Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ENDOTHELIUM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,081 records · Page 60Linked to original sources
PubMed1988

Release of endothelium-derived relaxing factor is inhibited by 8-bromo-cyclic guanosine monophosphate.

Endothelial cells are known to contain both soluble and particulate guanylate cyclase, but the functional role of cyclic guanosine monophosphate (cGMP) in endothelial cells remains unknown. We have investigated the effects of 8-bromo-cGMP on endothelium-dependent relaxations to acetylcholine, substance P, ATP, and the calcium ionophore A23187, and on endothelium-independent relaxations to sodium nitroprusside and glyceryl trinitrate (GTN). The ability of each of these agents to relax phenylephrine-preconstricted rings of rabbit aorta was tested in the absence and presence of 8-bromo-cGMP. In the presence of 8-bromo-cGMP, a greater concentration of phenylephrine had to be used to produce a similar level of tone and then endothelium-dependent relaxations to acetylcholine and substance P were inhibited, whereas endothelium-dependent relaxations to ATP and A23187 were unaffected. Endothelium-independent relaxations to sodium nitroprusside and GTN were only inhibited at the highest concentrations of nitroprusside and GTN. These results suggest that: (a) increasing GMP levels in endothelial cells inhibit agonist-induced release of endothelium-derived relaxing factor (EDRF); (b) a negative feedback mechanism may exist whereby EDRF stimulates soluble guanylate cyclase in endothelial cells to inhibit its own release; and (c) ATP does not induce EDRF release via phosphoinositol hydrolysis.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1989

Modulation of the vasodilator action of SIN-1 by the endothelium.

We studied the influence of endothelium-derived relaxing factor (EDRF) on sydnonimine (SIN-1)-induced vasodilatation and the accumulation of cyclic GMP in the rabbit femoral artery. The potency of SIN-1 to elicit vasodilatation in norepinephrine-contracted femoral arteries was significantly enhanced in the absence of the endothelium or following impairment of the synthesis of EDRF with gossypol or NG-nitro-L-arginine, whether the application of SIN-1 was intra- or extraluminal. The increase in cyclic GMP in the femoral segments by a combination of SIN-1 and endothelium-derived relaxant factor (released by the endothelium of either the rabbit thoracic aorta or the femoral artery) was significantly less than the sum of the increases in cyclic GMP induced by each agent alone. In contrast, stimulation of purified soluble guanylate cyclase by submaximal concentrations of SIN-1 was additive with the effect of EDRF, released from acetylcholine-stimulated rabbit aortas. This indicates the absence of a direct interaction between the factor and SIN-1 at the level of soluble guanylate cyclase. The interaction seems to be specific for cyclic GMP-mediated responses, since cyclic AMP-induced dilatations elicited by isoproterenol were not affected by the presence of the endothelium. The results indicate that the endothelium can modulate the vascular reactivity to SIN-1. This modulation may be mediated either by EDRF or by another endothelial substance that alters the metabolism or the action of cyclic GMP in vascular smooth muscle.

Animals↗
PubMed2002

Altered effect of cyclopiazonic acid on endothelium-dependent relaxation in femoral arteries from hypertensive rats.

The function of endoplasmic reticulum in hypertensive vascular endothelium has not been intensively studied. The current study was designed to investigate a role of intracellular Ca2+ stores in endothelium-dependent relaxations to acetylcholine using femoral arteries obtained from Wistar-Kyoto (WKYs) and spontaneously hypertensive rats (SHRs). Rings were prepared from the femoral arteries and changes in isometric tension were recorded. Endothelium-dependent relaxations induced by acetylcholine in rings contracted with serotonin were identical in WKYs and SHRs. Cyclopiazonic acid (CPA) inhibited the relaxation in SHRs but not in WKYs. In WKYs, acetylcholine evoked smaller relaxations in rings contracted with KCl than in those contracted with serotonin, whereas in SHRs the relaxation was not affected by the contractile agonists used. The relaxation in rings contracted with KCl was abolished by Nw-nitro-l-arginine methyl ester (l-NAME) and was reduced by CPA to a similar extent in both strains. In rings contracted with serotonin, l-NAME abolished the relaxation in SHRs, but the inhibitor only partially reduced the relaxation in WKYs. CPA did not alter the relaxation in the presence of l-NAME. Endothelium-independent relaxations to sodium nitroprusside were not affected by CPA. These results suggest that acetylcholine relaxes rat femoral arteries by releasing both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF). In SHRs, the relaxation is preserved, but the release of EDHF is absent. CPA inhibits the relaxation mediated by nitric oxide, but not EDHF and, thus, inhibits the relaxation in SHRs but not in WKYs. Functional alteration of endoplasmic reticulum in the hypertensive endothelium cannot be detected.

Acetylcholine↗
PubMed1994

Pharmacological reactivity of human epicardial coronary arteries: characterization of relaxation responses to endothelium-derived relaxing factor.

1. Human epicardial coronary artery rings, freshly obtained from cardiac transplant patients, were examined for their responses to endothelium-derived relaxing factor (EDRF)-releasing agents. 2. Functional antagonism profoundly influenced relaxation responses in this tissue. Increasing force with concentrations of U46619 above 3 nM (40% of maximum contraction response) resulted in a reduction of the maximum response to four vasorelaxants which relax vascular smooth muscle via different mechanisms: the EDRF-releasing agents, substance P and bradykinin; the endothelium-independent nitro-vasodilator, sodium nitroprusside (SNP); and the beta-adrenoceptor agonist, isoprenaline. 3. Substance P, histamine, bradykinin and the Ca2+ ionophores ionomycin and A23187 all caused concentration- and endothelium-dependent relaxation in vessels pre-contracted with the thromboxane A2-mimetic, U46619 (3 nM) to an active force optimal for relaxation responses. Nifedipine (0.1 microM), added to prevent spontaneous contractions, had no effect or relaxation responses to substance P, bradykinin and histamine. 4. Substance P was the most potent of the EDRF-releasing agents examined and all agents except for bradykinin caused near-maximal relaxation. Bradykinin caused only 46.2% +/- 7.3% relaxation. Responses were abolished when the endothelium was removed and, except for histamine, were not significantly affected by indomethacin (3-10 microM, P > 0.05). Histamine (0.1-10 microM) caused a concentration-dependent contraction of arterial rings without endothelium. 5. The L-arginine analogues NG-nitro-L-arginine (L-NOARG, 0.1 mM) and NG-monomethyl-L-arginine (L-NMMA, 0.1 mM) both caused no further contraction in arteries precontracted with U46619 (3 nM) and were in general, poor inhibitors of responses to EDRF agonists. L-NMMA, but not L-NOARG,caused small but significant decreases in the maximum responses to substance P, bradykinin (18.5 +/- 6.9% and 27.6 +/- 10.9% relaxation with L-NMMA and L-NOARG, respectively), histamine and A23187 (P<0.05). The analogues had no effect on SNP responses.6. In conclusion, EDRF release in human isolated coronary artery is only poorly antagonized by the nitric oxide synthase inhibitors L-NOARG and L-NMMA. These results indicate that either the nitricoxide transduction pathway present in human coronary artery is different from that in other tissues or that another factor(s) (e.g. endothelium-derived hyperpolarizing factor) is also released in response to EDRF-releasing agents and augments the relaxation to nitric oxide.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Endothelium-derived factors and hyperpolarization of the carotid artery of the guinea-pig.

1. Transmembrane potentials were recorded from isolated carotid arteries of the guinea-pig superfused with modified Krebs-Ringer bicarbonate solution. Smooth muscle cells were impaled from the adventitial side with intracellular glass microelectrodes filled with KCl (30-80 M omega). 2. Acetylcholine (1 microM) in the presence of inhibitors of nitric oxide synthase, (N omega-nitro-L-arginine (L-NOARG) 100 microM) and cyclo-oxygenase, (indomethacin 5 microM) induced an endothelium-dependent hyperpolarization (-18.9 +/- 1.6 mV, n = 15). 3. In the presence of these two inhibitors, S-nitroso-L-glutathione (10 microM), sodium nitroprusside (10 microM), 3-morpholinosydnonimine (SIN-1, 10 microM) and iloprost (0.1 microM) induced endothelium-independent hyperpolarizations of the smooth muscle cells (respectively: -16.0 +/- 2.3, -16.3 +/- 3.4, -12.8 +/- 2.0 and -14.5 +/- 1.5 mV, n = 4-6). 4. The addition of glibenclamide (1 microM) did not influence the acetylcholine-induced L-NOARG/ indomethacin-resistant hyperpolarization (-18.0 +/- 1.8 mV, n = 10). In contrast, the responses induced by S-nitroso-L-glutathione, sodium nitroprusside, SIN-1 and iloprost were abolished (changes in membrane potential: -0.8 +/- 1.1, 1.3 +/- 3.9, 4.5 +/- 4.6 and 0.3 +/- 0.8 mV respectively, n = 4-5). 5. In the presence of NO synthase and cyclo-oxygenase inhibitors, charybdotoxin (0.1 microM) or apamin (0.5 microM) did not influence the hyperpolarization produced by acetylcholine. However, in the presence of the combination of charybdotoxin and apamin, the acetylcholine-induced L-NOARG/indomethacin-resistant hyperpolarization was converted to a depolarization (4.4 +/- 1.2 mV, n = 20) while the endothelium-independent hyperpolarizations induced by S-nitroso-L-glutathione, sodium nitroprusside, SIN-1 and iloprost were not affected significantly (respectively: -20.4 +/- 3.4, -22.5 +/- 4.9, -14.5 +/- 4.7 and -14.5 +/- 0.5 mV, n = 4-5). 6. In the presence of the combination of charybdotoxin and apamin and in the absence of L-NOARG and indomethacin, acetylcholine induced a hyperpolarization (-19.5 +/- 3.7 mV, n = 4). This hyperpolarization induced by acetylcholine was not affected by the addition of indomethacin (-18.3 +/- 4.6 mV, n = 3). In the presence of the combination of charybdotoxin, apamin and L-NOARG (in the absence of indomethacin), acetylcholine, in 5 out of 7 vessels, still produced hyperpolarization which was not significantly smaller (-9.1 +/- 5.6 mV, n = 7) than the one observed in the absence of L-NOARG. 7. These findings suggest that, in the guinea-pig isolated carotid artery, the endothelium-independent hyperpolarizations induced by NO donors and iloprost involve the opening of KATP channels while the acetylcholine-induced endothelium-dependent hyperpolarization (resistant to the inhibition of NO-synthase and cyclo-oxygenase) involves the opening of Ca(2+)-activated potassium channel(s). Furthermore, in this tissue, acetylcholine induces the simultaneous release of various factors from endothelial origin: hyperpolarizing factors (NO, endothelium derived hyperpolarizing factor (EDHF) and prostaglandins) and possibly a depolarizing factor.

Animals↗
PubMed1994

The endothelium contributes to the contractile responses of the human umbilical artery to 5-hydroxytryptamine and endothelin-1 under low but not high PO2 conditions.

To determine the influences of both PO2 and the presence of the endothelium on contractile responses of the human umbilical artery (HUA), the effects of a series of vasoconstrictors were compared in ring preparations with and without endothelium at low (2.5% O2, PO2 < 55 mmHg (1 mmHg = 133.3 Pa)) and high PO2 (95% O2, PO2 > 600 mmHg). The results demonstrate the following. (i) 5-Hydroxytryptamine (5-HT) and endothelin-1 (ET-1) contracted the HUA at either low or high PO2. At low PO2, removal of the endothelium significantly reduced receptor-mediated responses. (ii) The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM) did not modulate 5-HT-initiated contractions at either level of PO2. (iii) alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT) and 5-carboxamidotryptamine (5-CT), relatively selective 5-HT1C/5-HT2 and 5-HT1-like receptor agonists, respectively, elicited contractions in the HUA, and the responses were reduced at low PO2 but unaffected by removal of the endothelium. (iv) Responses of the HUA to high potassium (hK+) were unaffected by either changes in PO2 or removal of the endothelium. (v) The 5-HT2 receptor antagonist ketanserin at low concentration (10 nM) inhibited contractile responses to 5-HT in an apparently competitive manner. However, with 100 nM ketanserin and at low PO2, inhibition became noncompetitive. Removal of the endothelium did not influence the action of ketanserin. (vi) Regardless of PO2, the Ca2+ channel antagonist nifedipine (1 microM) significantly inhibited 5-HT- and ET-1-mediated contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1986

Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor.

Experiments were designed to determine the effects of oxygen-derived free radicals on the production and biological activity of endothelium-derived relaxing factor or factors released by acetylcholine. Rings of canine coronary arteries without endothelium (bioassay rings) were superfused with solution passing through a canine femoral artery with endothelium. Superoxide dismutase caused maximal relaxation of the bioassay ring when infused upstream, but not downstream, of the femoral artery; this effect of superoxide dismutase was inhibited by catalase. Infusion of acetylcholine relaxed the bioassay rings because it released a labile relaxing factor (or factors) from the endothelium. When infused below the femoral artery, superoxide dismutase and, to a lesser extent, catalase augmented the relaxations to acetylcholine. Superoxide dismutase, but not catalase, doubled the half-life of the endothelium-derived relaxing factor(s). This protective effect of the enzyme was augmented fivefold by lowering the oxygen content of the perfusate from 95 to 10%. These data demonstrate that: superoxide anions inactivate the relaxing factor(s) released by acetylcholine from endothelial cells and hyperoxia favors the inactivation of endothelium-derived relaxing factor(s).

Acetylcholine↗
PubMed1991

Evidence against nonprostanoid endothelium-derived relaxing factor(s) in trout vessels.

Bradykinin (BK)- or acetylcholine (ACh)-mediated vasodilation has only rarely been observed in fish. This suggests that many fish vessels lack the endothelium-dependent relaxing mechanisms recently identified in mammals. To examine this hypothesis, isolated vascular rings were prepared from trout ventral aortas (VA), efferent branchial and celiacomesenteric (CM) arteries, and anterior cardinal veins (CV) and examined for endothelium-mediated responses. A doubly perfused trunk preparation was also used to evaluate the response of the microcirculation. ACh produced dose-dependent contractions in all vascular rings and increased vascular resistance when perfused into the CM but had no affect when perfused into the dorsal aorta. Neither ACh nor BK relaxed precontracted vessels or lowered resting tone. Removal of the endothelium did not affect ACh or BK responses. The calcium ionophore A23187 produced an endothelium-dependent relaxation of precontracted VA, CM, and CV. The A23187 response was abolished by indomethacin, indicating that a prostanoid was involved in the relaxation. ATP contracted and/or relaxed precontracted CM and CV. ATP effects were independent of an intact endothelium. Sodium nitroprusside and atrial natriuretic factor partially or completely relaxed all vessels, indicating the presence of soluble and particulate guanylate cyclases, respectively. These results suggest that nonprostanoid endothelium-derived relaxing factors (EDRFs) or EDRF-like vasodilator mechanisms are not present in trout vessels or, if they are, they are not released by classical agonists.

Acetylcholine↗
PubMed1990

Endothelium-derived hyperpolarizing factor.

Although nitric oxide appears to be the major endothelium-derived relaxing factor (EDRF), it cannot explain all endothelium-dependent responses of isolated arteries. Thus, acetylcholine causes an endothelium-dependent, transient hyperpolarization, which is due to the release from the endothelial cells of a diffusible substance (endothelium-derived hyperpolarizing factor, EDHF) other than nitric oxide. The muscarinic receptors on the endothelium that trigger the release of EDHF belong to the M1-muscarinic subtype, while those activating the liberation of EDRF are M2-muscarinic in nature. The importance of endothelium-dependent hyperpolarization varies among different blood vessels. The hyperpolarization, and the resulting relaxation caused by EDHF can be attributed to an increase in K+ conductance in the vascular smooth muscle. Although the nature of EDHF remains elusive, it may be a labile metabolic of arachidonic acid.

Acetylcholine↗
PubMed1995

Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia.

BACKGROUND: The release of endothelium-derived relaxing factors has been shown experimentally to be of pivotal importance for the maintenance of coronary blood flow during increased demand. In humans with coronary atherosclerosis, endothelial vasodilator dysfunction is not confined only to epicardial conductance vessels but may also extend into the coronary microcirculation. We therefore tested the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with myocardial ischemia during exercise in patients without hemodynamically significant epicardial artery stenoses. METHODS AND RESULTS: Coronary vasodilator function was assessed by subselective infusion of the endothelium-dependent dilator acetylcholine (0.036 to 3.6 micrograms/mL) and the endothelium-independent dilator papaverine (7 mg). Coronary blood flow responses were evaluated by intracoronary Doppler flow velocity recordings and quantitative angiography. Exercise-induced myocardial perfusion was determined by 201Tl single photon emission computed tomographic imaging. Thirteen patients had exercise-induced myocardial perfusion defects suggestive of myocardial ischemia, whereas 14 patients had normal thallium imaging during exercise. In patients with exercise-induced thallium perfusion defects, coronary blood flow responses to acetylcholine were significantly (P < .005) blunted compared with patients with normal thallium imaging during exercise. In contrast, coronary blood flow reserve to the endothelium-independent smooth muscle relaxant papaverine was similar in the two groups. Patients with exercise-induced thallium perfusion defects exhibited a significantly (P < .005) reduced (23.9 +/- 9.0% [mean +/- SD]) endothelium-mediated coronary vasodilator capacity compared with patients with normal thallium testing (56.2 +/- 27.8%). Epicardial artery vasoreactivity to acetylcholine did not differ between the two groups. CONCLUSIONS: Impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant epicardial artery lesions. Endothelial vasodilator dysfunction extending into the coronary microcirculation may thus contribute to the ischemic manifestations of coronary artery disease during times of increased myocardial demand.

Acetylcholine↗
PubMed1995

Selective depression of endothelium-dependent dilations during cerebral ischemia.

BACKGROUND AND PURPOSE: Pial arterioles have diverse mechanisms for endothelium-dependent dilations. In mice, different mechanisms or endothelium-derived mediators exist for each of the following dilators: acetylcholine, bradykinin, and calcium ionophore A-23187. This study tests the response to each of these dilators during profound ischemia. The response to sodium nitroprusside, an endothelium-independent dilator, was also tested. METHODS: In each mouse, ischemia was produced by bilateral carotid artery ligation that reduced cortical blood flow by approximately 90% as determined by laser-Doppler flowmetry. In separate studies of 10 mice each, dilations of pial arterioles to two doses of each dilator were compared before and after 10 minutes of occlusion, with the occlusion continuing during the second set of measurements. The dilator was applied in the suffusate bathing the pial surface exposed at a craniotomy site. Diameters were monitored by in vivo television microscopy and image splitting. RESULTS: The dose-dependent dilations to acetylcholine, bradykinin, and calcium ionophore A-23187 were each profoundly depressed during ischemia. The response to sodium nitroprusside was not depressed. In all cases, the ischemia was accompanied by arteriolar narrowing of approximately 25% and by obvious slowing of blood flow observed by intravital microscopy. Superoxide dismutase plus catalase failed to prevent the depressed response to acetylcholine. CONCLUSIONS: Endothelium-dependent dilations, mediated by diverse endothelium-derived relaxing factors, are depressed during ischemia of 10 to 15 minutes' duration. This cannot be a nonselective effect on vessel responsivity caused by constriction, reduced flow, or reduced intraluminal pressure during ischemia because under the same conditions dilation to endothelium-independent sodium nitroprusside is preserved. The selective endothelial dysfunction may play a role in exacerbating ischemia by precluding the ability of some dilators, released during ischemia, to dilate the resistance vessels.

Acetylcholine↗
PubMed2001

ACE genotype and endothelium-dependent vasodilation of conduit arteries and forearm microcirculation in humans.

The ACE gene is a candidate gene for cardiovascular disease. Endothelial dysfunction is considered an intermediate phenotype in the pathogenesis of hypertension and atherosclerosis. We evaluated the role of ACE gene polymorphism in endothelial function of young healthy humans. We assessed ACE genotype (deletion [D]/insertion [I] polymorphism) in 92 young healthy individuals. In 88 of them, endothelium-dependent (flow-mediated) vasodilation and endothelium-independent (nitroglycerin-induced) vasodilation were measured in the common femoral artery and in the brachial (n=84) artery by echo Doppler technique. In 35 subjects, we also applied the forearm perfusion technique to quantify the responses of the forearm vascular bed to 3 increasing doses of 2 endothelium-dependent vasodilators (acetylcholine and bradykinin) and 1 endothelium-independent vasodilator (sodium nitroprusside). The D allele of the ACE gene was associated with a significant blunting (Delta approximately 26%) of endothelium-dependent vasodilation in the femoral artery (P=0.02) but not in the brachial artery (P=0.55) or in the forearm microcirculation (P=0.70 to 0.80). Endothelium-independent vasodilation was unaffected by the ACE genotype. In young healthy humans, the D allele of the ACE gene is associated with selective endothelial dysfunction of the femoral artery. It remains to be determined whether this association discloses a causal role in vascular, particularly peripheral artery, disease.

Acetylcholine↗
PubMed1990

Mechanical and electrical properties of smooth muscle cells and their regulations by endothelium-derived factors in the guinea pig coronary artery.

Effects of high K+, acetylcholine (ACh), 9,11-epithio-11,12-methanothromboxane A2 (STA2), thrombin and endothelin were investigated on smooth muscles of the guinea pig coronary artery in intact and endothelium-denuded tissues. In intact tissues, ACh transiently inhibited but ATP produced maintained inhibition of the STA2-induced contraction. However, in the endothelium-denuded tissue, ACh produced contraction and ATP inhibited the STA2-induced contraction. In intact tissues, thrombin produced dual actions on the STA2-induced contraction with an initial relaxation followed by contraction. In endothelium-denuded tissues, thrombin enlarged the STA2-induced contraction without transient relaxation. In intact tissues prepared from both proximal and distal regions, endothelin showed the same dual action as observed with thrombin, whereas higher concentrations of endothelin showed only contraction. In endothelium-denuded tissues, endothelin consistently produced contraction. In intact tissues prepared from proximal and distal regions, ACh produced a biphasic response (initial hyperpolarization and subsequently generated depolarization). The amplitudes of both potential changes occurred in a membrane potential-dependent manner. In endothelium-denuded tissues, ACh depolarized the membrane in both tissues. In intact and endothelium denuded tissues, ATP hyperpolarized the membrane in inverse proportion to the membrane potential level, whereas thrombin and endothelin consistently depolarized the membrane. The results indicate that ACh acts on endothelial and smooth muscle cells, and the former releases both EDRF and EDHF. ATP only acts on smooth muscle cells and hyperpolarizes the membrane. STA2, thrombin and endothelin act on both endothelial and smooth muscle cells. STA2 and endothelin may release EDRF but not EDHF, and thrombin may release EDRF and endothelin.

Acetylcholine↗
PubMed1998

Endothelium-dependent vasodilation in response to Pseudomonas aeruginosa lipopolysaccharide: an in vitro study on canine arteries.

Early systemic arterial hypotension is a common clinical feature of Pseudomonas septicemia. To determine if Pseudomonas aeruginosa endotoxin induces the release of endothelium-derived nitric oxide (EDNO), an endogenous nitrovasodilator, segments of canine femoral, renal, hepatic, superior mesenteric, and left circumflex coronary arteries were suspended in organ chambers (physiological salt solution, 95% O2/5% CO2, pH 7.4, 37 degrees C) to measure isometric force. In arterial segments contracted with 2 microM prostaglandin F2 alpha, Pseudomonas endotoxin (lipopolysaccharide (LPS) serotype 10(Habs) from Pseudomonas aeruginosa (0.05 to 0.50 mg/ml) induced concentration-dependent relaxation of segments with endothelium (P < 0.05) but no significant change in tension of arteries without endothelium. Endothelium-dependent relaxation in response to Pseudomonas LPS occurred in the presence of 1 microM indomethacin, but could be blocked in the coronary artery with 10 microM NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthesis from L-arginine. The inhibitory effect of L-NMMA on LPS-mediated vasorelaxation of the coronary artery could be reversed by exogenous 100 microM L-arginine but not by 100 microM D-arginine. These experiments indicate that Pseudomonas endotoxin induces synthesis of nitric oxide from L-arginine by the vascular endothelium. LPS-mediated production of EDNO by the endothelium, possibly through the action of constitutive nitric oxide synthase (NOSc), may decrease systemic vascular resistance and may be the mechanism of early hypotension characteristic of Pseudomonas septicemia.

Animals↗
PubMed1993

Lysophosphatidylcholine-induced vascular relaxation and production of cGMP are mediated by endothelium-derived relaxing factor.

Endothelial cells produce powerful vasorelaxant substances, among them an endothelium-derived relaxing factor that is believed to be nitric oxide. It relaxes vascular smooth muscle via activation of guanylate cyclase and a subsequent rise in cyclic GMP level. Lysophosphatidylcholine is a potent endothelium-dependent vascular smooth muscle relaxant. Its action, similar to that of endothelium-derived relaxing factor, mediates an increase of cGMP in smooth muscle cells. The experiments reported here demonstrate that inhibitors of nitric oxide formation, such as N-omega-nitro-L-arginine and its methyl ester, inhibit relaxation and cyclic GMP formation by lysophosphatidylcholine in bovine pulmonary artery strips with intact endothelium in a dose-dependent manner. N-omega-Nitro-D-arginine methyl ester does not inhibit relaxation; L-arginine, but not D-arginine, reverses the effect of N-omega-nitro-L-arginine and its methyl ester. It is concluded that lysophosphatidylcholine-induced endothelium-dependent vasorelaxation is endothelium-derived relaxing factor-mediated.

Animals↗
PubMedDate not supplied

Role of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factor in bovine coronary arteries.

BACKGROUND: Acetylcholine and bradykinin cause endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle. These responses are mediated in part by an endothelium-derived hyperpolarizing factor (EDHF). Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid and appear to function as EDHFs in the coronary artery. This conclusion is based on the findings that EETs are synthesized by the vascular endothelium, open calcium-activated potassium (KCa) channels, hyperpolarize and relax vascular smooth muscle. METHODS: Bovine coronary arteries were precontracted with U46619 and isometric tension was measured to agonists. Whole cell K currents were measured in coronary smooth muscle cells by the patch clamp method. RESULTS: Bradykinin caused a concentration-related relaxation (ED50=10(-10) M) which was not affected by inhibitors of cytochrome P450. Inhibition of NO synthase and cyclooxygenase reduced the response to bradykinin (ED(50)=2 x 10(-9) M) and these responses were then completely blocked by cytochrome P450 inhibitors. 11, 12-EET relaxed the precontracted bovine coronary artery with an ED50 of 3 x 10(-8) M in the presence and absence of the endothelium. 14, 15-EET caused an increase in outward potassium current that was blocked by the KCa channel inhibitor iberiotoxin. A series of 14, 15-EET analogs were tested for agonist activity. CONCLUSIONS: These data indicate that cytochrome P450 metabolites contribute to bradykinin-induced, endothelium-dependent relaxations but only following inhibition of NO synthase and cyclooxygenase. EETs relax coronary arteries in an endothelium-independent manner. Carbon-1 carboxyl, 8, 9 and 11, 12-double bonds and 14, 15-epoxy groups are required for full agonist activity. These studies provide further support for the hypothesis that EETs represent EDHFs in the coronary artery and mediate the relaxation responses to bradykinin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Interaction of non-arginine compounds with the endothelium-derived relaxing factor inhibitor, NG-monomethyl L-arginine.

NG-Monomethyl L-arginine (L-NMMA) inhibits endothelium-dependent relaxation. It is widely accepted that this effect is due to the inhibition of L-arginine metabolism. Here we show that L-NMMA antagonizes the vasodilator effects of compounds other than L-arginine. In the endothelium intact rat aorta preparation, L-NMMA antagonizes the relaxation induced by N-alpha-benzoyl L-arginine ethyl ester, amiloride and dibutyryl cAMP. This effect of L-NMMA is not due to the inhibition of the basal release of endothelium-derived relaxing factor since relaxations of amiloride and dibutyryl cAMP are not significantly different in the presence or absence of endothelium. Addition of superoxide dismutase significantly attenuates the vasoconstrictor effect of L-NMMA and restores the endothelium-dependent relaxation, demonstrating that superoxide anion may be involved in the vascular effects elicited by L-NMMA. Paradoxically, at concentrations greater than 1 mM, L-NMMA elicits endothelium-independent relaxation, which is antagonized by methylene blue. The relaxation elicited by L-NMMA is accompanied by the formation of a citrulline-like product in the rat aorta. Thus, L-NMMA has properties other than simple inhibition of L-arginine metabolism in the rat aorta preparation.

Amiloride↗
PubMed1989

Phorbol dibutyrate inhibits release and action of endothelium-derived relaxing factor(s) in canine blood vessels.

The effects of phorbol esters on endothelium-dependent relaxations evoked by ACh and the calcium ionophore A23187 were analyzed in isolated canine femoral and coronary arteries mounted in organ chambers or in a bioassay system. In rings of femoral and coronary arteries, phorbol 12,13-dibutyrate (PDBu) (10(-7) M) evoked contraction (ED50 2.9 x 10(-8) M) and depressed endothelium-dependent relaxations to ACh (4-fold increase in ED50 and 72% depression of maximal response). PDBu depressed maximal relaxations to A23187 by 50% but had no effect on ED50. The inactive phorbol ester 4-alpha-phorbol didecanoate (10(-7) M) did not evoke contractions and had no effect on endothelium-dependent relaxations to ACh or A23187. Endothelium-independent relaxations to sodium nitroprusside were not effected by PDBu (10(-7) M) in femoral or coronary arteries. In bioassay experiments, selective treatment of perfused femoral artery segments with PDBu (10(-8)-10(-6) M) caused concentration-dependent inhibition of basal and ACh- (10(-6) M) and A23187-(10(-6) M) induced release of endothelium-derived relaxing factor (EDRF) (as assessed by relaxation of superfused bioassay coronary artery rings without endothelium). PDBu inhibited these responses with different potency: basal (10(-8) M) greater than ACh (10(-7) M) much greater than A23187 (only partial inhibition at 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗