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At least 1,063 records · Page 59Linked to original sources
PubMed1993

Acetylcholine stimulates release of endothelium-derived relaxing factor in coronary arteries of human organ donors.

OBJECTIVE: To determine whether cholinergic stimulation of human coronary endothelial cells induces the release of endothelium-derived relaxing factor (EDRF), denuded human coronary artery rings or denuded rabbit aorta rings were either directly perfused or superfused by the effluent of intact or denuded human coronary artery segments in a perfusion bioassay system. DESIGN: Coronary vessels were dissected from hearts of organ donors and prepared for use as donor segments and detector rings in the perfusion bioassay system. Segments were continuously perfused by an oxygenated Krebs-Ringer solution. Rings were suspended between two stirrups, one of which was connected to an isometric force transducer. They were either directly perfused (no tissue had been previously perfused by the same Krebs-Ringer) or superfused by the effluent of an endothelium-intact or -denuded coronary segment. Human rings were contracted with prostaglandin F2 alpha (2 x 10(-6) M) and rabbit rings were contracted with phenylephrine (10(-6) M). RESULTS: Tension in detector tissue did not change during superfusion with effluent from endothelium-denuded or -intact human coronary artery segments, showing that there was no basal release of EDRF/nitric oxide (NO) in this preparation. Acetylcholine (ACh) (10(-6) or 10(-5) M) added to the perfusate increased the tension of the precontracted endothelium-denuded human rings directly perfused (50 +/- 32%) but not of the precontracted rabbit rings, showing that ACh is a potent agonist of human coronary vascular smooth muscle. ACh added to the coronary segment in the endothelium-intact superfusion mode had no effect in 33% or induced a small relaxation (8.8 +/- 1.6%) in 66% of the preparations. Hemoglobin (10(-5) M), a scavenger of EDRF/NO, caused a further increase in tension (32 +/- 15%). Adding calcium ionophore (A 23187;10(-5) M), which stimulates EDRF/NO release through a nonreceptor-mediated mechanism, to the coronary artery segment induced a relaxation in the endothelium-perfused detector rings which did not relax to ACh (30 +/- 2%); this relaxation was reversed by methylene blue (10(-5) M), a blocker of soluble guanylate cyclase. NO endothelin, a potent vasoconstrictor released by the endothelial cells, was detected in the effluent of intact coronary vessels. CONCLUSION: The results suggest that in two-thirds of the six preparations studied, cholinergic stimulation can release EDRF from human donor coronary artery endothelial cells.

Acetylcholine↗
PubMed1993

Angiotensin-converting enzyme inhibitors unmask endogenous kinin production by bovine coronary artery endothelium.

The angiotensin converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat, relaxed preconstricted endothelium-intact bovine coronary artery rings and enhanced the relaxant response to bradykinin. The relaxation was observed in the presence of a cyclooxygenase inhibitor and without previous exposure to bradykinin. ACE inhibitor-dependent relaxation was attenuated by the selective B2-kinin receptor antagonist, Hoe 140, and completely abolished by removal of the endothelium. Bradykinin or moexiprilat also significantly increased the cyclic guanosine monophosphate (cGMP) content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA), or by removal of the endothelium. NNA also diminished the relaxant response to moexiprilat, but only partially inhibited that to bradykinin, suggesting that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part by another endothelium-dependent mechanism. These findings indicate that ACE inhibitors can elicit endothelium-dependent relaxations presumably by facilitating the accumulation of endothelium-derived kinins in or at the vessel wall. This local mechanism may significantly contribute to the antihypertensive action of these compounds in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1977

Effect of the ophthalmic preservative thimerosal on rabbit and human corneal endothelium.

Widespread use of the mercurial-containing preservative thimerosal as an antibacterial agent in ophthalmic drugs and solutions warranted an investigation into its possible cytotoxic effects on the functional and ultrastructural integrity of the corneal endothelium. No changes in corneal thickness were observed during 5 hours' perfusion of the endothelium of rabbit and human corneas with 0.0001 and 0.0005 percent thimerosal in glutathione bicarbonate Ringer's solution (GBR). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) of the endothelium of the 0.0001 percent group revealed normal ultrastructure. SEM and TEM of the endothelium of corneas perfused with 0.0005 percent thimerosal for 5 hours revealed condensed mitochondria, cytoplasmic vacuoles, and cytoplasmic flaps at the apical end of the cellular junctions. Perfusion of higher concentrations (0.001 and 0.005 perecnt) of thimerosal in GBR resulted in increases in corneal thickness after 2 hours and irreversible ultrastructural damage to the endothelial cells by 5 hours. Corneas perfused with 0.01 and 0.1 percent thimerosal in GBR showed a rapid and immediate increase in corneal thickness and endothelial cell death and necrosis within 1 hour. It is postulated that the mercury in thimerosal becomes bound to the cell membrane protein sulfhydryl groups, causing an increase in cellular permeability; These results suggest that the prolonged exposure of the corneal endothelium to thimerosal in the accepted antimicrobial dosage of 0.005 to 0.001 percent may result in functional and structural damage to the endothelium.

Animals↗
PubMed1993

Expression of the leukocyte common antigen CD45 by endothelium.

The CD45 family of Ag expressed by leukocytes play a key role in lymphocyte activation. In this study, we identify both a restricted pattern of expression of CD45 Ag by human endothelial cells and differences in m.w. of endothelial CD45 compared with lymphocyte CD45. Initially, immunoperoxidase staining of endothelial cells in culture revealed the presence of the CD45RO isoform provided the endothelial cells had been stimulated by IL-1 for several days. No other isoform of CD45 was detected by immunoperoxidase staining of endothelium. Leukocyte common antibodies, reputed to detect all isoforms of CD45, did not detect endothelial CD45RO. A polymerase chain reaction method was then used to demonstrate that the message for the CD45RO isoform was constitutively present, with increased levels after IL-1 stimulation. Western blot confirmed the presence of the RO isoform. No other CD45 isoform was detected, either by PCR amplification for message or by Western blot. There were clear differences between lymphocyte and endothelial CD45. The RO isoform expressed by endothelium has an estimated M(r) of 235,000 in contrast to lymphocyte RO that, on our gels, has an estimated M(r) of 190,000. Given the large surface area of endothelium (approximately 1 km2 in the human), the close apposition of lymphocytes and endothelium in immunologic tissues such as lymph nodes, and the pivotal role CD45 plays in activation, expression of CD45RO by endothelium may have important implications in lymphocyte-endothelial interactions. This is most likely to occur in endothelium after a few days of IL-1 stimulation, e.g., at sites of chronic inflammation, or in the draining lymph node of an inflammatory focus.

Actins↗
PubMed1993

Cyclopiazonic acid causes endothelium-dependent relaxation in rat aorta.

The effects of cyclopiazonic acid (CPA), a selective inhibitor of Ca(2+)-pump ATPase for endoplasmic reticulum (ER), on the contractility of rat aorta with and without intact endothelium were studied to investigate the possible involvement of endothelial ER Ca(2+)-pump in the release of endothelium-derived relaxing factor (EDRF), which is known to cause vascular relaxation or inhibition of phenylephrine (PE)-precontracted aorta. When added to the organ bath cumulatively, CPA concentration-dependently caused gradual development of contraction, which was much less in aortic rings with intact endothelium than in endothelium-denuded aortic rings. But CPA at low concentrations (1-3 mumol.L-1) induced vascular relaxation when added to PE (3 mumol.L-1)-precontracted aortic rings with intact endothelium, but not in denuded aortic rings. This relaxant effect of CPA is very similar to the effect of acetylcholine (ACh), which is well recognized to be mediated by the release of EDRF from the endothelium. NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, completely prevented the vascular relaxation induced by CPA or ACh and the inhibitory effect of L-NAME was partially reversed by L-arginine (L-Arg). Treatment of the aortic rings with nifedipine (Nif) 0.3 mumol.L-1 did not affect the relaxant effect of ACh or CPA on PE-induced contraction indicating that the Ca(2+)-entry to the endothelial cells as a result of receptor activation by ACh or ER Ca(2+)-pump inhibition by CPA was via channels other than L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMedDate not supplied

Altered endothelium-mediated relaxation by sympathectomy in isolated rabbit carotid artery rings.

The influence of cervical and periarterial sympathectomy on endothelium-dependent and endothelium-independent relaxations of the mature rabbit carotid artery was studied in vitro. The responses to adenosine, vasoactive intestinal polypeptide and substance P in sympathectomized and control rabbit carotid artery rings were recorded and analyzed. The effects of endothelium removal were also investigated. The maximal relaxation achieved by substance P, which produces endothelium-dependent relaxation, was significantly inhibited in 3 weeks in postsympathectomy arterial preparations as compared to controls. Adenosine and vasoactive intestinal polypeptide, which produce endothelium-independent relaxation, elicited similar relaxation in all tissues. These results demonstrated that the response to substance P was impaired by cervical and periarterial sympathectomy. The decreased maximum response to substance P may be the result of a decreased NK-1 receptor subtype density or excitation/response coupling, or it may be due to an impaired production and/or liberation of endothelium-derived relaxing factor (EDRF).

Adenosine↗
PubMed1995

beta-Adrenoceptor activates endothelium-dependent release of nitric oxide in rat aorta.

AIM: To examine the possible role of agents elevating cAMP to release NO from aortic endothelial cells. METHODS: NG-nitro-L-arg inine methylester (L-NAME), an inhibitor of NO synthase, partially inhibited endothelium-dependent relaxation evoked in phenylephrine-precontracted rings by isoproterenol and abolished relaxation mediated by forskolin 0.2 mumol L-1. RESULTS: In rings without endothelium, isoproterenol and forskolin were less effective relaxants and L-NAME had no effect on the responses. In methylene blue-treated rings isoproterenol- and forskolin-induced relaxation were prevented in both endothelium-intact and -denuded rings, but the inhibitory effect of methylene blue were significantly more in rings with endothelium than in those without. On the other hand, relaxation induced by sodium nitroprusside was not inhibited by L-NAME, but was inhibited by methylene blue in both the endothelium-intact and -denuded rings. The concentration-relaxation curves to sodium nitroprusside after methylene blue were identical for rings with and without endothelium. CONCLUSION: beta-Adrenoceptors or any agent which raises cAMP elevate NO release from endothelial cells.

Adrenergic beta-Agonists↗
PubMed1996

Phorbol ester stimulation increases sickle erythrocyte adherence to endothelium: a novel pathway involving alpha 4 beta 1 integrin receptors on sickle reticulocytes and fibronectin.

Sickle-cell adherence to endothelium has been hypothesized to initiate or contribute to microvascular occlusion and pain episodes. Adherence involves plasma proteins, endothelial-cell adhesion molecules, and receptors on sickle erythrocytes. It has previously been reported that sickle reticulocytes express the alpha 4 beta 1 integrin receptor and bind to cytokine-activated endothelium via an alpha 4 beta 1/vascular-cell adhesion molecule-1 (VCAM-1) interaction. To elucidate other roles for alpha 4 beta 1 in sickle-cell adherence, the ability of activated alpha 4 beta 1 to promote adhesion to endothelium via a ligand different than VCAM-1 was explored. Adherence assays were performed under dynamic conditions at a shear stress of 1 dyne/cm2. Preincubation of sickle erythrocytes with phorbol 12,13-dibutyrate (PDBu) increased adherence of sickle cells eightfold as compared with untreated sickle cells. Normal erythrocytes, whether treated with PDBu or not, did not adhere to the endothelium. Activating anti-beta 1 antibodies 4B4 and 8A2 also increased the adhesion of sickle, but not normal, red blood cell (RBC) adhesion to endothelium. Anti-alpha 4 antibodies HP1/2 and HP2/1, inhibitory antibody 4B5, or an RGD peptide inhibited sickle-cell adherence induced by PDBu. Additional studies were undertaken to examine if fibronectin, a ligand for activated alpha 4 beta 1, was involved in PDBu-induced sickle erythrocyte adherence. Adherence of PDBu-treated sickle cells was completely inhibited by the CS-1 peptide of fibronectin. Fibronectin was detected on the surface of washed endothelium using an antifibronectin antibody in enzyme-linked immunosorbent assays. Antifibronectin antibody pretreatment of endothelial cells inhibited PDBu-induced adherence by 79% +/- 17%. Incubation of sickle RBCs with exogenous fibronectin after PDBu treatment inhibited adherence 86% +/- 8%. Taken together, these data suggest that endothelial-bound fibronectin mediates adherence of PDBu-treated sickle cells. Interleukin-8 (IL-8), a chemokine released in response to bacterial infection, viral infection, or other injurious agents, and known to activate integrins, also increased adherence of sickle erythrocytes to endothelial cells via fibronectin. This novel adherence pathway involving sickle-cell alpha 4 beta 1 activated by PDBu or IL-8 may therefore be relevant in vivo at vascular sites that produce IL-8 or similar agonists in response to vascular injury or immune activation. These observations describe ways in which inflammation and immune responses cause vasoocclusive complications in sickle-cell disease.

Amino Acid Sequence↗
PubMed1996

[The effect of adaptation to a physical load on the endothelium-mediated reactions of isolated vessels and NO production in rats].

Adaptation to exercise exerts a beneficial therapeutic and protective effect in several cardiovascular diseases many of which are characterized by disorders of endothelium-dependent vascular responses. To evaluate a possible role of functional condition of the endothelium in protective effects of adaptation to exercise we studied the effect of such adaptation on endothelium-dependent constrictor and dilator responses of the isolated rat aorta and on nitric oxide (NO) production in the organism. It was shown that adaptation to exercise (swimming) increased the suppression by the endothelium of constrictor responses to norepinephrine and potentiated the endothelium-dependent relaxation to acetylcholine. Furthermore adaptation to exercise considerably increased the NO production in the heart, liver, spleen, kidney and intestine as assayed by the method of electron paramagnetic resonance. We suggest that the adaptive increase in synthesis and accumulation of NO in the organism may underlie the protective effect of dosed physical training in diseases attended by disturbance of the functional condition of vascular endothelium.

Acetylcholine↗
PubMed1997

5-Hydroxytryptamine-induced endothelium-dependent and -independent relaxations in isolated dog anterior spinal small arteries.

The mode of action of 5-hydroxytryptamine (5HT) was investigated in isolated dog anterior spinal small arteries. Lower concentrations of 5HT (10(-9)-10(-7) M) caused a dose-dependent contraction and higher concentrations (10(-6)-10(-3) M) produced a dose-dependent relaxation of the arteries precontracted by 10(-7) M U 46619. The 5HT-induced relaxation was significantly antagonized by methiothepin (10(-9)-10(-6) M). Ketanserin (10(-6) M) and ICS 205-930 (3 x 10(-6) M) did not affect the 5HT-induced relaxation of the arteries. The relaxant response to 5HT was reduced significantly by mechanical rubbing of the endothelial cells. The 5HT-induced endothelium-independent relaxation was also antagonized significantly by methiothepin (10(-6) M). Aspirin (5 x 10(-5) M) or N omega-nitro-L-arginine methyl ester (L-NAME) (10(-6) M) significantly suppressed the 5HT-induced endothelium-dependent relaxation. L-Arginine (10(-3) M) also significantly reversed the L-NAME induced reduction of the 5HT-induced endothelium-dependent relaxation. Treatment with L-NAME in the presence of aspirin also produced much greater reduction of the 5HT-induced endothelium-dependent relaxation. Isocarbacyclin (10(-9)-10(-5) M) induced a concentration-dependent relaxation of the isolated spinal small arteries precontracted by 10(-7) M U 46619. These results suggest that 5HT induces endothelium-dependent and -independent relaxations of the isolated anterior spinal small arteries mainly via activation of 5HT1-like receptor and that endogenous nitric oxide and vasodilative prostaglandins may contribute to the 5HT-induced endothelium-dependent relaxation of the arteries.

Animals↗
PubMed1996

[Possible mechanisms for reduced endothelium dependent responsiveness to norepinephrine in isolated aorta of rats with peritonitis shock].

Various antagonists were used to analyze the possible factors contributing to the reduced endothelium-dependent response to norepinephrine in isolated aorta of rats with peritonitis shock. The concentration-effect curves to norepinephrine in the aortic rings with endothelium pretreated by methyl blue, atropine, anisodamine and indomethacin were shift to the left and the largest contraction was raised. The concentration-effect curve to norepinephrine was also shift to the left and the largest contraction was raised in the aortic ring with endothelium pretreated by propranolol. However, the similar changes were also observed in rings without endothelium pretreated by propranolol. While the concentration-effect curves to norepinephrine were shift to the right and the largest contraction reduced in rings with or without endothelium that pretreated by Yohimbine. The results suggested that the reduced endothelium-dependent responsiveness to norepinephrine in the isolated aorta of rats with peritonitis shock may involve various factors of which vasodilatation mediated by cGMP may be the one of importance.

Animals↗
PubMedDate not supplied

[Nitrates and coronary vascular endothelium dysfunction].

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.

Coronary Vessels↗
PubMed1997

Role of gender and vascular endothelium in rat aorta response to 17 beta-estradiol.

Estrogen supplementation in postmenopausal women offers significant cardiovascular protection. The mechanism for this benefit is unclear but may be due to an interaction of estrogen with the blood vessel wall (vascular smooth muscle and endothelium). We examined the response of weight-matched female and male endothelium-intact and -denuded aortae to 17 beta-estradiol, its interaction with noradrenaline, and the effect of N-nitro-L-arginine. Estradiol produced relaxation responses that were significantly greater in female endothelium-intact preparations. This response was sensitive to N-nitro-L-arginine, while the response to 17 beta-estradiol in male endothelum-intact and both female and male endothelum-denuded preparations was resistant. Estradiol also inhibited contractions to noradrenaline, which was more pronounced in the female endothelium-intact aortic rings. These data imply that estradiol interacts preferentially with the female vascular endothelium, but there exists an endothelium-independent process that can also be activated in the male aorta. Further studies are warranted to elucidate these differential mechanisms.

Animals↗
PubMed2004

Hydrogen peroxide as an endothelium-derived hyperpolarizing factor.

Vascular endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, such as prostacyclin, nitric oxide (NO), and a yet unidentified endothelium-derived hyperpolarizing factor (EDHF). Possible candidates for EDHF include epoxyeicosatrienoic acids (EETs), endothelium-derived potassium ions (K(+)), and as we have recently identified, hydrogen peroxide (H2O2). Electrical communication between endothelial and smooth muscle cells through gap junctions has also been suggested to be involved in endothelium-dependent hyperpolarization. Among the above candidates, the H2O2 hypothesis well explains the pathophysiological interactions between NO and EDHF and re-highlights the physiological roles of the reactive oxygen species (ROS) in endothelium-dependent vascular responses. This brief review summarizes our current knowledge about H2O2 as an EDHF, with special reference to its production by the endothelium, its action on membrane potentials and its pathophysiological roles.

Animals↗
PubMed1999

Endothelium-derived nitric oxide enhances the effect of intraaortic balloon pumping on diastolic coronary flow.

BACKGROUND: High shear rate with pulsation is one of the major stimuli for the release of endothelium-derived nitric oxide leading to coronary arteriolar dilation. Intraaortic balloon pumping mechanically enhances shear rate and diastolic-to-systolic flow oscillation. We aimed to evaluate whether or not coronary blood flow augmentation during intraaortic balloon pumping is mediated by coronary arteriolar dilation through endothelium-derived nitric oxide release. METHODS: Using a charge-coupled device intravital videomicroscope, we observed epicardial coronary arterioles (40 to 220 microm in diameter) in anesthetized open-chest dogs (n = 10) during 2:1 mode of intraaortic balloon pumping. Endothelium-derived nitric oxide-mediated vasodilatory effects of intraaortic balloon pumping were evaluated by comparing end-diastolic arteriolar diameters between the coupled beats of on and off intraaortic balloon pumping before and after intracoronary endothelium-derived nitric oxide synthesis inhibition with Nomega-nitro-L-arginine (L-NNA, 2 micromol/min) administration. RESULTS: Intraaortic balloon pumping increased coronary arteriolar diameters and coronary blood flow by 11.4%+/-1.8% (p < 0.0001) and 33.4%+/-4.1% (p < 0.001), respectively. Vasodilation was greater in small arterioles (<110 microm; 15.4%+/-2.2%) than in large arterioles (> or =110 microm; 4.2%+/-1.2%, p < 0.0001). L-NNA attenuated the intraaortic balloon pumping-induced vasodilation and augmentation of coronary blood flow to 4.6%+/-1.0% (p < 0.001) and to 20.8%+/-2.1%, (p < 0.05), respectively. Attenuation of vasodilatory effect by L-NNA was observed mainly in small arterioles (from 15.4%+/-2.2% to 5.9%+/-1.2%). CONCLUSIONS: Intraaortic balloon pumping augmented coronary blood flow by dilating coronary arterioles in diastole, more significantly in small arterioles than in large arterioles. Endothelium-derived nitric oxide inhibition markedly attenuated these effects. We conclude that, in a canine model, endothelium-derived nitric oxide contributes to mechanical enhancement of the coronary blood flow with diastolic arteriolar vasodilation during intraaortic balloon pumping.

Acetylcholine↗
PubMed1997

Flow-induced release of endothelium-derived relaxing factor during pulsatile bypass: experimental study in the fetal lamb.

OBJECTIVE: This study was initiated to test the hypothesis that fetal hemodynamic changes observed under pulsatile flow bypass might be related to the release of endothelium-derived relaxing factor through oscillating shear stress. METHODS: Normothermic bypass was instituted in utero in 21 preterm fetal lambs for a 1-hour period through the right atrium and main pulmonary artery. Ultrasonic flowmeters were positioned around the descending aorta and the umbilical artery. The circuit consisted of an oxygenator and a pump set to either continuous flow (n = 7) or pulsatile flow (n = 7) and adjusted to maintain a fetal main arterial pressure of 50 mm Hg. In seven other animals, endothelium-derived relaxing factor was blocked by a continuous infusion of N omega-nitro-L-arginine after 30 minutes of pulsatile flow. RESULTS: During the first 30 minutes of bypass, pump flows were significantly lower in the continuous-flow group than in the pulsatile-flow or blocked-flow groups (respectively, 612 +/- 144, 907 +/- 153 and 987 +/- 228 ml/min), with similar changes in aortic and umbilical flows. Systemic vascular resistances were significantly lower in the pulsatile-flow and blocked-flow groups than in the continuous-flow group (550 +/- 106 vs 821 +/- 212 dynes/sec/cm-5). However, after blockade of endothelium-derived relaxing factor, resistances increased gradually in the blocked-flow group to reach the level of that of the continuous-flow group at the end of bypass (943 +/- 77 vs 556 +/- 143 dynes/sec/cm-5 in the pulsatile-flow group). CONCLUSIONS: Blockade of endothelium-derived relaxing factor after 30 minutes of pulsatile flow returns fetal hemodynamics to continuous flow conditions. The specific inhibitor of endothelium-derived relaxing factor used in this experiment suggests that nitric oxide may be released by fetal endothelium during pulsatile bypass.

Animals↗
PubMed2000

Evidence for an endothelium-derived hyperpolarizing factor in the superior mesenteric artery from rats with cirrhosis.

In cirrhosis, in splanchnic arteries, endothelium-dependent relaxation may persist even if overactive nitric oxide synthase (NOS) and cyclooxygenase (COX) are inhibited. In normal arteries, a significant endothelium-dependent relaxation to acetylcholine persists after NOS/COX inhibition. This relaxation is caused by smooth muscle cell (SMC) membrane hyperpolarization, which is sensitive to a combination of the potassium channel blockers apamin and charybdotoxin, and is mediated by an endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to detect EDHF and evaluate its pathophysiologic role in isolated superior mesenteric arteries from cirrhotic rats. Arterial rings were obtained and exposed to N(w)-nitro-L-arginine (L-NNA, a NOS inhibitor) and indomethacin (a COX inhibitor). Acetylcholine-induced membrane potential responses and concentration-response curves to the relaxant of acetylcholine were obtained with and without apamin plus charybdotoxin. Acetylcholine-induced responses were measured in certain rings from endothelium-denuded arteries. Contractions caused by the alpha(1)-adrenoceptor agonist phenylephrine were obtained in cirrhotic and normal rings with and without apamin and charybdotoxin. Significant acetylcholine-induced, endothelium-dependent, apamin- and charybdotoxin-sensitive, SMC membrane hyperpolarization and relaxation were found. An apamin- and charybdotoxin-sensitive hyporesponsiveness to the contractile action of phenylephrine was found in cirrhotic rings. In conclusion, in cirrhotic rats, in the superior mesenteric artery exposed to NOS/COX-inhibitors, an EDHF exists that may replace NOS/COX products to induce endothelium-dependent arterial relaxation.

Acetylcholine↗
PubMedDate not supplied

Perfused rabbit heart: endothelium-derived relaxing factor in coronary arteries.

The study was performed to demonstrate the presence of the endothelium-derived relaxing factor (EDRF), previously found to be active in isolated artery preparations in vitro, in the coronary arteries of rabbits remaining in contact with the beating perfused heart. This was accomplished by following the response of the preconstricted obtuse marginal coronary artery to topically administered acetylcholine (ACH). Both intact arteries and arteries in which the endothelium had been removed were studied. Preconstriction of the obtuse marginal coronary artery was accomplished by topical application (spray) of histamine (10 microM), in 2 ml Krebs-Henseleit (KH) solution. This resulted in a decrease in internal diameter of the coronary artery, a decline in coronary flow, and an increase in total coronary vascular resistance. The principal difference between intact coronary arteries and those in which the endothelium had been removed was in the response to ACH. In arteries with intact endothelium preconstricted with histamine, topical administration (spray) of ACH (0.6 mM in 2 ml KH solution) caused, as compared with histamine, an increase in coronary flow, a significant decrease in total coronary vascular resistance, and a rise in internal vascular diameter. Arteries in which the vascular endothelium had been removed, as compared to those pretreated with histamine, responded to topical administration of ACH (0.6 mM in 2 ml KH solution) with a decrease in coronary flow, coronary vascular resistance, and internal vascular diameter. No change in the dose-response curve to histamine between the two preparations was noted. The results demonstrate that coronary vascular endothelium exerts a protective effect in coronary arteries remaining in contact with the perfused beating heart.

Acetylcholine↗