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PubMed2000

Flow modulation of pressure-sensitive tone in rat pial arterioles: role of the endothelium.

BACKGROUND: Cerebral arteriolar tone is modulated in response to changes in transmural pressure and luminal flow. The effect of flow on the relation between pressure and diameter has not been fully evaluated in these vessels. This study was conducted to investigate this interaction and to determine the role of the endothelium in mediating it. METHODS: Rat pial arterioles from the territory of the posterior cerebral artery were mounted in a perfusion myograph. In some arterioles, the endothelium was removed by air perfusion. Diameters were recorded at pressures from 20 to 200 mmHg in the presence and absence of flow (10 microl/min). The response to flow (0-30 microl/min) was recorded at 60 and 120 mmHg. RESULTS: In the absence of flow, endothelium-intact arterioles demonstrated tone at distending pressures between 40 and 140 mmHg. In the presence of flow, tone did not develop until pressure exceeded 100 mmHg, and the vessels remained active at pressures up to 200 mmHg. Endothelium-denuded arterioles developed tone at the same pressure when perfused as when unperfused, but perfused vessels were able to maintain active tone at higher pressures. At 60 mmHg, flow caused dilation if the endothelium was intact and constriction if it had been removed. At 120 mmHg, flow caused constriction. Endothelium-dependent flow-relaxation was inhibited by N(G)-nitro-L-arginine methyl ester (10(-5) M) and abolished by indomethacin (10(-5) M). CONCLUSION: Flow inhibits the development of pial arteriolar tone at low intraluminal pressures through endothelium-dependent mechanisms. Conversely, perfusion extends the upper limit of the myogenically regulated pressure range through endothelium-independent activation of arteriolar smooth muscle contraction.

Animals↗
PubMed1990

Indirect evidence for an endothelium-derived contracting factor release in aorta of deoxycorticosterone acetate-salt hypertensive rats.

In order to investigate the involvement of endothelium-derived vasoactive substances in deoxycorticosterone acetate (DOCA)-salt hypertension, the responses to noradrenaline, acetylcholine, sodium nitroprusside and papaverine were studied in the absence and presence of indomethacin. Noradrenaline was equally effective in evoking a constrictor response of aorta, with or without endothelium, isolated from DOCA-salt hypertensive rats, while in controls, noradrenaline induced higher submaximal responses in rubbed than in unrubbed preparations. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in aorta with endothelium which had been precontracted with noradrenaline isolated from hypertensive rats. The relaxant response was lost after removal of the endothelium in both control and DOCA-salt hypertensive groups. The response to sodium nitroprusside, an endothelium-independent agent, in aorta isolated from hypertensive rats as well as the response to papaverine, an agent partially dependent on the endothelium, was not altered. Indomethacin treatment altered the response to noradrenaline only in unrubbed aorta of hypertensive rats. In these preparations, a biphasic response to noradrenaline was observed. At lower concentrations noradrenaline induced the characteristic constrictor response, while at higher concentrations a relaxant response was obtained that was abolished by methylene blue, a guanylate cyclase inhibitor. This could indicate that noradrenaline induced the release of endothelium-derived relaxing factor (EDRF) in aorta of hypertensive rats. Furthermore, indomethacin treatment restored the decreased response to acetylcholine in aorta isolated from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction: role of the endothelium.

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction occur in aortas from New England Deaconess Hospital (NEDH) rats harboring pheochromocytoma (PHEO) and following chronic exposure to the alpha-adrenergic agonist phenylephrine in vitro. Endothelium is known to release an endothelial cell-derived relaxing factor that promotes smooth muscle relaxation. We wondered if the endothelium might contribute to the desensitization of contraction. The role of the endothelium in desensitization was studied using aortic rings with endothelium [E(+)] and with endothelium removed [E(-)]. Maximal phenylephrine (PE)-induced contraction (Emax) for E(+) was 1.7 +/- 0.3 g in controls and 0.4 +/- 0.1 g in PHEO (p less than 0.001), demonstrating desensitization; however, for E(-), Emax was 2.4 +/- 0.2 g in PHEO vs. 2.5 +/- 0.2 g in controls, demonstrating restoration of maximal contraction when the endothelium was removed. However, sensitivity [-log EC50(M)] to PE in E(-) remained significantly lower in PHEO compared to controls (6.94 +/- 0.12 vs. 7.51 +/- 0.14, respectively, p less than 0.001). Similarly, in aortic ring segments desensitized in vitro with phenylephrine, the maximal contraction in phenylephrine-exposed aortas was 60% of that seen in controls. Removal of the endothelium from the vessels pretreated with phenylephrine fully restored the maximal response and sensitivity of these vessels. Treatment of desensitized vessels with hemoglobin (5 x 10(-5) M) restored the maximal contraction and sensitivity to phenylephrine. When the endothelium was removed prior to chronic exposure to phenylephrine, the sensitivity to phenylephrine decreased while the Emax remained similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed2003

Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta.

Our laboratory previously demonstrated that nitric oxide and natriuretic peptides can synergistically enhance cAMP elevations and vasorelaxations in rat aortic rings induced by calcitonin gene-related peptide, likely involving cyclic guanosine monophosphate (cGMP)-mediated inhibition of type-3 phosphodiesterase (PDE3). It was predicted that this cellular mechanism may also serve as a point of synergism between adrenomedullin (ADM) and brain natriuretic peptide (BNP) in aortic smooth muscle cells. The current study shows that ADM (100 nM)-induced vasorelaxations in isolated aortic rings of Sprague-Dawley rats are dependent on endothelium (34.1 +/- 4.2% relaxation with endothelium versus 3.0 +/- 0.6% relaxation without endothelium; P < 0.001). To determine interactions between ADM and BNP in smooth muscle cells without interference from endothelium-derived factors, further studies used aortic rings denuded of endothelium. Pretreatment with BNP (1 nM), which elevated cGMP levels 1.6 fold, uncovered direct vasorelaxant effects of ADM in endothelium-denuded rings, showing 5.6 +/- 1.8%, 20.9 +/- 6.1%, and 55 +/- 9.4% relaxations with ADM at 1, 10, and 100 nM, respectively (n = 6). ADM (100 nM) significantly (P < 0.05) increased cyclic adenosine monophosphate (cAMP) levels in denuded aortic rings pretreated with BNP (1 nM), but not in denuded rings without BNP. Quazinone (20 microM), a PDE3 inhibitor, caused similar enhancement of direct cAMP elevations to ADM (100 nM). The data indicate vasodilatory synergism between ADM and BNP in aorta, likely mediated by enhanced accumulation of cAMP in smooth muscle cells resulting from BNP/cGMP-induced inhibition of PDE3. This synergistic mechanism may be especially important in subjects with dysfunctional endothelium, in which BNP may uncover direct vasorelaxant effects of ADM in arteries that normally require healthy (nitric oxide-releasing) endothelium for ADM-induced vasorelaxations to occur.

Adrenomedullin↗
PubMed2004

Impairment of endothelium-dependent dilation response after resuscitation from hemorrhagic shock involved postreceptor mechanisms.

Resuscitation from hemorrhagic shock is associated with impairment of the endothelium-dependent dilation response, whereas the dilation response induced by the endothelium-independent pathway, which is mediated by nitroprusside, a nitric oxide (NO) donor and a direct activator of guanylate cyclase, remains unaltered. Whether the impairment of the endothelium-dependent dilation response is caused by a specific receptor alteration or generally a defect in signal transduction pathway remains undetermined. Anesthetized rats were monitored for hemodynamics, and the terminal ileum was prepared for intravital videomicroscopy. Hemorrhage was 50% of mean arterial pressure for 60 min followed by resuscitation with the shed blood returned plus 2 volumes of normal saline. Intestinal microvascular reactivity to the endothelium-dependent receptor-dependent agonists acetylcholine or substance P (10(-8) or 10(-6) M), as well as the endothelium-dependent receptor-independent calcium ionophore, was determined at baseline and at 2 h postresuscitation from hemorrhagic shock. Measured vascular diameters for premucosal A3 arterioles (pA3 and dA3) were normalized and expressed as percentage of the maximal dilation capacity, as obtained from the response to the endothelium-independent NO donor sodium nitroprusside (10(-4) M). At 2 h postresuscitation, there was a marked constriction of pA3 (-70.1 +/- 20) and dA3 (-61.5 +/- 11.6) from maximal dilation capacity. Baseline premucosal arteriolar response to substance P (10(-8) M) was 30.68 +/- 4.19% and 34.66 +/- 5.82% for pA3 and dA3 arterioles, respectively. This was significantly reduced to 20.97 +/- 2.41% and 17.94 +/- 3.60% at 2 h postresuscitation. However, no significant difference between baseline and postresuscitation arteriolar responses was observed at the higher dose of substance P (10(-6) M). Postresuscitation premucosal arteriolar response to the endothelium-dependent receptor-independent calcium ionophore (10(-9) to 10(-5) M) is characterized by a marked decrease in sensitivity and an enhanced threshold for calcium ionophore-mediated dilation. The logEC50 was -7.62 +/- 0.39 and -7.75 +/- 0.32 for the pA3 and dA3 at baseline, respectively. This was significantly (P < 0.01) reduced to -5.15 +/- 0.14 and -4.39 +/- 0.71 at 2 h postresuscitation. These data suggest that impairment of the endothelium-dependent dilation response after resuscitation from hemorrhagic shock is not mediated by specific receptor alteration. Cellular mechanisms that participate in or are part of oxygen free radical formation after resuscitation from hemorrhagic shock such as Ca2+ and leukocytes, appear to have a pivotal role in the mechanism of cellular dysfunction.

Animals↗
PubMed1996

Endothelium-derived hyperpolarizing factor.

1. Not all endothelium-dependent relaxations can be fully explained by the release of either nitric oxide (NO) and/or prostacyclin. Another unidentified substance(s) that hyperpolarizes the underlying vascular smooth muscle cells (endothelium-derived hyperpolarizing factor; EDHF) contributes to endothelium-dependent relaxations. 2. In blood vessels from various species these hyperpolarizations are resistant to inhibitors of NO synthase (NOS) and cyclo-oxygenase. In canine, porcine and human blood vessels the hyperpolarization cannot be mimicked by nitrovasodilators or exogeneous NO. However, in other species (rat, guinea-pig, rabbit) endothelium-dependent hyperpolarizations resistant to inhibitors of NOS and cyclo-oxygenase and hyperpolarizations to endothelium-derived or exogeneous NO can be observed in the same vascular smooth muscle cells. 3. In blood vessels where NO causes hyperpolarization, the response is blocked by glibenclamide, suggesting the involvement of ATP-dependent potassium channels. Hyperpolarizations caused by EDHF are insensitive to glibenclamide but, depending on the tissue, are inhibited by relatively small concentrations of tetraethylammonium (TEA) or by apamin or the combination of charybdotoxin plus apamin, indicating that calcium-dependent potassium channels are likely to be involved. 4. Metabolites of arachidonic acid, through the cytochrome P450 mono-oxygenase pathway (epoxyeicosatrienoic acids), are produced by the endothelial cells, increase the open-state probability of calcium-activated potassium channels sensitive to TEA or charybdotoxin, and induce the hyperpolarization of arterial smooth muscle cells, indicating that epoxyeicosatrienoic acids could be EDHF. However, in blood vessels from various species, cytochrome P450 inhibitors do not affect endothelium-dependent hyperpolarizations, indicating that EDHF is not yet identified with certainty. 5. Endothelium-derived hyperpolarizing factor released from cultured endothelial cells reduces the intracellular calcium concentration in vascular smooth muscle cells and the EDHF component of the relaxation is proportionally more important in smaller than larger arteries. In aging animals and in various models of diseases, endothelium-dependent hyperpolarizations are diminished. 6. The identification of EDHF and/or the discovery of specific inhibitors of its synthesis and its action may allow a better understanding of its physiological and pathophysiological role(s).

Animals↗
PubMed1998

Mechanisms of impairment of endothelium-dependent relaxation to acetylcholine in Watanabe heritable hyperlipidaemic rabbit aortas.

1. The mechanism of impairment of the endothelium-dependent relaxation in response to acetylcholine (ACh) in aortas from Watanabe heritable hyperlipidaemic (WHHL) rabbits was investigated using a modified sandwich (layered) technique. Intact aortas from WHHL rabbits or Japanese white (JW) rabbits as the control were used as donor strips of endothelium-derived relaxing factor (EDRF) and endothelium-denuded aortas from JW rabbits were used as detector strips. The EDRF released from a donor strip could be directly detected as the relaxation response in a detector strip. 2. The endothelium-dependent relaxations in all rabbit arteries were almost abolished by treatment with N(G)-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase). 3. The ACh-induced endothelium-dependent relaxations in the donor strips were impaired in WHHL rabbits in comparison with relaxations in JW and heterozygous WHHL rabbits. Similarly, the relaxation in the detector strips induced by EDRF released from donor strips was reduced in WHHL rabbits. There was a good negative correlation between the aortic total cholesterol content in the donor strips and the degree of relaxation in the detector strips from WHHL rabbits. 4. The reduced relaxation in the detector strips when using donor strips with high cholesterol accumulation or atheromatous plaque was not affected by superoxide dismutase plus catalase (scavengers of superoxide anions), indomethacin (an inhibitor of cyclo-oxygenase), ONO-3708 (an antagonist of endoperoxide/thromboxane receptor) and 97-139 (an antagonist of endothelin ET(A) receptor). 5. These results suggest that the mechanism of impaired endothelium-dependent relaxations in atherosclerotic WHHL rabbit aortas may be due to the reduced amount of EDRF, probably nitric oxide, from the endothelium and not due to its inactivation by oxygen-derived free radicals or masking by increased production of endothelium-derived contracting factors.

Acetylcholine↗
PubMed1986

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta.

The effect of endothelium on the adrenolytic action of prazosin was studied in the rat isolated aorta. Prazosin showed a non-competitive type of antagonism in preparations with intact endothelium while in preparations where endothelium had been removed, prazosin at concentrations between 0.3 nM-10 nM acted as a competitive antagonist. Methylene blue, used to decrease tissue levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP), converted prazosin from a non-competitive antagonist into an apparently competitive antagonist in the presence of endothelium. Increasing tissue levels of cyclic GMP by incubation with 8-bromo-cyclic GMP converted prazosin from an apparently competitive antagonist into a non-competitive antagonist in the absence of endothelium. Analysis of concentration-response curves for noradrenaline in the presence and absence of endothelium showed that the affinity for noradrenaline was the same but the efficacy, measured by estimating the receptor reserve, was not; it was lower in the presence than in the absence of endothelium. It was concluded that the change in the mode of antagonism of prazosin after endothelium removal could be related to an alteration in the efficacy of the agonist, brought about by a change in the tissue levels of cyclic GMP.

Animals↗
PubMed1991

Modulation by endothelium of the responses induced by endothelin-1 and by some of its analogues in rat isolated aorta.

1. The contractile effects of endothelin-1 and various analogues were studied in rat isolated rings. The potency of the peptides studied was endothelin-1 greater than sarafotoxin S6b greater than [Ala3,11]endothelin-1 greater than [Ala1,15]endothelin-1. [Ala1,3,11,15]endothelin-1 was neither agonist nor antagonist. 2. The concentration of endothelin-1 required to induced contractions equal to 50% of those induced by 1 microM noradrenaline was reduced from 5.8 nM when the vascular endothelium was present to 1.4 nM after it had been mechanically removed. 3. Contractions elicited by [Ala3,11]endothelin-1, [Ala1,15]endothelin-1 and sarafotoxin S6b were not modulated by the endothelium. 4. Endothelin-1 increased the tissue content of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in rat aortic segments with endothelium by about 4 fold, suggesting that it increased the release of endothelium-derived relaxing factor. Sarafotoxin S6b did not reduce, or significantly increase, tissue cyclic GMP levels and therefore had little effect on EDRF release. 5. The concentration of sodium nitroprosside required to relax half-maximally aortae denuded of endothelium was 430 nM if the aortae had been precontracted with 10 nM endothelin-1 and 35 nM if 10 nM sarafotoxin S6b was used as the spasmogen. This indicates that differential sensitivities of the smooth muscle to cyclic GMP cannot explain differences between responses to endothelin-1 and sarafotoxin S6b in the presence of endothelium. 6. It is concluded that endothelin-1 contractions of rat aorta are modified by the endothelium, probably by enhancing the release of endothelium-derived relaxing factor (EDRF) and not by affecting the sensitivity of the smooth muscle to EDRF. This suggests that a stimulated release of an adequate amount of EDRF is necessary to modulate contractile responses to these peptides.

Animals↗
PubMed1991

Endothelium-dependent mesenteric vasorelaxant effects and systemic actions of endothelin (16-21) and other endothelin-related peptides in the rat.

1. The rat isolated superior mesenteric bed, perfused with Krebs-Henseleit solution containing 10 microM indomethacin and precontracted with 100 microM methoxamine, was used to study the vasorelaxation produced by some fragments of endothelin-1, by two alanyl-substituted analogues, and by human and porcine proendothelins. The systemic cardiovascular effects of some of these peptides were also studied in anaesthetized rats. 2. Endothelin (16-21) was an endothelium-dependent vasodilator about 10 times less potent than acetylcholine and its amide was about 500 times less potent than the free acid. Human proendothelin-1 and porcine proendothelin-1 also caused endothelium-dependent relaxations but neither [Ala3,11]endothelin-1 nor [Ala1,3,11,15]endothelin-1 produced significant reductions in the methoxamine-induced tone. Sodium nitroprusside was approximately 200 times less potent than acetylcholine in the presence of the endothelium and was the only vasorelaxant to be active after destruction of the endothelium by perfusion with 0.3% CHAPS; in the absence of the endothelium it was 3.7 times more potent as a vasodilator than in its presence. 3. Porcine proendothelin-1 had weak contractile activity in the isolated mesenteric bed but porcine endothelin (22-39), endothelin (16-21) and endothelin (16-21) amide did not have vasoconstrictor actions. 4. Endothelin-3, [Ala3,11]endothelin-1, [Ala1,3,11,15]endothelin-1 and endothelin (16-21) all had systemic blood pressure effects in the anaesthetized rat. Although endothelin (16-21) did not cause vasoconstriction in vitro, it increased mean arterial pressure in vivo but was at least 100 times less potent than endothelin-3. Despite causing no vasorelaxation in vitro, [Ala1,3,11,15]endothelin-1 and [Ala3,11]endothelin-1 induced short-lived systemic depressor responses which were followed by pressor responses. Endothelin-3 was more potent as a systemic depressor agent than as a pressor agonist and, as a vasodepressor agent, it was 3-4 times more potent than either of the alanyl-substituted analogues. Endothelin-3, [Ala3,11]endothelin-1 and [Ala1,3,11,15]endothelin-1 were equipotent vasopressor agents. Porcine endothelin (22-39) had no systemic blood pressure effects. 5. This study shows directly that the presence of both disulphide bonds is required in the endothelins for them to be able to cause endothelium-dependent relaxation in the mesenteric vascular bed and that this response is mediated by different receptors from those causing contraction of the vascular smooth muscle in the mesentery. Vasorelaxation caused by endothelin (16-21) and its amide suggests that there is a receptor on the endothelium similar to one reported in the guinea-pig trachea. Finally, the ability of endothelin peptides to cause systemic vasodepressor responses is not related to their ability to cause endothelium-dependent relaxation, at least in the mesenteric circulation, and, for endothelin (16-21), its systemic pressor response is not likely to be the result of vasoconstriction in the mesenteric bed.

Acetylcholine↗
PubMed1994

Effects of P1 and P2Y purinoceptor antagonists on endothelium-dependent and -independent relaxations of rat mesenteric artery to GTP and guanosine.

1. Guanosine 5'-triphosphate (GTP) and guanosine can relax both endothelium-intact and -denuded arterial preparations. In the present work the P1 and P2Y purinoceptor antagonists, 8-phenyltheophylline and reactive blue 2, respectively, were used to study the mechanisms of relaxation responses induced by GTP, guanosine, adenosine 5'-triphosphate (ATP) and adenosine in noradrenaline-precontracted rat mesenteric artery rings. 2. GTP (10 microM-1mM) dose-dependently relaxed endothelium-intact mesenteric artery rings and also induced moderate relaxation responses in endothelium-denuded preparations. Pretreatment of the rings with 8-phenyltheophylline (10 microM) or reactive blue 2 (10 microM) did not attenuate the relaxant effect of GTP. 3. Guanosine (10 microM-1mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The presence of 8-phenyltheophylline or reactive blue 2 had no effects on guanosine-induced relaxations. 4. ATP-induced (0.1 microM-0.1 mM) relaxation of endothelium-intact artery rings was attenuated by reactive blue 2 while 8-phenyltheophylline was ineffective. ATP also relaxed endothelium-denuded artery rings and this relaxation was inhibited by 8-phenyltheophylline, but not by reactive blue 2. 5. Adenosine-induced (10 microM-1 mM) relaxation of endothelium-intact and -denuded artery rings was attenuated by the presence of 8-phenyltheophylline, but not of reactive blue 2. 6. In conclusion, the endothelium-dependent and -independent relaxations of rat mesenteric arteries to GTP and guanosine are not mediated via P1 and P2Y purinoceptors. Therefore, these results support our previous suggestion on the presence of a novel guanine nucleotide-specific receptor, a putative PG receptor, on both endothelial and smooth muscle cells, which may participate in the regulation of arterial tone.

Adenosine↗
PubMed1995

Thapsigargin- and cyclopiazonic acid-induced endothelium-dependent hyperpolarization in rat mesenteric artery.

1. The present study was designed to determine whether putative, selective inhibitors of the Ca(2+)-pump ATPase of endoplasmic reticulum, thapsigargin (TSG) and cyclopiazonic acid (CPA), induce endothelium-dependent hyperpolarization in the rat isolated mesenteric artery. The membrane potentials of smooth muscle cells of main superior mesenteric arteries were measured by the microelectrode technique. 2. In tissues with endothelium, TSG (10(-8)-10(-5) M) caused sustained hyperpolarization in a concentration-dependent manner. In tissues without endothelium, TSG did not cause any change in membrane potential. CPA (10(-5) M) also hyperpolarized the smooth muscle membrane, an effect that was endothelium-dependent and long-lasting. 3. The hyperpolarizing responses to these agents were not affected by indomethacin or NG-nitro-L-arginine (L-NOARG). 4. In Ca(2+)-free medium, neither TSG nor CPA elicited hyperpolarization, in contrast to acetylcholine which generated a transient hyperpolarizing response. 5. In rings of mesenteric artery precontracted with phenylephrine, TSG and CPA produced endothelium-dependent relaxations. L-NOARG significantly inhibited the relaxations to these agents, but about 40-60% of the total relaxation was resistant to L-NOARG. The L-NOARG-resistant relaxations were abolished by potassium depolarization. 6. These results indicate that TSG and CPA can cause endothelium-dependent hyperpolarization in rat mesenteric artery possibly by releasing endothelium-derived hyperpolarizing factor and that membrane hyperpolarization can contribute to the endothelium-dependent relaxations to these agents. The mechanism of hyperpolarization may be related to increased Ca2+ influx into endothelial cells triggered by depletion of intracellular Ca2+ stores due to inhibition of endoplasmic reticulum Ca(2+)-pump ATPase activity.

Acetylcholine↗
PubMed1987

The role of endothelium in tolerance to ethanol-induced contraction of the rat aorta.

After 2 days of intoxication an endothelium-dependent tolerance to ethanol-induced contraction of the rat aorta develops. This study investigates the possibility that the observed tolerance may be due to the recently described endothelium-dependent vasodilator system which mediates the action of several potent vasodilators. The maximum response induced by ethanol in control and intoxicated aortic rings with endothelium was significantly increased by treatment with eicosatetraynoic acid and methylene blue. In addition, these agents significantly decreased the EC50 of ethanol in intoxicated but not control rings with endothelium. The response of control and intoxicated aortic rings without endothelium was unaltered by eicosatetraynoic acid or methylene blue. Indomethacin, nordihydroguaiaretic acid, and FPL 55712 did not alter either the maximum response or the EC50 of ethanol in control or intoxicated rings with endothelium. These observations support the hypothesis that the endothelium-dependent tolerance observed in the aorta may be due to the release of an endothelium-derived relaxing factor.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1988

Influence of endothelium on the response to calcium agonists, calcium, potassium and noradrenaline in rat aorta.

We have studied the influence of endothelium on BAY K 8644, CGP 28392, potassium, noradrenaline and calcium induced responses in isolated thoracic aorta from rats. In aortic preparations with intact endothelium BAY K 8466 and CGP 28392 (10(-9)-10(-5) M) had a concentration dependent contractile effect, but BAY K 8644 was more effective in contracting the vessels than CGP 28932. Removal of endothelium increased the contractile response to both substances without affecting the difference in contractile effect between the two calcium agonists. In high concentrations (10(-4) M) BAY K 8644 and CGP 28392 had an equal relaxing effect on potassium precontracted preparations, which was unaffected by removal of endothelium. Removal of endothelium caused a shift to the left of the potassium and noradrenaline concentration response curves without any change in maximal contractile response. The contractile response to calcium in BAY K 8644 and potassium activated vessels was unaffected by removal of endothelium. We conclude that endothelium derived factor(s) depress the contractile response to calcium agonists, potassium, and noradrenaline but has no influence on the relaxant effect of BAY K 8644 and CGP 28392 in rat aorta. The influence of endothelium on the contractile effect on BAY K 8644 and potassium seems not to be due to a direct effect on calcium influx but rather to an influence on the membrane potential of the smooth muscle cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Regional differences in endothelium-dependent relaxation in the rat: contribution of nitric oxide and nitric oxide-independent mechanisms.

Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene-related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (phi approximately 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium-dependent relaxation in all arteries. Histamine induced an endothelium-dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium-dependent and mainly endothelium-independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium-independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium-dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. N omega-nitro-L-arginine (L-NOARG, 0.3 mM) reduced the maximum ACh-induced relaxation (in the presence of 10 microM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked L-NOARG/indomethacin-resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration-dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K+ solution, all arteries responded to ACh with a relaxation that was abolished by L-NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium-dependent relaxation regardless of the vascular region, an L-NOARG/indomethacin-resistant relaxation, presumably mediated by an endothelium-deprived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Increased influence of endothelium in obese Zucker rat aorta.

The ability of endothelium to alter contractile events in phenylephrine (PE)-triggered contraction has been tested on ring segments of the thoracic aorta removed from obese Zucker rats (plasma cholesterol 3.63 mM; n = 8) and from age matched lean rats (plasma cholesterol 2.38 mM; n = 8). In normal medium, PE (1 microM) elicited similar contractions in endothelium-denuded arteries of both strains. However, the presence of endothelium reduced these contractile events and the endothelium-dependent relaxation induced by carbachol (10 microM) was higher in obese rats. In rings incubated in Ca2+ free medium containing EGTA (1 mM), PE (1 microM) induced a phasic contraction and a sustained contraction following addition of Ca2+ (2.5 mM) to the medium. The phasic contraction was due to intracellular Ca2+ release, whereas the sustained response was dependent on extracellular Ca2+ influx. In endothelium-free preparations, the size of both the phasic and sustained contraction was similar for the two strains. The Ca2+ antagonist gallopamil (1 microM) reduced the sustained contraction of lean (24%) and obese (34%) rats without affecting the phasic contraction. In preparations possessing endothelium, the sustained, but not the phasic contraction, of both strains was inhibited. This inhibitory effect of endothelium on the sustained contraction was significantly higher in obese than in lean rats. Thus, it can be concluded that phenylephrine elicited quantitatively and qualitatively similar contractions in obese and lean rats. In both strains, the endothelium diminished the contraction induced by PE, however, this effect was more pronounced in obese rats than in lean ones. These results may explain, in part, the described absence of atherosclerotic lesions in the obese strain.

Animals↗
PubMed1989

Pertussis toxin inhibits endothelium-dependent relaxations to certain agonists in porcine coronary arteries.

1. Pertussis toxin inactivates Gi-protein, which mediates the inhibitory effects of receptors on adenylate cyclase. The effects of the toxin on endothelium-dependent and independent relaxations were determined in porcine coronary arteries. 2. Arterial rings (with and without endothelium) were suspended for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution (maintained at 37 degrees C, gassed with 95% O2 and 5% CO2). 3. Incubation of the tissues with pertussis toxin (100 ng/ml for 60 min) virtually abolished the endothelium-dependent relaxations produced by the alpha 2-adrenergic agonist, UK 14304, and by 5-hydroxytryptamine. Endothelium-dependent relaxations to thrombin and to aggregating platelets were markedly reduced, whereas those produced by bradykinin were only minimally affected. Endothelium-dependent responses produced by the calcium ionophore (A23187) and by adenosine diphosphate were not altered by pertussis toxin. 4. Pertussis toxin did not affect the direct, endothelium-independent relaxations produced by nitric oxide, or by adenosine diphosphate. 5. These experiments demonstrate that pertussis toxin interferes with the release of endothelium-derived relaxing factor(s) evoked by certain, but not all, endothelial activators. The release of endothelium-derived relaxing factor(s) may occur through different pathways involving Gi-protein-dependent and independent mechanisms.

Adenylate Cyclase Toxin↗
PubMed1993

Electrical properties of resting and acetylcholine-stimulated endothelium in intact rat aorta.

1. The passive electrical properties and the effects of acetylcholine on the membrane potential of the endothelium of intact rat aorta were investigated using the whole cell mode of the patch clamp technique. 2. Unstimulated endothelium had a membrane potential of -58 +/- 8 mV (S.E.M., n = 193; range -47 to -76 mV). The input resistance was 43 +/- 13 M omega (S.E.M., n = 8; range 26-64 M omega). KCl and BaCl2, but not tetraethylammonium (2 mM), 4-aminopyridine (5 mM) or 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS; 100 microM) depolarized the endothelium. 3. Acetylcholine (0.2-4 microM) evoked in most preparations a biphasic response with a transient hyperpolarization to a value close to the K+ reversal potential, followed by depolarization beyond the resting potential. In 46% of recordings, the depolarization was followed by oscillations in membrane potential. The duration of the hyperpolarization and magnitude of the depolarization was similar in all recordings from a given aorta, but varied greatly between different preparations. 4. Hyperpolarization of the endothelium below the K+ reversal potential reversed the direction of the first phase of the acetylcholine-evoked response, which was unaffected by tetraethylammonium, 4-aminopyridine, or DIDS. 5. The removal of extracellular Ca2+ evoked a depolarization of the endothelium from -61 +/- 3 to -34 +/- 3 mV (S.E.M., n = 9) over 2-15 min. Restoration of external Ca2+ evoked a transient hyperpolarization. 6. ACh applied in nominally Ca(2+)-free medium shortly after Ca2+ removal evoked only a transient hyperpolarization. After the establishment of a stable membrane potential in Ca(2+)-free medium, acetylcholine was without effect. 7. NiCl2 (2 mM) evoked a small depolarization of the endothelium (6 +/- 2 mV; S.E.M., n = 7). The subsequent removal of Ni2+ evoked a transient hyperpolarization. 8. In the presence of Ni2+, acetylcholine evoked a short-lived hyperpolarization. Both the application of Ni2+ and the removal of extracellular Ca2+ immediately blocked oscillations in membrane potential evoked by acetylcholine. 9. The blockers of voltage-operated Ca2+ channels, nifedipine (1-10 microM) and verapamil (20 microM) were without effect on the biphasic acetylcholine-evoked responses. 10. In preparations in which acetylcholine evoked large (20-45 mV) oscillations in membrane potential, depolarization of the endothelium alone, by current injection or application of KCl, did not evoke oscillations. 11. The activator of protein kinase C, phorbol 12, 13-dibutyrate (200 nM) depolarized and greatly increased the input resistance of the endothelium, presumably due to an effect on gap junctions.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗