium-dependent relaxing substances, examination of frozen sections of vessels, labeled with fluorescent-tagged acetylated low-density lipoprotein, with fluorescent light microscopy and scanning electron microscopy of vessel segments. Air drying effectively removed the endothelium and abolished mechanical responses to endothelium-dependent vasodilators but did not affect the function of the smooth muscle. We propose the use of air to remove endothelium from veins to be used to study endothelium-derived factors since this method achieves complete removal of endothelium without causing detectable damage (morphological or functional) to the remainder of the vessel wall.

Air↗
PubMed1987

Reactivity of aorta and mesenteric microvessels to drugs in spontaneously hypertensive rats: role of the endothelium.

The response to vasoactive agents of microvessels in situ and aortae in vitro was studied in normal and spontaneously hypertensive rats (SHR). Noradrenaline (NA) was equally effective in evoking a constrictor response of mesenteric microvessels in normal rats and SHR. The vasodilator response to acetylcholine (ACH), as endothelium-dependent relaxing agent, was lower in SHR microvessels whereas isoproterenol, papaverine, agents which are partially dependent on endothelium, and sodium nitroprusside, an endothelium-independent vasodilator, induced similar responses in control rats and SHR. Median effective concentrations and maximal responses to NA obtained in isolated SHR aortae, with or without endothelium, were similar to those obtained in their respective controls. NA-precontracted aortae with intact endothelium were less responsive to ACH in SHR than in controls. The relaxant response of the preparations was lost after endothelial cell removal in both groups. Sodium nitroprusside evoked similar relaxing effect in SHR and control NA-precontracted aortae. Isoproterenol-induced responses were potentiated in SHR-precontracted aortae, with or without endothelium. Removal of the endothelium diminished isoproterenol-induced relaxation, both in controls and SHR. With submaximal concentration of papaverine there was no difference between SHR aortae with or without endothelium and control aortae with endothelium. Control aortae without endothelium relaxed less than control aortae with endothelium and SHR aortae with or without endothelium. The rate of relaxation after papaverine was altered in aortae without endothelium isolated from SHR or control rats. These results indicate that the endothelium of SHR is altered. This could explain its decreased response to ACH. It is suggested that smooth muscle cells develop a compensatory mechanism that increases the response of agents that mobilize cAMP, such as papaverine and isoproterenol.

Acetylcholine↗
PubMed1990

Serotonin and the endothelium.

Serotonin has many and opposing effects in the cardiovascular system. The vascular endothelium importantly contributes as a modulator and mediator of the cardiovascular effects of serotonin. Endothelial cells contain the enzyme monoaminooxidase which inactivates serotonin. In addition, endothelial cells are a source of vasodilator substances such as endothelium-derived relaxing factor, the endogenous nitrovasodilator. Nitric oxide is continuously formed by the arterial endothelium to inhibit the effects of vasoconstrictor substances such as serotonin. Accordingly, removal of the endothelium enhances contractions induced by serotonin in most vascular preparations. In certain blood vessels, such as the porcine and canine coronary artery, serotonin stimulates the release of endothelium-derived nitric oxide. Endothelium-dependent relaxations to serotonin also occur in intramyocardial porcine coronary resistance arteries. In contrast to porcine and canine arteries, endothelium-dependent relaxations to serotonin have not been demonstrated in the human coronary and internal mammary artery. In the porcine coronary artery with regenerated endothelium and in that with atherosclerotic changes, the endothelium facilitates contractions to serotonin, suggesting that an endothelium-derived contracting factor is released. Since indomethacin prevents this endothelium-dependent facilitation of contractions to serotonin in atherosclerotic porcine coronary arteries, a cyclooxygenase product is likely involved. Similarly, in the aorta of spontaneously hypertensive rats, the endothelium facilitates the contractions to serotonin. Thus, the endothelium can importantly modulate the response to serotonin. While in normal arteries, the cells inhibit the vasoconstrictor effects of the monoamine, the endothelium facilitates its contractions in atherosclerotic and hypertensive blood vessels.

Animals↗
PubMed1997

Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta.

1. The aim of this work was to investigate the mechanism of vasorelaxation induced by red wine polyphenolic compounds (RWPC) and two defined polyphenols contained in wine, leucocyanidol and catechin. The role of the endothelium, especially endothelium-derived nitric oxide (NO), was also investigated. 2. Relaxation produced by polyphenols was studied in rat aortic rings with and without functional endothelium, pre-contracted to the same extent with noradrenaline (0.3 and 0.1 microM, respectively). RWPC and leucocyanidol, but not catechin, produced complete relaxation of vessels with and without endothelium. However, 1000 fold higher concentrations were needed to relax endothelium-denuded rings compared to those with functional endothelium. 3. High concentrations of catechin (in the range of 10(-1) gl-1) only produced partial relaxation (maximum 30%) and had the same potency in rings with and without endothelium. 4. The NO synthase inhibitor, N omega-nitro-L-arginine-methyl-ester (L-NAME, 300 microM) completely abolished the endothelium-dependent but not the endothelium-independent relaxations produced by all of the polyphenolic compounds. 5. In contrast to superoxide dismutase (SOD, 100 u ml-1), neither RWPC nor leucocyanidol affected the concentration-response curve for the NO donor, SIN-1 (3-morpholino-sydnonimine) which also produces superoxide anion (O2-). 6. In aortic rings with endothelium, RWPC (10(-2) gl-1) produced, a 7 fold increase in the basal production of guanosine 3':5'-cyclic monophosphate (cyclic GMP) which was prevented by L-NAME (300 microM). 7. Electron paramagnetic resonance (e.p.r.) spectroscopy studies with Fe(2+)-diethyldithiocarbamate as an NO spin trap demonstrated that RWPC and leucocyanidol increased NO levels in rat thoracic aorta about 2 fold. This NO production was entirely dependent on the presence of the endothelium and was abolished by L-NAME (300 microM). 8. These results show that RWPC and leucocyanidol, but not the structurally closely related polyphenol catechin, induced endothelium-dependent relaxation in the rat aorta. They indicate that this effect results from enhanced synthesis of NO rather than enhanced biological activity of NO or protection against breakdown by O2. It is concluded that some polyphenols, with specific structure, contained in wine possess potent endothelium-dependent vasorelaxing activity.

Animals↗
PubMed2000

The action of sevoflurane on vascular smooth muscle of isolated mesenteric resistance arteries (part 1): role of endothelium.

BACKGROUND: The direct action of sevoflurane on systemic resistance arteries is not fully understood. METHODS: Isometric force was recorded in isolated rat small mesenteric arteries. RESULTS: Sevoflurane (2-5%) enhanced contractile response to norepinephrine only in the presence of endothelium, but inhibited it in its absence. Sevoflurane still enhanced the norepinephrine response after inhibitions of the nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase and lipoxygenase pathways, or after blockade of either endothelin-1 ET-1), angiotensin-II, or sevotonin receptors. Sevoflurane (3-5%) inhibited contractile response to potassium chloride only in the absence of endothelium but did not influence it in its presence. In the endothelium-intact strips, inhibition of the norepinephrine response, which was enhanced during application of sevoflurane, was observed after washout of sevoflurane and persisted for approximately 15 min. In the endothelium-denuded strips, the inhibition of norepinephrine response was similarly prolonged after washout of sevoflurane. However, no significant inhibitions of potassium chloride response were observed after washout of sevoflurane in both the endothelium-intact and the endothelium-denuded strips. CONCLUSIONS: The action of sevoflurane on norepinephrine contractile response consists of endothelium-dependent vasoconstricting and endothelium-independent vasodilating components. In the presence of endothelium, the former predominates over the latter, enhancing the norepinephrine response. The endothelium-independent component persisted after washout of sevoflurane, leading to prolonged inhibition of the norepinephrine response. The mechanisms behind the sevoflurane-induced inhibition of norepinephrine response are at least in part different from those behind its inhibition of potassium chloride response. Nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase products, lipoxygenase products, endothelin-1, angiotensin-II, and serotonin are not involved in the vasoconstricting action. (Key words: Halogenated volatile anesthetics; sympathetic nervous system; systemic hypotension; vascular endothelium.)

Acetylcholine↗
PubMed1985

Modulation by endothelium of contractile responses in rat aorta in absence and presence of flunarizine.

The possible modulation by endothelium of phenylephrine- and prostaglandin F2 alpha-induced mobilization of calcium for contraction in the rat aorta has been investigated. Contractions elicited by these and other agonists are inhibited in the presence of endothelium. For any single concentration of phenylephrine in the presence of endothelium, the initial phasic components of contractions were significantly greater, the maximal contractions were achieved sooner and were less well maintained as compared to contractions elicited in the absence of endothelium. The kinetic characteristics of contractions stimulated by single concentrations of PGF2 alpha were similar in the presence and absence of endothelium and did not exhibit initial phasic components of contraction. Sub-maximal contractions-elicited by both PGF2 alpha and phenylephrine in the absence of endothelium were inhibited to a greater extent by flunarizine 3 microM than equieffective contractions elicited in the presence of endothelium. Maximal contractions elicited by phenylephrine (1 microM) were inhibited to a similar extent by flunarizine in the presence and absence of endothelium, but maximal contractions elicited by PGF2 alpha (30 microM) were inhibited by flunarizine to a greater extent in the presence than in the absence of endothelium. It is concluded that an endothelium-derived factor, perhaps distinct from endothelium-derived relaxing factor, can modulate the ability of both phenylephrine and PGF2 alpha to mobilize calcium for contraction. This modulatory effect is associated with an enhanced mobilization of intracellular calcium. Thus, submaximal concentrations of both agonists were less dependent on extracellular calcium than on intracellular calcium to elicit contractions in the presence of endothelium, as compared to contractions elicited in the absence of endothelium.

Animals↗
PubMed1989

Effect of endothelium on basal and on stimulated accumulation and efflux of cyclic GMP in rat isolated aorta.

1. The aim of this study was to examine the possible role of the release of guanosine 3':5'-cyclic monophosphate (cyclic GMP) into the extracellular space in the regulation of rat aortic cyclic GMP content. 2. Rat aortic segments incubated in physiological solution released cyclic GMP into the medium in a time-dependent manner. This release was greatly enhanced when intact instead of tissues without endothelium were used. After 120 min of observation, a maximal 33 fold difference in extracellular cyclic GMP content was detected. 3. Treatment of rat aortic preparations with either a Ca2+-free solution or methylene blue, both conditions known to inhibit endothelium-derived relaxing factor (EDRF)-mediated responses, markedly reduced the extracellular accumulation of cyclic GMP from tissues with but not without endothelium. 4. Endothelium-dependent vasodilators such as acetylcholine (10 microM) and carbachol (10 microM) greatly increased tissue cyclic GMP content, in a time-dependent manner in rat aortic preparations with endothelium, but only slightly in tissues without. Maximal increases in intact tissues were obtained after about 1 min of agonist contact and amounted to about 35 and 15 fold respectively, thereafter tissue cyclic GMP content rapidly declined. Histamine (10 microM) elicited only minor effects on tissue cyclic GMP content of both intact preparations and those without endothelium. 5. Acetylcholine (10 microM), carbachol (10 microM) and histamine (10 microM) stimulated a time-dependent release of the cyclic nucleotide into the incubation medium from tissues with endothelium. After 120 min of observation, extracellular accumulation of cyclic GMP from intact tissues was increased by about 2.6, 6.6 and 1.7 fold respectively. Carbachol and histamine induced only minor effects on release from tissues without endothelium. 6. Sodium nitroprusside (0.3 and 10 microM), a direct activator of soluble guanylate cyclase, induced a concentration-dependent accumulation of cyclic GMP in tissues with and without endothelium that was associated with a concentration-dependent accumulation of cyclic GMP in the extracellular space. Peak tissue cyclic GMP content reached similar levels in preparations with and without endothelium, while extracellular cyclic GMP levels were about two times greater when experiments were performed with intact compared to endothelium-denuded tissues. 7. Atriopeptin II, an activator of particulate guanylate cyclase, increased tissue cyclic GMP content by about 8 and 18 fold respectively in tissues with and without endothelium. As was the case with sodium nitroprusside, atriopeptin II-stimulated release was markedly enhanced from intact tissues compared with those without endothelium. After 120 min of observation, there was a 16 fold difference in the amount of extracellular cyclic GMP.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1991

Endothelium-dependent relaxations of piglet pulmonary arteries augment with maturation.

To determine whether maturation alters endothelium-dependent responses in porcine pulmonary arteries, rings, with and without endothelium, of small pulmonary arteries taken from piglets of 3, 10, and 30 d of age were suspended in organ chambers filled with buffered salt solution, bubbled with 95% O2-5% CO2, and maintained at 37 degrees C. These studies were performed in the presence of indomethacin (10(-5) M) to inhibit prostaglandin synthesis. In rings without endothelium, potassium chloride (10(-2) to 8.5 x 10(-2) M) and histamine (10(-9) to 10(-5) M) caused concentration-dependent contractions. When normalized to maximal contractions achieved to each agonist, the concentration-effect curves to potassium chloride and histamine in rings without endothelium were similar at each age. Rings with endothelium showed a progressive shift to the right of the concentration-effect curve to histamine, possibly secondary to an increase in the basal release of, or responsiveness to, the endothelium-derived relaxing factor with maturation. Relaxations to sodium nitroprusside (10(-9) to 10(-5) M) were unaffected by age. In precontracted rings, acetylcholine (10(-9) to 10(-6) M), bradykinin (10(-10) to 10(-6) M), and the calcium ionophore A23187 (10(-9) to 10(-6) M) caused relaxations in rings with endothelium, but not in those without endothelium, which were greater at 10 and 30 d compared to 3 d; further augmentation at 30 d compared to 10 d was not observed. In rings without endothelium, changes in the responsiveness to nitric oxide (10(-9) to 10(-5) M), one of the proposed endothelium-derived relaxing factors, with age were comparable to those observed with endothelium-dependent relaxing agents. These studies demonstrate that endothelium-dependent relaxations increase with age, possibly due to changes in sensitivity of the smooth muscle to the endothelium-derived relaxing factor.

Animals↗
PubMed1998

Nonuniformity of endothelial constitutive nitric oxide synthase distribution in cardiac endothelium.

Endocardial endothelium and endothelium of coronary vessels produce NO. Histochemical methods have suggested that coronary arterial endothelial cells contain more endothelial constitutive NO synthase (ecNOS) than does coronary venous endothelium. We have further investigated the distribution of ecNOS in cardiac endothelium using immunofluorescence and en face confocal microscopy of rat heart. In endocardial endothelium, confocal microscopy revealed distinct ecNOS labeling of peripheral cell borders, cytoplasmic labeling, and labeling of the Golgi complexes. Labeling of the cell borders and of the Golgi complexes was confirmed by double staining for ecNOS and for platelet and endothelial cell adhesion molecule or Golgi 58k protein, respectively. Cytoplasmic labeling was strongest in coronary arterial endothelium. The size of the ecNOS-labeled Golgi complexes decreased from coronary arterial endothelial cells (8.63 +/- 0.39 microm2, mean +/- SE of 5 rats) to endocardial endothelium (7.07 +/- 0.61 microm2) and to coronary venous endothelium (3.65 +/- 0.20 microm2). In addition, pixel intensity of ecNOS labeling was higher in arterial endothelial cells than in venous endothelial cells. Endothelium of myocardial capillaries also contained small ecNOS-labeled Golgi complexes. No correlation was observed between endothelial cell surface area and Golgi complex size. Caveolin-1 labeling was strongest in capillaries and did not coincide completely with ecNOS labeling in endocardial and venous endothelium. These results suggest that endocardial and coronary arterial endothelium in the rat have a higher synthetic activity and might express more ecNOS than is expressed by cardiac venous and capillary endothelium. The observed heterogeneity in ecNOS distribution might be related to the specific mechanochemical environment and function of each endothelial compartment.

Animals↗
PubMed1995

Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats.

1. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established. 2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin. 3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-L-arginine methyl ester or NG-nitro-monomethyl-L-arginine (inhibitors of nitric oxide synthase) and by 10 mumol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 mumol/l ouabain (inhibitor of Na+, K(+)-ATPase), and, when combined with NG-nitro-L-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 mumol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-L-arginine methyl ester-resistant endothelium-dependent relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1991

Endothelium-derived contracting factor released by serotonin in the aorta of the spontaneously hypertensive rat.

Contractions to serotonin are augmented in aortas with endothelium from spontaneously hypertensive rats (SHR) compared to normotensive controls (WKY). Experiments were designed to determine whether this is due to the release of a vasoconstrictor prostanoid from the endothelium. Rings of aortas with and without endothelium were taken from SHR and WKY and suspended in organ chambers for isometric tension recording. Contractions to serotonin were similar in rings without endothelium from both strains. The presence of the endothelium reduced the contractions to all concentrations of serotonin in the WKY; in the SHR the endothelium inhibited only the response to lower concentrations of serotonin. Indomethacin (or meclofenamate) reduced the contractions to high concentrations of serotonin only in rings from SHR with endothelium; it did not affect the response in SHR rings without endothelium or in rings from WKY (with and without endothelium). The endothelium inhibited contractions to norepinephrine only in the presence of indomethacin in both strains. These experiments suggest that serotonin stimulates the release of vasoconstrictor prostanoids from the endothelium of the SHR but not from the WKY aorta. Norepinephrine may release endothelium-derived contracting factor(s) in both strains.

Animals↗
PubMed1999

Alpha2-adrenoceptor antagonists evoke endothelium-dependent and -independent relaxations in the isolated rat aorta.

This study was designed to determine whether the alpha2-adrenoceptor antagonists idazoxan, yohimbine, and rauwolscine cause endothelium-dependent and -independent responses in the rat aorta. Rings of rat aorta, with and without endothelium, were suspended for the measurement of isometric force in modified Krebs-Ringer bicarbonate solution (37 degrees C; aerated with 95% O2 and 5% CO2). The alpha2-adrenoceptor antagonists, in the concentration range of 10(-8)-10(-6) M, relaxed phenylephrine-contracted rings with, but not those without endothelium. alpha2-Adrenoceptor antagonists (3 x 10(-6) M for 1 min) increased the accumulation of cyclic guanosine monophosphate (cGMP) about twofold in the aortas with endothelium. The relaxation and the increased cGMP induced by alpha2-antagonists were attenuated by methylene blue (10(-6) M) and N(G)-nitro-L-arginine (L-NA, 3 x 10(-5) M), whereas propranolol (10(-6) M) did not affect the relaxation. In concentrations >10(-6) M, alpha2-adrenoceptor antagonists relaxed the rat aorta without endothelium. The endothelium-independent relaxation by alpha2-adrenoceptor antagonists was abolished by increased external K+ and reduced significantly by tetraethylammonium (TEA, 10(-2) M, a Ca2+-dependent K+ channel blocker), but not inhibited by glibenclamide (10(-5) M, an ATP-sensitive K+ channel blocker). In the rabbit aorta, only endothelium-independent relaxations were observed with alpha2-adrenoceptor antagonists in the concentration range of 10(-8)-10(-5) M, and these relaxations were not antagonized by TEA. These results suggest that alpha2-adrenoceptor antagonists relax the rat aorta through endothelium-dependent mechanism at lower concentrations and endothelium-independent mechanisms at higher concentrations. The endothelium-dependent relaxations are likely to be mediated by the endothelium-derived relaxing factor (EDRF)/NO pathway because they are associated with the accumulation of cGMP, whereas the endothelium-independent relaxations may be caused by the opening of potassium channels in the vascular smooth muscle.

Adrenergic alpha-Antagonists↗
PubMed1998

Role of endothelium and K+ channels in dobutamine-induced relaxation in rat mesenteric artery.

1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a beta 1-adrenoceptor agonist, in rat isolated mesenteric arteries, the effects of inhibitors of nitric oxide (NO) activity, blockers of K+ channels and high extracellular K+ were studied by measuring isometric tension in both endothelium-intact and -denuded arteries. 2. Dobutamine inhibited the phenylephrine (PE)-induced sustained tension with a pEC50 of 7.40 +/- 0.08 in endothelium-intact arteries. Removal of functional endothelium attenuated the effect of dobutamine. The relaxation induced by dobutamine was inhibited by the beta 1-adrenoceptor antagonist CGP 20712A (3 mumol/L) but not by the beta 2-adrenoceptor antagonist ICI 118,551 (3 mumol/L) in endothelium-denuded arteries. 3. Pretreatment with NG-nitro-L-arginine (L-NNA; 100 mumol/L) or methylene blue (3 mumol/L) induced a similar degree of inhibition of the dobutamine-induced relaxation in endothelium-intact arteries, while NG-nitro-D-arginine (100 mumol/L) and indomethacin (10 mumol/L) had no effect. In contrast, pretreatment with L-NNA (100 mumol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3 mumol/L) inhibited the relaxant response to SNP. 4. Charybdotoxin (CTX; 100 nmol/L), iberiotoxin (IBX; 100 nmol/L) and tetraethylammonium ions (TEA+; 3 mmol/L) significantly reduced the dobutamine-induced relaxation. Tetrapentylammonium ions (TPA+; 5 mumol/L) markedly inhibited the relaxant effect of dobutamine. The pEC50 values for control and in the presence of TPA+ in endothelium-intact arteries were 7.35 +/- 0.11 and 6.14 +/- 0.17, respectively, and 6.35 +/- 0.09 and 5.87 +/- 0.17 for control and in the presence of TPA+ in endothelium-denuded arteries, respectively. In contrast, glibenclamide (3 mumol/L) was ineffective. At 5 mumol/L, TPA+ also inhibited the relaxation induced by forskolin. 5. The maximal relaxation of PE-contracted arteries induced by 3 mumol/L dobutamine was completely abolished in the 60 mmol/L K(+)-contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 mumol/L induced inhibition of the high-K+ response. 6. The present results indicate that endothelium, probably NO but not prostacyclin, was involved in the dobutamine-induced relaxation in rat mesenteric arteries. Activation of CTX-, IBX- and TPA(+)-sensitive K+ channels contributed towards the observed relaxation. Loss of the ability to relax the 60 mmol/L K(+)-contracted arteries suggests that endothelium-derived vasoactive factors affected by concentrations of dobutamine less than 3 mumol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium-independent relaxant effect.

Adrenergic beta-Agonists↗
PubMed1988

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with alpha-adrenoceptors in the rat aorta.

1. We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline. 2. The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non-competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non-competitive antagonist against clonidine in the absence of endothelium. 3. Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non-competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium. 4. Analysis of the concentration-response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium. 5. The rank order of agonist potency in the absence of endothelium was noradrenaline greater than phenylephrine greater than clonidine. The rank order of antagonist potency was prazosin greater than or equal to doxazosin greater than phentolamine greater than yohimbine. 6. The results show that vascular endothelium modulates the contractile response to alpha-adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the alpha-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the alpha 1-subtype.

Adrenergic alpha-Agonists↗
PubMed1990

Endothelium-dependent vascular activities of endothelin-like peptides in the isolated superior mesenteric arterial bed of the rat.

1. The vasoconstrictor activities of endothelin-2, endothelin-3, sarafotoxin S6b, human proendothelin1-38 and mouse vasoactive intestinal contractor (VIC) were studied in the isolated Krebs-Henseleit perfused mesenteric arterial bed of the rat in the presence and absence of the endothelium. The vasoconstrictor properties of endothelin-1 were studied in control preparations and in preparations treated with methylene blue or N omega-nitro-L-arginine methyl ester (NAME). Finally, the direct vasodilator properties of endothelin-2, endothelin-3 and sarafotoxin S6b were studied in preparations preconstricted with methoxamine. 2. In the presence of an intact endothelium, all of the peptides caused dose-dependent increases in perfusion pressure and sarafotoxin S6b was a full agonist relative to the other peptides studied (maximum increase in perfusion pressure, Rmax = 106 +/- 11 mmHg). Endothelin-1, endothelin-2 and VIC were more potent vasoconstrictors (ED50 93.0 +/- 40.0, 90.8 +/- 20.5 and 106 +/- 63 pmol, respectively) than endothelin-3 and sarafotoxin S6b, which were found to be equipotent (ED50 values 411 +/- 195 and 345 +/- 86 pmol, respectively). A full dose-response relationship could not be constructed for proendothelin, but the highest dose used (4 nmol) increased the perfusion pressure by 15.4 +/- 1.6 mmHg. 3. Destruction of the endothelium with the zwitterionic detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate (CHAPS) significantly enhanced the pressor activity of all 5 peptides. The Rmax for sarafotoxin S6b was not significantly altered by removal of the endothelium but its potency was significantly increased (ED50 = 115 +/- 15 pmol). Although their R,,, values were significantly increased, endothelin-2 and VIC were still partial agonists relative to sarafotoxin S6b in CHAPSpretreated preparations; their potencies were unchanged (ED5o values 118 + 53 and 416 + 196pmol, respectively). Removal of the endothelium significantly reduced the potency of endothelin-3 (ED5o, 6.3 + 2.2 nmol) but this peptide then exhibited full agonist activity (R..x = 106 + 14 mmHg). After endothelial cell destruction, the pressor responses to proendothelin were increased; 4 nmol gave a response of 38.8 + 5.5 mmHg. 4. Exposure of preparations to either 100 microM NAME (R,,,X = 42.6 + 2.4mmHg and EDSo = 57.5 + 13.7 pmol) or 10 microM methylene blue (R,,,. = 36.0 + 5.1 mmHg and ED50 = 81.5 + 26.1 pmol) significantly enhanced the maximum pressor responses to endothelin-l (control: R.,=X = 22.5 + 2.6 mmHg; ED5o = 93.0 + 40.Opmol). The values in the presence of NAME or methylene blue were not significantly different from those found previously for endothelin-1 after removal of the endothelium with CHAPS. 5. Endothelin-2, endothelin-3 and sarafotoxin S6b all caused vasorelaxation in preparations which had been precontracted with 100 microM methoxamine. This action was endothelium-dependent as it was abolished by perfusing the mesentery with CHAPS. Endothelin-3 and sarafotoxin S6b caused relaxation at much lower doses than were needed with endothelin-1 and endothelin-2. 6. The endothelium significantly modulates the vasoconstrictor activity of all the endothelin-like peptides studied, including the precursor peptide proendothelin (which was the least potent of the peptides). This modulation is likely to be due to the release of endothelium-derived relaxing factor, since similar results to destruction of the endothelium were obtained when endothelin-l was investigated in the presence of either methylene blue or NAME (an inhibitor of nitric oxide formation) in the perfusion fluid. The vasodilator effects of the peptides were also endothelium-dependent. There was a different order of potency for vasoconstriction and vasodilatation supporting the suggestion that there are sub-types of receptor for the endothelin-like peptides in the vasculature; one type on the vascular smooth muscle and a second type on the endothelium.

Animals↗