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PubMed1989

Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat.

This study was undertaken to compare age-related changes in endothelium-dependent vascular responses in both hypertensive and normotensive rats. Aorta from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) aged 4-6 weeks (young), 3-6 months (adult), and 12-25 months (old) were examined for relaxation to acetylcholine, adenosine 5'-triphosphate (ATP), and sodium nitroprusside. Rubbed (endothelium denuded) aorta from all groups displayed neither relaxation nor contraction to acetylcholine. Maximal relaxation responses to acetylcholine were reduced progressively with increasing age in unrubbed aorta of both SHR and WKY rats. In addition, acetylcholine caused not only dose-dependent relaxations at lower concentrations but also increases in tension at higher concentrations in unrubbed aorta of old WKY rats as well as adult and old SHR. However, indomethacin completely inhibited the tension development. As a result, aorta treated with indomethacin demonstrated similar acetylcholine-induced, endothelium-dependent relaxations in all groups. The thromboxane A2 synthetase inhibitor (E)-7-phenyl-7-(3-pyridyl)-6-heptanoic acid (CV-4151) partially but significantly depressed the increases in tension in aorta of old WKY rats. The degrees of endothelium-dependent relaxations to ATP and endothelium-independent relaxations to sodium nitroprusside were almost similar in all groups. These findings suggest that the release of or vascular responsiveness to endothelium-derived relaxing factor in the aorta is well maintained through senescence in both strains and that, in the aorta of not only SHR but also old normotensive WKY rats, the endothelium releases contracting factors that may be thromboxane A2 and other vasoconstrictor prostanoids.

Acetylcholine↗
PubMed1991

Regulation of cerebral blood vessels by humoral and endothelium-dependent mechanisms. Update on humoral regulation of vascular tone.

Recent studies suggest that humoral and endothelium-dependent mechanisms may play an important role in the cerebral circulation. Angiotensin may acutely and chronically increase resistance of large cerebral arteries and reduce cerebral microvascular pressure without changing cerebral blood flow. We hypothesize that the brain may sense reductions in microvascular pressure and initiate compensatory neurohumoral responses to raise arterial pressure. Vasopressin appears to play an important role in regulation of production of cerebrospinal fluid and brain fluid volume. Vasopressin also may be protective when intracranial pressure is elevated. Endothelium-dependent mechanisms also may have important influences on tone of cerebral vessels. Synthesis of the endothelium-derived relaxing factor nitric oxide, or a nitric oxide-containing compound, appears to influence both basal tone and responses of large cerebral arteries to acetylcholine in vivo. Large cerebral arteries dilate in response to increased blood flow in vivo, and this response may be mediated in part by release of a humoral factor by endothelium. Endothelium-dependent responses of cerebral arterioles to receptor- and nonreceptor-mediated agonists are impaired during chronic hypertension. The mechanism of impairment of endothelium-dependent responses of cerebral arterioles appears to involve production of an endothelium-derived contracting factor.

Animals↗
PubMed1992

Enhanced release of endothelium-derived relaxing factor in mineralocorticoid hypertension.

Ring segments of superior mesenteric arteries studied in vitro were used to determine the role of the vascular endothelium in regulating vascular contractile and relaxant sensitivity in deoxycorticosterone acetate (DOCA)-salt hypertension. Wistar rats were given DOCA (20 mg/kg s.c. twice per week) and 1% NaCl drinking water for 5 weeks. In ring segments containing endothelium, there was a decrease in contractile sensitivity to arginine vasopressin, no change in contractile sensitivity to norepinephrine and KCl, and no change in relaxant sensitivity to acetylcholine or isoproterenol in arteries from hypertensive rats compared with normotensive controls. Removal of the vascular endothelium by rubbing had no effect on the contractile response to arginine vasopressin and KCl or the relaxant response to isoproterenol in control arteries. In arteries without endothelium, DOCA-salt hypertension caused a threefold increase in contractile sensitivity for arginine vasopressin, norepinephrine, and KCl; a 50% reduction in maximal relaxation to isoproterenol; and a threefold decrease in relaxant sensitivity to sodium nitroprusside. Indomethacin (10 microM) had no effect on contraction or relaxation. However, N-monomethyl L-arginine unmasked altered contractile sensitivity to norepinephrine in arteries from DOCA-salt hypertensive rats. These data show that the endothelium compensates for increased contractile and reduced relaxant responses of vascular muscle in DOCA-salt hypertension by increasing the release of endothelium-derived relaxing factor. These data suggest that altered vascular responsiveness is masked by the endothelium, thus preventing these alterations from contributing to increased peripheral resistance during the development of DOCA-salt hypertension.

Animals↗
PubMed1994

Removal of endothelium-dependent relaxation by antibody and complement in afferent arterioles.

Studies of endothelial regulation of microvascular function have been hampered by the technical difficulty of removing the endothelium without damaging the vascular smooth muscle cells. This study presents a novel method of endothelial damage and lysis based on the facts that endothelial cells express specific antigens and that complement reacts with antibody/antigen complexes, causing cell lysis. We isolated and perfused rabbit glomerular afferent arterioles in vitro and examined vascular responses before and after treating them with an antibody against factor VIII-related antigen and complement. The treatment consisted of perfusing afferent arterioles with medium containing the antibody and complement for 10 minutes, followed by a 20-minute washout period. Before treatment, acetylcholine and the calcium ionophore A23187 (receptor- and nonreceptor-mediated endothelium-dependent vasodilators, respectively) dilated norepinephrine-preconstricted afferent arterioles, whereas neither dilated the arterioles after treatment, suggesting loss of endothelium-dependent vasodilation. In contrast, responses to nicardipine and norepinephrine (endothelium-independent vasodilator and constrictor, respectively) were not altered by the treatment, indicating intact vascular smooth muscle cell function. Transmission electron microscopy revealed that the antibody- and complement-treated arterioles had various degrees of endothelial damage, including areas of detachment from the basement membrane and marked loss of the number and structure of mitochondria, but no evidence of vascular smooth muscle cell damage. These results indicate that treatment with anti-factor VIII-related antigen antibody and complement is an effective method for eliminating endothelium-dependent vasodilation without altering endothelium-independent responses. Thus, this method may be useful for studying the functional role of the endothelium in microvessels.

Acetylcholine↗
PubMed1996

Indigo carmine inhibits endothelium-dependent and -independent vasodilation.

To investigate the potential mechanisms by which indigo carmine produces hypertension, we tested the hypothesis that indigo carmine inhibits endothelium-dependent vasodilation and determined the possible site of the inhibition (endothelium versus smooth muscle). Using isolated rat thoracic aortic rings that were precontracted with phenylephrine, we examined vasodilatory responses to acetylcholine, histamine, and Ca2+ ionophore A23187 (in endothelium-intact rings) and sodium nitroprusside and isoproterenol (in endothelium-denuded rings) in the presence and absence of indigo carmine. In addition, the effects of methylene blue on the acetylcholine- and sodium nitroprusside-induced vasodilation were compared with those of indigo carmine. Indigo carmine (10(-6), 10(-5), and 10(-4) mol/L) significantly inhibited receptor- and non-receptor-mediated endothelium-dependent vasorelaxation. Indigo carmine (10(-4) mol/L) also inhibited endothelium-independent vasorelaxation induced by sodium nitroprusside (an activator of vascular smooth muscle soluble guanylyl cyclase), although to a lesser extent than vasodilation from acetylcholine, histamine, and Ca2+ ionophore A23187. In contrast, indigo carmine (10(-4) mol/L) had no effect on the vasodilation induced by isoproterenol (an activator of adenylyl cyclase), indicating that indigo carmine selectively inhibits nitric oxide-mediated responses. Methylene blue, a known inhibitor of soluble guanylyl cyclase, inhibited both acetylcholine- and sodium nitroprusside-induced vasorelaxation. The inhibition was also greater in the acetylcholine- than the sodium nitroprusside-induced vasodilation. These results suggest that indigo carmine, like methylene blue, may inhibit endothelium-dependent relaxation by a mechanism that involves two levels. The major action of indigo carmine appears to be at the level of nitric oxide generation and/or release from the endothelial cell. In addition, indigo carmine appears to inhibit vascular smooth muscle guanylyl cyclase. Thus, indigo carmine may elevate blood pressure by interfering with these nitric oxide-mediated vasodilatory mechanisms.

Acetylcholine↗
PubMed2000

Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat.

Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to 4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0. 7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/-0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0. 1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100 micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3) N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium-intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3) N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.

Acetylcholine↗
PubMed2001

Role of endothelin B receptors in enhancing endothelium-dependent nitric oxide-mediated vascular relaxation during high salt diet.

High salt diet is often associated with increases in blood pressure, and the state of activation of endothelium-dependent vascular relaxation pathways is critical under these conditions. Basal activation of endothelial endothelin B (ET(B)) receptors by endothelin has been suggested to stimulate the release of factors that promote vascular relaxation. However, whether ET(B) receptors play a role in enhancing endothelium-dependent vascular relaxation during high salt diet is unclear. In this study, we investigated whether chronic treatment with an ET(B) receptor antagonist is associated with impaired endothelium-dependent vascular relaxation and enhanced vascular reactivity particularly during high salt diet. Isometric contraction was measured in aortic strips isolated from male Sprague-Dawley rats on normal sodium (NS, 1%) and high sodium diet (HS, 8%) for 7 days and untreated or treated with the ET(B) receptor antagonist A-192621 (30 mg/kg per day) for 5 days. The mean arterial pressure was (in mm Hg) 122+/-3 in NS, 132+/-3 in HS, 144+/-2 in NS/ET(B) antagonist, and 171+/-12 in HS/ET(B) antagonist rats. In endothelium-intact strips, phenylephrine (Phe, 10(-5) mol/L) increased active stress to 7.6+/-1.0x10(3)N/m(2) in NS rats and 8.2+/-0.9x10(3)N/m(2) in HS rats. Phe (10(-5) mol/L) -induced stress was significantly greater in NS/ET(B) antagonist (11.3+/-0.9x10(3)N/m(2)) than NS and far greater in HS/ET(B) antagonist (14.1+/-0.1.2x10(3)N/m(2)) than HS rats. Also, Phe was more potent in NS/ET(B) antagonist and HS/ET(B) antagonist rats (ED(50)=0.3x10(-7) and 0.15x10(-7) mol/L) than in NS and HS rats (ED(50)=0.8x10(-7) and 0.7x10(-7) mol/L). Removal of the endothelium enhanced Phe-induced contraction significantly in NS and to a greater extent in HS, but not in NS/ET(B) antagonist or HS/ET(B) antagonist rats. In endothelium-intact strips, acetylcholine (ACh) caused relaxation of Phe contraction that was less in NS/ET(B) antagonist than NS and far less in HS/ET(B) antagonist than HS rats. Pretreatment of endothelium-intact strips with L-NAME (10(-4) mol/L), to inhibit nitric oxide (NO) synthase, or with methylene blue (10(-5) mol/L) or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10(-6) mol/L), to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced contraction significantly in NS and HS, slightly in NS/ET(B) antagonist, but not in HS/ET(B) antagonist rats. Measurement of basal and ACh-induced nitrite/nitrate production from aortic strips showed a significant reduction in NS/ET(B) antagonist compared with NS, and a greater reduction in HS/ET(B) antagonist compared with HS rats. Relaxation of Phe contraction with sodium nitroprusside was not significantly different among the different groups of rats. Thus, an endothelial ET(B) receptor-mediated pathway of vascular relaxation involving release of NO seems to be active under basal conditions and may protect against excessive vasoconstriction and increased blood pressure particularly during high salt diet.

Acetylcholine↗
PubMed1987

Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats.

Experiments were designed to study endothelium-dependent responses in salt-sensitive (DS) and salt-resistant Dahl rats (DR). The rats were fed a low sodium (0.1% NaCl) or high sodium (8% NaCl) diet for 8 weeks. Blood pressure in DS fed a high sodium diet was higher than that in the remaining animals. Aortic rings with and without endothelium were suspended for isometric tension recording. Acetylcholine, adenosine 5'-diphosphate, and thrombin induced endothelium-dependent relaxations that were significantly depressed in the aorta of DS fed a high sodium diet. The relaxations in response to sodium nitroprusside were only slightly, but significantly, depressed in DS fed a high sodium diet. Removal of the endothelium greatly enhanced the response to serotonin and norepinephrine. In rings with, but not without, endothelium taken from rats fed a high sodium diet, the tension developed in response to serotonin and norepinephrine was significantly greater than that in animals fed a low sodium diet. These experiments indicate that endothelium-dependent relaxations to acetylcholine, adenosine 5'-diphosphate, and thrombin are depressed in hypertensive Dahl rats; this effect probably reflects a decreased release of endothelium-derived relaxing factor(s), although structural changes might contribute; and the responsiveness to vasoconstrictor agents is increased in DS and DR fed a high sodium diet. These findings may indicate differential effects of blood pressure and dietary salt on endothelial function.

Acetylcholine↗
PubMed1987

Antihypertensive treatment normalizes decreased endothelium-dependent relaxations in rats with salt-induced hypertension.

Endothelium-dependent responses are impaired in various models of hypertension. The effects of antihypertensive treatment on endothelium-dependent relaxations were studied in Dahl salt-sensitive (DS) and Dahl salt-resistant rats (DR) on a high or low sodium diet. The rats were given either a diet containing 8% NaCl or 0.1% NaCl for 8 weeks or a diet containing 8% NaCl and a combination of reserpine, hydrochlorothiazide, and hydralazine for 8 or 2 weeks. DS on the 8% NaCl diet developed hypertension, while the other rats did not. Antihypertensive therapy for 8 or 2 weeks prevented or reversed hypertension in DS and lowered blood pressure in DR on the 8% NaCl diet. Aortic rings with and without endothelium were suspended in organ chambers for isometric tension recording. In all groups, acetylcholine, adenosine 5'-diphosphate, and thrombin caused endothelium-dependent relaxations. The relaxations in response to all agonists were significantly decreased in DS on 8% NaCl compared to relaxations in the other rats. Antihypertensive treatment for 8 or 2 weeks prevented or reversed the decreased endothelium-dependent relaxations in response to all agonists tested, but not those to the endothelium-independent agonist, sodium nitroprusside. These results suggest that antihypertensive treatment normalizes endothelium-dependent relaxations. This effect of antihypertensive treatment might be important for the prevention of cardiovascular complications in patients with hypertension.

Animals↗
PubMed1986

Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries.

The present study was designed to investigate the hypothesis that, during acetylcholine-induced endothelium-dependent relaxation, a factor(s) is released from endothelial cells which directly activates soluble guanylate cyclase. We attempted to determine what similarities or differences existed between this factor and endothelium-derived relaxing factor. The study was performed on segments of rabbit aorta and canine femoral artery. Purified soluble guanylate cyclase was injected into the lumen of these vascular segments, together with its substrate, for intraluminal incubation of the enzyme. In endothelium-intact vascular segments, the activity of guanylate cyclase was enhanced over control values obtained by incubation in test tubes. The stimulation was further increased by acetylcholine in concentrations which caused relaxation of the vascular segments. The stimulating principle could not be transferred from the vessel lumen to an external solution of guanylate cyclase, indicating a short life-time. Removal of the endothelium prevented formation and release of the guanylate cyclase stimulating factor(s). Atropine, mepacrine, or nordihydroguaiaretic acid, which inhibit acetylcholine-induced endothelium-dependent relaxations, also inhibited acetylcholine-induced endothelium-mediated activation of guanylate cyclase. The results support the hypothesis that acetylcholine-induced endothelium-derived relaxing factor increases cyclic guanosine monophosphate levels of vascular smooth muscle by a stimulation of soluble guanylate cyclase.

Acetylcholine↗
PubMed1989

Rabbit polymorphonuclear neutrophils elicit endothelium-dependent contraction in vascular smooth muscle.

The present studies were designed to investigate the interaction between activated polymorphonuclear neutrophils (PMNs) and endothelial regulation of vascular smooth muscle function. Rabbit peritoneal PMNs (4 x 10(3)-4 x 10(5) cells/ml) added to muscle bath chambers containing phenylephrine-precontracted rabbit isolated aortic rings produced no effect on vascular tone. However, when PMNs were activated with the chemotactic peptide, f-met-leu-phe (0.1 microM), PMNs produced concentration-dependent vascular contraction, which was dependent on the presence of the endothelium. Aortic rings denuded of endothelium were unaffected by activated PMNs. Superoxide dismutase (100 units/ml) treatment of tissues blocked completely PMN-induced vascular contraction, whereas mannitol (20 mM) had no significant effect on PMN-induced vascular contraction. Pyrogallol (a generator of superoxide anion) produced a response that was similar to that observed with activated PMNs. Superoxide anion production was measured separately, and the time of peak rate of superoxide anion production corresponded to the time of the maximal vascular contractile responses. Activated PMNs added to vascular tissues undergoing endothelium-dependent relaxation mediated by either acetylcholine or A23187 produced a reversal of vascular relaxation. Furthermore, activated PMNs did not have any effect on endothelium-independent vascular relaxation produced by either isoproterenol or nitroglycerin. The present investigation reveals that activated PMNs can release superoxide anion and produce endothelium-dependent contraction. The endothelium-dependent contraction may be the result of superoxide anion inactivation of endothelium-derived relaxing factor.

Animals↗
PubMed1991

Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis.

A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis, the canine heartworm, depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine, endothelium-dependent dilators (acetylcholine, histamine, and A23187), and nitroglycerin were done. In some experiments, inhibitors of cyclooxygenase (indomethacin and aspirin), guanylate cyclase (methylene blue), and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast, endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG, acetylcholine relaxation in control abdominal aorta was completely abolished; however, in abdominal aorta of Brugia-infected rats, acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however, relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control, suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.

Animals↗
PubMed1992

Reduced production of cGMP underlies the loss of endothelium-dependent relaxations in the canine basilar artery after subarachnoid hemorrhage.

Endothelium-dependent relaxations are inhibited during chronic vasospasm after subarachnoid hemorrhage in the canine basilar artery, although the luminal release of endothelium-derived relaxing factor (EDRF) is maintained. The present study investigated the mechanisms underlying the impaired vascular reactivity and in particular whether the loss of responsiveness of the smooth muscle to EDRF is due to an impaired production of cGMP. Bradykinin and nitric oxide evoked concentration-dependent relaxations in isolated canine basilar arteries with and without endothelium, respectively, which were reduced in the subarachnoid hemorrhage group. Relaxations evoked by M&B22,948 (an inhibitor of cGMP phosphodiesterases) were smaller, but those evoked by the lipophilic cGMP analogue 8-bromo-cGMP were potentiated slightly in the subarachnoid hemorrhage group. The resting levels of cGMP in rings with endothelium (reflecting the effect of spontaneous release of EDRF) and those evoked by bradykinin in rings with endothelium and by nitric oxide in rings without endothelium were diminished in the subarachnoid hemorrhage group. These data indicate that the altered endothelium-mediated relaxations of the smooth muscle after subarachnoid hemorrhage is due, at least in part, to an impaired activation of soluble guanylate cyclase leading to a reduced production of cGMP in the smooth muscle.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation. Restoration of endothelium-dependent responses by L-arginine.

The goals of this study were 1) to quantitate the effects of atherosclerosis on physiological and pharmacological endothelium-dependent vasoactive responses in coronary arterioles downstream from arterial lesions and 2) to determine if administration of L-arginine, the precursor for endothelium-derived was induced in pigs, and vasomotor responses of isolated, cannulated coronary arterioles (30-70 microns in diameter) were assessed by measuring diameter changes in vitro. To assess pharmacological alterations of endothelium-dependent responses, dose-response curves were constructed to ADP, serotonin, and histamine. To assess physiological alterations in endothelial function, different flow rates were established across the vessel. Arteriolar diameters were measured in vessels from normal and atherosclerotic pigs under control conditions, after administration of L-arginine, and after endothelial denudation. In arterioles from normal pigs, administration of serotonin, histamine, or ADP produced dose-dependent vasodilation, which was abolished by endothelial denudation. In arterioles from atherosclerotic pigs, administration of histamine, serotonin, and ADP produced dilation at only the highest doses (10(-6)-10(-7) M), and the extent of dilation was only 20-30% of that observed in arterioles from normal pigs. Initiation of flow also produced vasodilation in arterioles from normal pigs that was completely abolished after endothelial denudation. In arterioles from atherosclerotic pigs, flow-induced responses were absent. These abnormal physiological and pharmacological responses (i.e., blunted vasodilation to pharmacological stimulation and to flow) were restored after administration of L-arginine for 40 minutes. The vascular responses after administration of L-arginine were not different from those observed under control conditions in arterioles from normal pigs. In addition, L-arginine did not restore vasodilation to the endothelium-dependent agonists in denuded segments. From these data in arterioles downstream from atherosclerotic lesions, we conclude that 1) the ED50 and maximal responses of endothelium-dependent vasodilation to ADP, histamine, and serotonin are attenuated; 2) the physiological response to flow, that is, flow-mediated endothelium-dependent vasodilation, is absent; and 3) the abnormality in arteriolar responsiveness during large vessel disease involves an impairment of the synthesis and/or release of endothelium-derived relaxing factor.

Animals↗
PubMed1997

The effects of hypoxia on pHi in porcine coronary artery endothelium and smooth muscle. A novel method for measurements in endothelial cells in situ.

Endothelium-dependent relaxation of porcine coronary arteries is attenuated under hypoxic conditions. Recent evidence also indicates that pHi may modulate the release of the endothelium-derived relaxing factor. We tested the hypothesis that hypoxia-induced attenuation of endothelium-dependent relaxation is mediated by alterations in pHi. We developed a novel method for loading surface cells, whereby endothelial cell pHi could be measured in situ on the intact porcine coronary artery. Endothelial cells of arterial ring segments were selectively loaded with the fluorescent indicator BCECF-AM. Differential loading of the endothelial cell layer was verified by confocal microscopy. pHi of the endothelial cells in situ and of endothelium-denuded arteries was measured with a Photon Technology International spectrofluorimeter. The functional integrity of the endothelium was assessed by the endothelium-dependent relaxation to substance P in a paired adjacent ring. In the experimental protocol for pHi measurements, preparations were perfused with a physiological bicarbonate buffer (pH 7.4), stimulated with KCI (29 mmol/L), and then subjected to hypoxia and reoxygenation. The mean basal pHi in endothelial cells on the intact six arteries was 6.92 +/- 0.07. Addition of KCI to the perfusion medium decreased (P = .025) pHi to 6.79 +/- 0.07. Subsequent bubbling with N2 increased (P = .009) pHi to 7.00 +/- 0.06, which was reversed by reoxygenation. In contrast to the in situ endothelium, pHi of the smooth muscle was not significantly altered from its basal value of 7.24 +/- 0.06 (n = 5) by either KCI or hypoxia. This differential behavior corroborated the confocal data indicating differential dye loading. These data thus suggest that oxygen-sensitive alterations in pHi may be an important mechanism of signal transduction in endothelial cells.

Animals↗
PubMed1988

Endothelium-dependent and -independent responses to vasodilators of isolated dog cerebral arteries.

We compared responses to calcium ionophore A23187, vasopressin, and substance P in helical strips of dog middle cerebral, basilar, and posterior communicating arteries to obtain a better understanding of humoral control of cerebrovascular tone in different brain regions and its potential impact on mechanisms of cerebral vasospasm. A23187 relaxed these different arterial strips partially precontracted with prostaglandin F2 alpha to a similar extent. Vasopressin produced concentration-dependent relaxation in basilar and posterior communicating arterial strips, whereas middle cerebral arterial strips either contracted or relaxed slightly. Relaxations induced by A23187 and vasopressin were either abolished or converted to contractions by removal of the endothelium. In contrast, the relaxation of cerebral arterial strips to substance P was markedly attenuated but not abolished by endothelium denudation; the remaining relaxation was suppressed by indomethacin. In some cerebral arterial strips with intact endothelium, substance P caused a transient contraction that was reversed to a relaxation by indomethacin or ONO-3708, a prostaglandin antagonist. In arterial strips denuded of endothelium from the same dogs, substance P always produced relaxations. Relaxations of cerebral arterial strips to A23187 and vasopressin appear to be mediated by endothelium-derived relaxing factor. The function of vasopressin receptors in endothelial cells differs markedly in basilar and posterior communicating arteries versus middle cerebral arteries. Substance P-induced relaxations appear to be primarily associated with endothelium-derived relaxing factor and with prostaglandin I2, whereas contractions appear to be mediated by endothelium-derived prostaglandins.

Animals↗
PubMed1993

Flow-induced relaxation of the rabbit middle cerebral artery is composed of both endothelium-dependent and -independent components.

BACKGROUND AND PURPOSE: The flow-induced relaxation of a branch of the rabbit middle cerebral artery was examined to determine if an endothelial-independent as well as -dependent component occurs in pial as well as systemic small arteries and the possible role of products of the cyclooxygenase and the L-arginine nitric oxide synthase pathways. METHODS: Intraluminal flow was achieved by the infusion of a tissue bath solution into isometrically mounted rabbit pial arteries in a resistance artery myograph through a small pipette. RESULTS: Intraluminal flow caused relaxation of the artery segment precontracted with 10 microM histamine. Treatment of endothelium-intact vessels with the nitric oxide synthase inhibitors NG-nitro-L-arginine (L-NNA) (100 microM) or NG-nitro-L-arginine methyl ester (L-NAME) (0.3 mM) significantly reduced the relaxation at flow rates of 5-30 microliters/min. This effect was partially reversed by 1 mM L-arginine. These inhibitors had no effect on the flow-induced relaxation of endothelium-denuded vessels. L-NNA did not influence the relaxation to 1 and 3 microM papaverine. Exposure to 10 microM aspirin, 10 microM indomethacin, or 300 nM tetrodotoxin had no effect on the flow-induced relaxation of either endothelium-intact or -denuded vessels (n = 6). Flow-induced relaxation was attenuated, but not abolished, by removal of the cerebrovascular endothelium. This reduction was not statistically significant. CONCLUSIONS: These results show that intraluminal flow caused relaxation of a branch of the rabbit middle cerebral artery, in part through a mechanism sensitive to inhibitors of nitric oxide synthase, most likely the generation of nitric oxide from the vascular endothelium. The major component of the relaxant response is independent of the endothelium and of nitric oxide synthesis through an L-NNA- or L-NAME-sensitive mechanism. The relaxation does not involve cyclooxygenase products nor neurogenic mediators. These results suggest that pial arteries, like those of the rabbit ear, exhibit a novel mechanism for the flow-induced relaxation of agonist-induced tone that is intrinsic to the tissues of the vascular wall subjacent to the endothelium.

Animals↗
PubMed2001

Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women.

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.

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