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PubMed1989

[Vasodilator agents and the vascular endothelium].

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).

Endothelium, Vascular↗
PubMed1989

Role of the LFA-1 adhesion glycoprotein in neutrophil adhesion to endothelium and plastic surfaces.

Neutrophil adherence to endothelium is known to be mediated, at least in part, by adhesion molecules such as LFA-1. Deficiency of these adhesion molecules leads to recurrent infection and early death from infection. As screening for defects of these adhesion glycoproteins is often performed by the ability of neutrophils to adhere to plastic plates, in this study a comparison of neutrophil adherence by the CD18/CD11a (LFA-1) mechanism to endothelium and plastic surfaces was examined. Baseline neutrophil adherence was two-fold higher to plastic than to endothelium (17% +/- 9 for plastic, 8% +/- 5 for endothelium). Baseline adherence to endothelium was partially inhibitable by anti-LFA-1 antibodies, whereas no inhibition of adherence occurred on plastic. Neutrophil stimulants increased adherence to both surfaces, although only on endothelium was this increase attributable to the LFA-1 mechanism. IL-1 increased adherence to endothelium, but had no effect on plastic. We conclude that adherence of neutrophils to plastic surfaces probably represents overall activation status through undefined mechanisms, is not by LFA-1 receptor ligand interactions, and is therefore a non-physiological phenomenon. Endothelial receptors are pivotal in neutrophil adherence. It would be more appropriate to screen leucocytes for leucocyte adhesion deficiency by assaying for specific receptor occupancy with monoclonal antibodies, rather than an assay such as adhesion to plastic where the adhesion ligand is non specific.

Antigens, Differentiation↗
PubMed1989

Endothelium-dependent vascular responses: effect of hypertension and cyclosporin A.

Through the release of endothelium-derived relaxing and contracting factors, the endothelium can profoundly affect local vascular tone. In hypertension and during chronic cyclosporin A therapy, morphological changes of the endothelium develop. Recent studies in isolated arteries have demonstrated that endothelium-dependent relaxations induced by a variety of substances are decreased in acute and chronic hypertension and during cyclosporin A therapy. A reduced vascular smooth muscle responsiveness to endothelium-derived relaxing factor, the release of a cyclooxygenase-dependent endothelium-derived contracting factor in some animal models of hypertension, and possibly a decreased release of EDRF under some conditions may contribute to these functional alterations. In hypertension and during cyclosporin. A therapy, functional changes of the endothelium may contribute to increased peripheral vascular resistance and to vascular damage occurring under these conditions.

Animals↗
PubMed1986

Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid.

The objective of this study was to ascertain whether "endothelium-derived relaxing factor" (EDRF) released from bovine intrapulmonary artery and vein is capable of directly activating soluble guanylate cyclase, thereby accounting for elevated vascular levels of cyclic GMP during EDRF release. Isolated arterial and venous rings, after equilibration and depolarization in bath chambers, were transferred to reaction tubes and incubated with soluble guanylate cyclase that had been purified to homogeneity from bovine lung. Addition of test agents to either bath chambers or enzyme reaction mixtures enabled the determination of their sites of action. Arterial and venous rings caused an endothelium-dependent 2- to 3-fold enzyme activation that was inhibited by methylene blue. Endothelium-dependent enzyme activation in artery but not vein was enhanced several-fold by acetylcholine in an atropine-sensitive manner. Bradykinin, which relaxes both artery and vein when endothelium is intact, activated guanylate cyclase upon addition of endothelium-intact rings to enzyme reaction mixtures. Vasoactive intestinal peptide, which causes endothelium-dependent relaxation of artery but not vein, also activated guanylate cyclase in the presence of endothelium-intact artery but not vein. Arachidonic acid activated the enzyme directly as well as through EDRF release from artery but not vein. Atrial peptides, prostacyclin, isoproterenol and nitroglycerin were inactive. Methylene blue was a powerful inhibitor of EDRF-elicited activation of guanylate cyclase but was without effect when rings were merely pretreated with methylene blue in bath chambers with no further addition to enzyme reaction mixtures. Thus, methylene blue did not interfere with the formation, release or chemical stability of EDRF, but rather inhibited its influence on guanylate cyclase. No agent was found to inhibit EDRF generation or release.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1985

[Regulation of vascular tone by the endothelium].

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such different stimuli as increases in blood flow and hypoxia as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23 187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.

Animals↗
PubMed1987

Blood flow- and endothelium-mediated vasomotion of iliac arteries in conscious dogs.

The effects of removal of endothelium and changes in blood flow in conscious dogs on the responses of large iliac artery diameter to local infusion of nitroglycerin, acetylcholine, epinephrine, and norepinephrine into the iliac artery were studied. Infusion of agonists did not change mean arterial pressure or heart rate. In vessels with intact endothelium, iliac diameter increased with nitroglycerin (5.1 +/- 0.5%), acetylcholine (4.5 +/- 0.5%), and epinephrine (3.5 +/- 0.9%) and decreased with norepinephrine (-6.7 +/- 1.7%). Preventing increases in blood flow during infusions of agonists abolished the dilation with epinephrine but not with nitroglycerin or acetylcholine. When blood flow was completely stopped by occlusion of the iliac artery, local injection of nitroglycerin (5.7 +/- 0.7%) and acetylcholine (3.0 +/- 0.6%) dilated, but epinephrine constricted (-9.1 +/- 1.7%), the iliac artery. Removal of the iliac artery endothelium did not change the dilation with nitroglycerin (4.6 +/- 0.5%), abolished the dilation with acetylcholine (0.0 +/- 0.3%), reversed the dilation with epinephrine to constriction (-3.3 +/- 0.7%), and enhanced the constriction with norepinephrine (-13.6 +/- 1.6%). These results indicate that epinephrine and acetylcholine dilate the iliac artery via a mechanism mediated by the endothelium. The endothelium-dependent dilation observed with epinephrine is mediated by an increase in iliac blood flow, while that observed with acetylcholine is due partially to a direct effect on the endothelium as well as an effect of blood flow superimposed on the direct effect. The results further indicate that the endothelium attenuates vasoconstriction produced by the alpha-adrenergic agonists, norepinephrine and epinephrine.

Acetylcholine↗
PubMed1988

Endothelium-dependent and independent responses to prostaglandin H2 and arachidonic acid in isolated dog cerebral arteries.

The addition of prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog cerebral arteries partially contracted with PGF2 alpha or K+. The contraction was abolished by removal of endothelium, and the relaxation was potentiated. Relaxation induced by PGI2 was not influenced by endothelium denudation. The PGH2-induced contraction in strips with intact endothelium was not influenced by OKY-046, a thromboxane A2 synthesis inhibitor, but was abolished by treatment with ONO3708, an antagonist of vasoconstrictor PGs, whereas the relaxation was inhibited by tranylcypromine or diphloretin phosphate, a nonselective PG antagonist. Contraction induced by arachidonic acid (AA) was reversed to relaxation by removal of endothelium or treatment with ONO3708. Treatment with indomethacin attenuated the AA-induced contraction in the intact strips and also the relaxation in the strips treated with ONO3708 or denuded of endothelium. It may be concluded that vasoconstrictor PGs are synthesized from PGH2 or AA mainly in endothelium, and the production of PGI2 from PGH2 is not dependent on endothelium. Thromboxane A2 in concentrations sufficient to elicit significant contractions does not appear to be liberated from the cerebroarterial wall stimulated by PGH2.

Animals↗
PubMedDate not supplied

Influence of endothelium on the vasoconstrictor effect of dihydroergotamine in the isolated rat aorta.

The vasoconstrictor effect of dihydroergotamine was studied in endothelium-containing and endothelium-denuded rat aortic rings. The integrity of the endothelium was assessed by the relaxant effect of acetylcholine on precontracted aortic rings, which was absent after removal of endothelium by mechanical rubbing or exposure to saponin. Dihydroergotamine (0.01-10 mumol/l) caused no or only a small contractile effect in the presence of endothelium, while in endothelium-denuded aortic rings a pronounced concentration-dependent increase in tension was observed. The 5-HT antagonist cyproheptadine (2 mumol/l) inhibited the dihydroergotamine-induced vasoconstriction, that means, 5-HT receptors are involved in the vasoconstrictor effect. In the presence of endothelium, the contractile effect of dihydroergotamine was enhanced by the guanylate cyclase inhibitor methylene blue (2 mumol/l) and became comparable in magnitude to that observed in deendothelialized preparations. 8-Bromo-cGMP (50 mumol/l) counteracted the potentiating effect of methylene blue. In the presence of cyproheptadine, methylene blue failed to enhance the dihydroergotamine effect. These results might explain the occurrence of undesired vasospastic effects of dihydroergotamine in arterial vessels with endothelial lesions.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1988

The endothelium inhibits the penetration of serotonin and norepinephrine in the isolated canine saphenous vein.

Serotonin can accumulate in the adrenergic nerves of vascular tissues. We have determined whether in the isolated perfused dog saphenous vein 1) luminal administration of serotonin can result in its accumulation in the adrenergic nerves and 2) endothelium can interfere with the transport of the amine into the vessel wall. Saphenous veins were perfused with medium containing [3H]serotonin, [3H]norepinephrine or [3H]epinephrine; after washout, significant amounts of 3H were detected in the veins. The 3H-accumulation was augmented when the endothelium was removed mechanically; the augmented accumulation was only observed when the [3H]amines reached the tissues from the intimal side. In coronary arteries perfused with [3H]serotonin, similar results were obtained. No increased 3H-accumulation was noted in veins without endothelium perfused in the presence of cocaine. Nerve stimulation of veins labeled with [3H]serotonin caused an augmented release of 3H from the tissues without endothelium. Pargyline augmented the accumulation of [3H]serotonin and [3H]norepinephrine and decreased the difference between tissues with or without endothelium only for norepinephrine. Perfusion of venous segments with platelets, labeled with [3H]serotonin, resulted in a 3H-content which was significantly higher in the veins without endothelium. Our experiments show that serotonin and other amines, applied luminally to perfused blood vessels, can accumulate in the adrenergic nerves and that the endothelium can reduce this accumulation. Serotonin, originating from aggregating platelets, can penetrate the vessel wall much easier at sites of endothelial denudation and this serotonin also can enter the adrenergic nerves.

Animals↗
PubMed1986

[The endothelium and arterial reactivity].

Endothelial cells of the arterial wall can generate vasodilator and vasoconstrictor substances. The prototype of a vasodilator substance formed primarily in the endothelium is prostacyclin, although its main target under physiological conditions are the platelets. In addition, the endothelial cells respond to a variety of neurohumoral mediators by the liberation of an unidentified substance(s) (endothelium-derived relaxing factor) with a potent inhibitory effect on vascular smooth muscle, presumably because it accelerates the production of cyclic GMP in the latter. Endothelium-derived relaxing factor is very unstable, and has an extremely short half-life. It is inactivated by plasma proteins and thus does not fulfill a hormonal role. A metabolite of arachidonic acid may be involved in the production of endothelium-derived relaxing factor. Among the neurohumoral mediators which release it are: acetylcholine (through activation of muscarinic receptors), adenosine di- and triphosphate (P2-purinergic receptors), bradykinin, histamine (H1- or H2-histaminergic receptors, depending on the species), serotonin (S1-serotonergic receptors), substance P, oxytocin, thrombin and vasopressin (V1-vasopressinergic receptors). The release of the factor can also be triggered by aggregating platelets (because they release adenine nucleotides and serotonin) and by increases in shear stress. It is likely that endothelium-dependent dilatation helps to prevent intraluminal coagulation in arteries with a normal intima. Absence, or dysfunction of the endothelium may favor the occurrence of vasospasm. Endothelium-dependent relaxations are reduced in atherosclerotic blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1987

Magnesium deficiency produces endothelium-dependent vasorelaxation in canine coronary arteries.

In the present study, effects of magnesium deficiency on coronary vascular reactivity changes were studied in isolated canine coronary arteries before and after endothelium disruption. Lowering of extracellular magnesium produced a potent vasorelaxant response in coronary arteries with intact endothelium, whereas in arteries with disrupted endothelium a potent vasoconstrictory response was observed. The magnitude of magnesium deficiency-induced vasorelaxation is also dependent on the extracellular calcium concentrations, such that lowering of extracellular calcium from 1.75 to 0.22 mM completely abolished the magnesium deficiency-induced vasorelaxant effects. Similar inhibition, as well as reversal, of magnesium deficiency-induced vasorelaxation was also observed with dichlorobenzamil, a known inhibitor of the Na+/Ca++ exchange mechanism, but not with nifedipine, a known inhibitor of the voltage-operated calcium channel. The magnesium deficiency-induced vasoconstriction, on the other hand, is endothelium-independent. Although a similar dependency on extracellular calcium concentration was observed in this vasoconstrictory response, nifedipine, but not dichlorobenzamil, was found to be effective in inhibiting the vasoconstrictory effect. Hemoglobin, a known inhibitor of the endothelium-derived relaxing factor, also completely inhibited the magnesium deficiency-induced vasorelaxation but had no effect on the latter vasoconstrictory effect. These results suggest that circulating magnesium ion may have a dual effect in the modulation of coronary vascular reactivity. In coronary vessels with intact endothelium, lowering of extracellular magnesium may potentiate calcium-induced basal release of endothelium-derived relaxing factor and result in vasodilation, whereas in pathological vessels with injured endothelial cells, a similar lowering of magnesium may increase coronary vascular tone by accentuating the calcium-induced coronary constrictory response in vascular smooth muscle cells and result in vasoconstriction.

Amiloride↗
PubMed1985

Acetylcholine induces constriction of epicardial coronary arteries in anesthetized dogs after removal of endothelium.

The acetylcholine-induced relaxation of isolated coronary arteries is reversed to contraction in the absence of endothelium. The importance of endothelium for the regulation of coronary blood flow remains unclear. We thus tested the effects of acetylcholine on epicardial arteries and on coronary resistance vessels in situ in 8 anesthetized dogs. The left circumflex coronary artery was perfused at constant pressure. Epicardial vasomotion was evaluated by sonomicrometry, the vasomotion of coronary resistance vessels by calculated end-diastolic resistance. Acetylcholine (1 microgram/kg/min i.c.) decreased epicardial resistance by 8.6 +/- 1.6% and end-diastolic resistance by 65.8 +/- 6.3%. The epicardial coronary segment was perfused with distilled water for 65 +/- 5 s to denude it of endothelium. After removal of epicardial endothelium, the decrease in end-diastolic resistance caused by acetylcholine was unchanged (59.6 +/- 1.2%); however, epicardial resistance was increased by 7.7 +/- 1.7%. Application of glyceryl trinitrate (5 micrograms/kg/min i.c.) induced a similar decrease of epicardial resistance before and after removal of endothelium:7.9 +/- 1.4 and 6.2 +/- 1.9%, respectively. We conclude that acetylcholine-induced dilation of epicardial coronary arteries is endothelium-dependent in vivo. However, the constriction of epicardial coronary arteries in the absence of endothelium is insufficient to reduce blood flow and to induce myocardial ischemia.

Acetylcholine↗
PubMed1983

Endothelium-dependent relaxation of rabbit aorta. I. Relaxation stimulated by arachidonic acid.

Vascular responses to the addition of arachidonic acid (AA) were characterized in rings of rabbit thoracic aorta. In preparations which were precontracted to a stable plateau by 10(-7) M phenylephrine, AA (10-100 microM) elicited transient relaxation if the endothelium was intact. The same concentrations of AA only contracted tissues in which the endothelium was purposely disrupted. Indomethacin pretreatment (14 microM, 30 min) potentiated the relaxation response in intact rings. Under these conditions, relaxation in response to 100 microM AA was 32(+/- 3)% of the tension stimulated by 10(-7) M phenylephrine. Preincubation with 5,8,11,14-eicosatetraynoic acid (50 microM) or nordihydroguaiaretic acid (25 microM) completely prevented AA-induced relaxation. Contractile responses to AA were examined in rings lacking pre-existing active tension. AA (3-100 microM) elicited rapidly developing and somewhat transient contractions in rings with endothelium. Slow developing contractions which were significantly smaller in magnitude were observed in rings lacking endothelium. Indomethacin or 5,8,11,14-eicosatetraynoic acid pretreatment inhibited AA-stimulated contractions both in intact and de-endothelialized tissues. Nordihydroguaiaretic acid pretreatment had no effect on contractile responses in rings lacking endothelium and slightly potentiated responses in intact rings. We conclude that endothelium-dependent relaxation of rabbit aorta by AA is mediated by a noncyclooxygenase metabolite(s). Contractile responses are mediated by cyclooxygenase metabolites, which in intact rings are derived largely from the vascular endothelium.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1984

Facilitation of granulocyte migration into bovine pulmonary artery intimal explants by intact viable endothelium.

To characterize the role of normal endothelium in granulocyte chemotaxis, the authors measured granulocyte adherence to and migration into bovine pulmonary artery intimal explants. Explants were placed, endothelium uppermost, in chemotaxis chambers with zymosan-activated plasma in the lower well and 5 X 10(6)/ml 51Cr-labeled granulocytes in the upper well. After 15, 30, 60, 120, 180, or 240 minutes incubation at 37 C, granulocyte adherence was measured by removal of adherent granulocytes from the endothelial layer with a 0.1% trypsin wash and counting of radioactivity in the wash. Scanning electron microscopy confirmed that this technique removed the majority of adherent cells from the endothelial surface without disrupting its continuity. Migration was calculated by counting of the remaining radioactivity in the explant. Granulocyte migration with Medium 199 alone in the lower well (random migration) was 36 +/- 3% by 3 hours. Chemotaxis-induced migration at each time studied was 1.5-2 times random migration. Granulocyte adherence was between 4% and 9% in both groups at all times examined. In some experiments, either endothelium was removed from explants or explants were fixed with glutaraldehyde prior to experimentation. Removal of endothelium resulted in a two-fold increase in granulocyte adherence but no significant difference in migration, compared with intact intimal explants. Glutaraldehyde fixation of explants resulted in more tightly adherent granulocytes and significantly less migration. With lactate dehydrogenase as a marker of endothelial cell damage, granulocyte migration in response to zymosan-activated plasma did not injure endothelium. It is concluded that, in blood vessels, chemotaxis is an interactive process between granulocytes and endothelium and that intact, viable endothelium facilitates granulocyte migration.

Animals↗
PubMed1995

Effects of exercise training on endothelium-dependent peripheral vascular responsiveness.

Endurance training results in peripheral vascular adaptations in skeletal muscle which enhance perfusion and vascular flow capacity. These adaptations could result from structural modifications of the vasculature and/or alterations in the control of vascular tone. One potential mechanism through which vascular control may be modified is through adaptive changes in the intrinsic responsiveness of vascular endothelium. Experiments have demonstrated that vascular responsiveness to endothelium-dependent vasodilators are enhanced in exercise-trained animals. The enhanced endothelium-dependent relaxation appears to be mediated through elevations in the formation of endothelium-derived nitric oxide. Training also results in a decreased sensitivity to the vasoconstrictor effects of norepinephrine. This alteration appears to be due to an endothelium-dependent mechanism involving alpha 2-adrenergic receptors. One stimulus that appears to be important in initiating the adaptation of the endothelium to training is the increase in muscle blood flow and shear stress which occurs during exercise. However, other factors associated with exercise may be necessary to induce endothelial adaptations produced by endurance training. Further research is needed to determine the significance of changes in endothelium-dependent vascular responsiveness and whether this is associated with training-induced increases in muscle perfusion and vascular flow capacity.

Adaptation, Physiological↗
PubMed1995

Endothelium-derived relaxing factors and converting enzyme inhibition.

Endothelial cells can produce at least 3 substances which cause relaxation of vascular smooth muscle: (1) endothelium-derived nitric oxide (NO, which is secreted not only toward the underlying vascular smooth muscle but also into the blood vessel lumen). NO also has a physiological role at the interface between the endothelial cells and the blood content; in particular, NO inhibits the adhesion of platelets and leukocytes to the endothelium. (2) Endothelium-derived hyperpolarizing factor, presumably a labile metabolite of arachidonic acid formed through the P-450 pathway, which appears to act on smooth muscle by being one of the few physiologic openers of the potassium channels. (3) Prostacyclin, which can be considered as an endothelium-derived relaxing substance, given its vasodilator activity and its primarily endothelial origin. One of the main factors modulating the release of these EDRFs is the shear stress of blood on the arterial wall, which explains why flow-induced vasodilation is endothelium-dependent in the intact organism. The peptide bradykinin is a potent stimulus for EDRF release. The normal lifespan of an adult human endothelial cell is some 30 years, after which aging takes its toll and the cells must be replaced. The regenerated cells lose some of their ability to release EDRF, in particular in response to platelet aggregation and thrombin. Finally, in hypertension and atherosclerosis, a decrease in endothelium-dependent relaxation is obvious in response to a variety of stimuli. All converting enzyme inhibitors tested so far share a potentiating effect on endothelium-dependent relaxation to bradykinin, and augmented local production of bradykinin may help to explain the acute vasodilator properties of these compounds.

Adult↗
PubMed1995

Modulation of extraluminally induced vasoconstrictions by endothelium-derived nitric oxide in the canine basilar artery.

The present study was undertaken to investigate the role of endothelium in extraluminally induced vasospasm of the cerebral artery using isolated perfused canine basilar arteries. The extraluminal applications of high K+ and prostaglandin F2 alpha (PGF2 alpha) induced concentration-dependent vasoconstriction. Both constrictive responses were significantly enhanced by denuding endothelium. Additionally, the responses in the endothelium-intact arteries were markedly augmented by intraluminal perfusion with NG-monomethyl-L-arginine (L-NMMA). These results suggest that the inhibition of nitric oxide (NO) synthase in endothelium enhances increase in transmembrane Ca(2+)-influx which is a common constrictive mechanism to the vasoconstrictors. The augmentative action induced by L-NMMA was inhibited by intraluminal perfusion of L-arginine, but not by D-arginine. Furthermore, the augmentation was not observed in the arteries without endothelium. These results suggest that the endothelium may have a great significance on responsiveness to extraluminal vasoactive substances and that endothelium-derived NO may modulate the extraluminally induced vasoconstriction which is responsible for cerebral vasospasm after subarachnoid hemorrhage.

Amino Acid Oxidoreductases↗
PubMed1995

Barium inhibits the endothelium-dependent component of flow but not acetylcholine-induced relaxation in isolated rabbit cerebral arteries.

An increase in blood flow can cause vasodilation through a local action on the blood vessel wall. We examined the involvement of potassium channels in the relaxation of segments of the rabbit middle cerebral artery to intraluminal infusion of physiological saline. In segments with intact endothelium, intraluminal flow (20 microliters/min) produced a relaxation of 81.7 +/- 3.0% of pre-flow tone. This relaxation was significantly reduced upon endothelium removal (43%, n = 5) or inhibition of nitric oxide synthase (34%, n = 6). Inhibition of nitric oxide synthase had no effect on the relaxation in endothelium denuded preparations. This suggests that the overall response to flow is a combination of endothelium/nitric oxide dependent and smooth muscle components. Barium chloride (10 and 300 microM) reduced flow-induced relaxations by 30 and 61%, respectively, in intact arteries but had no effect following endothelium removal or nitric oxide synthase inhibition. Micromolar concentrations of barium are thought to block selectively the inward rectifier potassium channel. These concentrations of barium were without effect on the relaxation produced by the endothelium-dependent vasodilator acetylcholine. Blockers of other potassium channels, glibenclamide (10 microM, ATP-sensitive K+ channel), charybdotoxin (100 nN) and tetraethylammonium (0.3 mM, Ca(++)-activated K+ channel) and 4-aminopyridine (1 mM, delayed rectifier K+ channel) did not effect either endothelium-dependent or endothelium-independent flow-induced relaxation. Our results suggest that flow-induced shear stress activates endothelial cell inward rectifier potassium channels leading to increased synthesis/release of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗