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At least 595 records · Page 33Linked to original sources
PubMed1997

Evidence against the involvement of cytochrome P450 metabolites in endothelium-dependent hyperpolarization of the rat main mesenteric artery.

1. The influence of different inhibitors of cytochrome P450 mono-oxygenase on the endothelium-dependent and -independent hyperpolarization in the isolated rat main mesenteric artery was investigated. 2. Application of acetylcholine (ACh; 1 microM) for 10 min evoked an endothelium-dependent peak hyperpolarization of about 18 mV followed by a partial recovery to a level 7 mV more negative than the resting value (-50.2 +/- 0.5 mV). 3. Proadifen (30 microM) completely and reversibly inhibited the ACh-induced hyperpolarization. Conversely, the imidazole antimycotics clotrimazole (30 microM) and miconazole (100 microM) had less effect on the peak endothelium-dependent hyperpolarization. The suicide substrate inhibitors 17-octadecynoic acid (17-ODYA; 5 microM) and 1-aminobenzotriazole (1-ABT; 2 mM) did not significantly influence endothelium-dependent hyperpolarization. 4. The endothelium-independent hyperpolarization (16 mV) evoked by leveromakalim (300 nM) was completely inhibited by proadifen as well as by clotrimazole and miconazole but was not affected by 17-ODYA or 1-ABT. 5. These results do not support the view that the ACh-induced endothelium-dependent hyperpolarization in the rat mesenteric artery is mediated by cytochrome P450 mono-oxygenase metabolites. Proadifen and imidazole antimycotics impair the activation of ATP-regulated K+ channels in mesenteric artery cells, rendering non-specific inhibition of smooth muscle K+ channel activation an alternative explanation for the inhibitory influence of some (but not all) P450 inhibitors on endothelium-dependent hyperpolarization in this preparation.

Animals↗
PubMed1998

Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries.

1. The contribution of gap junctions to endothelium-dependent relaxation was investigated in isolated rabbit conduit artery preparations pre-constricted by 10 microM phenylephrine (PhE). 2. Acetylcholine (ACh) relaxed the thoracic aorta by approximately 60 % and the superior mesenteric artery (SMA) by approximately 90 %. A peptide possessing sequence homology with extracellular loop 2 of connexin 43 (Gap 27, 300 microM) inhibited relaxation by approximately 40 % in both artery types. Gap 27 also attenuated the endothelium-dependent component of the relaxation induced by ATP in thoracic aorta but did not modify force development in response to PhE. 3. NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), an inhibitor of NO synthase, attenuated ACh-induced relaxation by approximately 90 % in the aorta but only by approximately 40 % in SMA (P < 0.05). Residual L-NAME-insensitive relaxations were almost abolished by 300 microM Gap 27 in aorta and inhibited in a concentration-dependent fashion in SMA (approximately 50 % at 100 microM and approximately 80 % at 10 mM). Gap 27 similarly attenuated the endothelium-dependent component of L-NAME-insensitive relaxations to ATP in aorta. 4. Responses to cyclopiazonic acid, which stimulates endothelium-dependent relaxation through a receptor-independent mechanism, were also attenuated by Gap 27, whereas this peptide exerted no effect on the NO-mediated relaxation induced by sodium nitroprusside in preparations denuded of endothelium. 5. ACh-induced relaxation of 'sandwich' mounts of aorta or SMA were unaffected by Gap 27 but completely abolished by L-NAME. 6. We conclude that direct heterocellular communication between the endothelium and smooth muscle contributes to endothelium-dependent relaxations evoked by both receptor-dependent and -independent mechanisms. The inhibitory effects of Gap 27 peptide do not involve homocellular communication within the vessel wall or modulation of NO release or action.

Acetylcholine↗
PubMed1999

ATP released from perivascular nerves hyperpolarizes smooth muscle cells by releasing an endothelium-derived factor in hamster mesenteric arteries.

1. The interaction between perivascular nerves and endothelium was investigated by measuring the changes in smooth muscle membrane potentials using intracellular microelectrode techniques in hamster mesenteric thin (100-150 microm) and thick (300-350 microm) arteries. 2. In both arteries, nerve stimulation evoked excitatory junction potentials (EJPs) which were strongly inhibited by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (0.5-5 microM). This result indicated that the EJPs were induced by the activation of P2X receptors. 3. Transient hyperpolarizations were evoked by trains of pulses at 20 Hz in PPADS (5 microM)-pre-treated thin arteries, but not in the thick arteries. ATP (100 microM) applied to adventitial surfaces mimicked the hyperpolarizations. Both the ATP- and nerve stimulation-induced hyperpolarizations were blocked by cibacron blue F3GA (2-100 microM) and were also abolished after endothelium removal, indicating that the neurally released ATP evoked transient hyperpolarization through the activation of P2Y receptors located on the endothelium. 4. In endothelium-intact preparations, intimal application of uridine 5'-triphosphate (UTP 100 microM), a P2Y2-like receptor agonist, but not 2-methylthio ATP (7 microM), hyperpolarized the smooth muscle. The UTP-induced hyperpolarization was significantly inhibited by cibacron blue F3GA and was abolished after endothelium removal. 5. These results suggest that ATP released from the perivascular nerves may reach the endothelium and activate P2Y2-like receptors to induce the release of an endothelium-derived hyperpolarizing factor in thin arteries.

Adenosine Triphosphate↗
PubMed1988

Altered function of pulmonary endothelium following monocrotaline-induced lung vascular injury in rats.

1. Based on the findings in the preceding paper we investigated the ability of pulmonary endothelial cells to metabolize prostaglandin F2 alpha (PGF2 alpha) and angiotensin I (AI), and to produce endothelium-derived relaxing factor (EDRF) following lung vascular injury induced by monocrotaline in rats. The isometric tension of pulmonary artery rings isolated from rats 3-5 weeks after an injection of monocrotaline or saline was measured. For comparison the responses to drugs of the artery denuded of endothelium by rubbing were tested. 2. Acetylcholine-induced relaxation of the rings precontracted by noradrenaline was diminished in the artery from monocrotaline-treated rats, depending on the duration after treatment. The diminution was comparable to that in the control artery denuded of endothelium. 3. The contractile response to PGF2 alpha was significantly augmented in the artery injured by monocrotaline. The similar augmentation was observed after the mechanical removal of endothelium in the control artery. Decrease of EDRF was not involved in the enhancement of contractile response to PGF2 alpha in the monocrotaline-injured artery. 4. AI caused a contraction, which was sensitive to captopril, in control rings, and also in monocrotaline-injured rings to a similar degree. Removal of endothelium from the control artery did not modify the response to AI or to AII. 5. These results suggest that the monocrotaline treatment of rats suppresses the ability of pulmonary endothelium to produce EDRF and to degrade prostaglandins. The relative resistance of the AI response to endothelial injury suggests that the existence of converting enzyme is not restricted to the endothelium.

Acetylcholine↗
PubMed1988

Modulatory role of the vascular endothelium in the contractility of human isolated internal mammary artery.

1. Endothelium-dependent relaxant responses and modulation of contractile responses were investigated in human isolated internal mammary artery (HIMA), a vessel widely used for coronary bypass surgery. 2. Acetylcholine and ionophore A23187 (both 10 nM-1 microM) elicited concentration-dependent relaxations of precontracted HIMA. These relaxations were abolished after rubbing of the endothelium, they were inhibited by methylene blue and were insensitive to indomethacin. 3. Histamine at concentrations lower than 10 microM elicited an endothelium-dependent, methylene blue-sensitive relaxation of precontracted HIMA. This effect of histamine was inhibited by the H1-receptor antagonist mepyramine. Bradykinin, noradrenaline and alpha 2-adrenoceptor agonists (in the presence of prazosin) did not relax unrubbed HIMA in which acetylcholine or A23187 were shown to be efficient. 4. Tissue levels of guanosine-3':5'-monophosphate (cyclic GMP) were found to be significantly higher in unrubbed HIMA rings than in matched rubbed rings. 5. Methylene blue evoked a slow contraction in resting HIMA, and this contraction was significantly greater in unrubbed than in rubbed preparations. Also, methylene blue enhanced the contractile response of HIMA to noradrenaline and this potentiating effect was significantly greater in unrubbed than in rubbed preparations. Indomethacin induced a slow contraction, of similar magnitude in unrubbed and rubbed HIMA rings. 6. In resting HIMA, the concentration-effect curve of noradrenaline-induced contraction was significantly shifted to the left after rubbing of the endothelium, without change in the maximal responses. In unrubbed rings the EC50 value of noradrenaline was about 2 fold that in rubbed rings. 7. Histamine also contracted resting HIMA in a concentration-dependent manner and in addition, it triggered rhythmic activity. This rhythmic activity was more prominent in unrubbed preparations and could be partially inhibited by indomethacin. The concentration-effect curve of histamine-induced contractions was displaced to the left after rubbing the endothelium, without changes in the maximal responses. The EC50 value of histamine in unrubbed rings was 4 to 9 fold that found in rubbed rings, depending on the level of tension taken into account for the concentration-effect curve during rhythmic contractions. 8. In the presence of nifedipine (3 microM), noradrenaline-induced contractions were not significantly altered, whereas histamine-induced contractions were found to be inhibited by about 70%. 9. It is concluded that in HIMA, both spontaneous and stimulated endothelium-dependent relaxing factor (EDRF) release may occur, and that basal EDRF can itself be responsible for the modulatory effect of endothelium on contractile responses.

Acetylcholine↗
PubMed1989

A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation.

1. The role of L-arginine in the basal and stimulated generation of nitric oxide (NO) for endothelium-dependent relaxation was studied by use of NG-monomethyl L-arginine (L-NMMA), a specific inhibitor of this pathway. 2. L-Arginine (10-100 microM), but not D-arginine (100 microM), induced small but significant endothelium-dependent relaxations of rings of rabbit aorta. In contrast, L-NMMA (1-300 microM) produced small, endothelium-dependent contractions, while its enantiomer NG-monomethyl-D-arginine (D-NMMA; 100 microM) had no effect. 3. L-NMMA (1-300 microM) inhibited endothelium-dependent relaxations induced by acetylcholine (ACh), the calcium ionophore A23187, substance P or L-arginine without affecting the endothelium-independent relaxations induced by glyceryl trinitrate or sodium nitroprusside. 4. The inhibition of endothelium-dependent relaxation by L-NMMA (30 microM) was reversed by L-arginine (3-300 microM) but not by D-arginine (300 microM) or a number of close analogues (100 microM). 5. The release of NO induced by ACh from perfused segments of rabbit aorta was also inhibited by L-NMMA (3-300 microM), but not by D-NMMA (100 microM) and this effect of L-NMMA was reversed by L-arginine (3-300 microM). 6. These results support the proposal that L-arginine is the physiological precursor for the basal and stimulated generation of NO for endothelium-dependent relaxation.

Acetylcholine↗
PubMed1989

Hypoxia- and endothelium-mediated changes in the pharmacological responsiveness of circumflex coronary artery rings from the sheep.

1. The role(s) of the endothelium in modulating the responsiveness of isolated circumflex coronary artery rings (o.d. = 2.0-2.5 mm and o.d. = 0.6-1.3 mm) from sheep was investigated under oxygenated and hypoxic conditions. 2. Removal of the endothelium abolished the contraction produced by lowering the PO2 from 620 to 8 mmHg (either under optimal resting tension or precontracted by 40 mM KCl). In denuded artery rings sudden hypoxia caused relaxation. 3. Under oxygenated conditions, removal of the endothelium augmented the vasoconstrictor effects of U46619, 5-hydroxytryptamine (5-HT) and K+. In the denuded artery rings, hypoxia abolished the contractile effects of U46619 and reduced the contractile effects of 5-HT and K+. 4. Under oxygenated conditions, the vasorelaxant effect of adenosine was depressed by removal of the endothelium. In endothelium-denuded preparations, the small relaxant effect of adenosine remaining was greatly potentiated. 5. Haemolysate (1 microliter ml-1) caused an endothelium-dependent contraction under oxygenated conditions. The hypoxic contraction observed in the artery ring under resting tension was significantly potentiated by haemolysate (1 microliter ml-1). Haemolysate 1 microliter ml-1 had no effect on the denuded artery rings under hypoxic conditions. 6. Haemolysate (1 microliter ml-1) potentiated the vasoconstrictor effects of U46619 (0.5 microM), 5-HT (1 microM) and K+ (24 mM) under oxygenated conditions. 7. These results indicate that endothelium profoundly modifies the effect of hypoxia on the responsiveness of sheep isolated left circumflex coronary artery rings.

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

Role of endothelium in hypoxic contraction of canine basilar artery.

1. Reversible contraction of canine basilar artery, produced by hypoxia, persisted after mechanical and chemical removal of the endothelium. The removal of endothelium was confirmed by scanning electron microscopy as well as by the abolition or reversal of the relaxant response to acetylcholine or arginine8-vasopressin. 2. Hydroquinone, believed to block selectively endothelium-mediated relaxation, also preferentially attenuated hypoxic contractions even in the absence of endothelium but did not reduce responses to 5-hydroxytryptamine (5-HT) or high external potassium. 3. Contractions induced by red blood cell haemolysate, which occur independently of the endothelium, were also selectively attenuated by hydroquinone. 4. Contractions caused by hypoxia were inhibited by pretreatment with adenosine or by its application after contraction had developed. 5. Hypoxic contraction in canine basilar artery may result partly from a direct effect on smooth muscle as well as through the endothelium. 6. Hydroquinone may have an additional locus of action in smooth muscle cells besides its well known effect on the endothelium.

Adenosine↗
PubMed1990

Endothelium modulation of the effects of nitroglycerin on blood vessels from dogs with pacing-induced heart failure.

1. The relaxant actions of nitroglycerin (previously considered to be an endothelium-independent relaxing agent) and acetylcholine (an endothelium-dependent relaxing agent) were compared on 4 vascular preparations (dorsal pedal artery, saphenous vein, left anterior descending coronary artery and circumflex coronary artery) from dogs with and without pacing-induced congestive heart failure (CHF). 2. Responses of the coronary arteries to acetylcholine were unaltered in endothelium-intact rings from dogs with and without heart failure. Similarly no such changes were observed in the peripheral vessels. The maximum relaxation produced by acetylcholine was always greater in the coronary vessels compared to the peripheral vessels. 3. Before heart failure, the coronary vessels were more sensitive and reactive to nitroglycerin compared to the peripheral vessels. 4. Removal of the endothelium in both the control (dogs without CHF) and experimental (dogs with CHF) rings enhanced the relaxant effects of nitroglycerin, such that the EC50 for nitroglycerin became significantly lower in all denuded rings, with the exception of the saphenous vein and the left anterior descending coronary artery, before the development of CHF. 5. When CHF was maximally developed, vascular sensitivity to nitroglycerin was increased in peripheral vessels with an intact endothelium, but not in the coronary vessels. 6. These findings indicate that relaxation produced by nitroglycerin cannot be considered as entirely endothelium-independent but should be considered endothelium-modulated.

Acetylcholine↗
PubMed1991

Effect of endothelium removal on the vasoconstrictor response to neuronally released 5-hydroxytryptamine and noradrenaline in the rat isolated mesenteric and femoral arteries.

1. The role of the vascular endothelium in the vasoconstrictor response to transmural nerve stimulation (TNS) was studied in isolated ring segments of rat mesenteric and femoral arteries. 2. In both types of artery, TNS (1 to 16 Hz) produced frequency-dependent vasoconstriction, which was abolished by 100 nM tetrodotoxin, 10 microM guanethidine or 10 nM prazosin, indicating that the response was mediated by endogenous noradrenaline (NA) released from noradrenergic nerves. NA-mediated vasoconstriction in response to TNS was significantly potentiated by removal of the endothelium. 3. In the presence of 10 nM prazosin, the reduced vasoconstriction in response to TNS was restored by incubation with 10 microM 5-hydroxytryptamine (5-HT) for 20 min. Restoration of the response to TNS was markedly attenuated by treatment with 10 nM ketanserin, 100 nM tetrodotoxin, or 10 microM guanethidine, indicating that the restored response was mediated by 5-HT released from noradrenergic nerves. Vasoconstriction mediated by 5-HT in response to TNS was not modified by removal of the endothelium. 4. In both types of artery with intact endothelium, treatment with 3 microM methylene blue potentiated the NA-mediated contractile response to TNS, but did not potentiate the 5-HT-mediated response to TNS. 5. In both types of artery, the contractile responses to exogenous NA and 5-HT were potentiated by removal of the endothelium. 6. These results suggest that endothelial cells regulate neurogenic vasoconstriction by releasing endothelium-derived relaxing factor. Furthermore, it appears likely that the response to neuronally released 5-HT is not affected by the endothelium.

Animals↗
PubMed1992

Endothelium-dependent increase in vascular sensitivity to phenylephrine in long-term streptozotocin diabetic rat aorta.

1. The effect of short- and long-term streptozotocin (STZ)-induced diabetes (12 and 52 weeks) on the vascular response to phenylephrine was examined in the isolated thoracic aorta with and without intact endothelium from diabetic, age matched control rats and diabetic rats treated with insulin. 2. Twelve weeks after induction of diabetes, aortae with intact endothelium demonstrated no changes either in sensitivity (defined as pD2) or contractility (defined as the maximal developed tension per aortic tissue wet weight) to phenylephrine. 3. In contrast, 52 weeks after induction of diabetes, aortae with intact endothelium demonstrated an increased sensitivity to phenylephrine while contractility to phenylephrine was not changed. Insulin treatment partially corrected the increased sensitivity to phenylephrine observed in diabetic rat aorta. 4. Removal of endothelium abolished the difference in phenylephrine sensitivity between diabetic and control aortae at 52 weeks. 5. Pretreatment of intact aortae with methylene blue, an inhibitor of endothelium-derived relaxing factor (EDRF), abolished the difference in phenylephrine sensitivity between control and diabetic rat aortae at 52 weeks, while pretreatment with indomethacin, an inhibitor of cyclo-oxygenase, had no effect. These results suggest that decreases in production or release of EDRF might be responsible for the increased vascular sensitivity to phenylephrine observed in long-term STZ diabetic rats. 6. Acetylcholine-induced relaxation, which is EDRF-dependent, was less in diabetic rat aortae with intact endothelium at 52 weeks, but not at 12 weeks. These results further support the theory that decreases in capacity of the endothelium to synthesize or release EDRF may occur in long-term STZ diabetic rats.

Acetylcholine↗
PubMed1992

Cooling and response to adrenoceptor agonists of rabbit ear and femoral artery: role of the endothelium.

1. The effects of cooling on the response of the rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries to stimulation of adrenoceptors and the role of the endothelium in these effects, were studied in 2 mm long cylindrical segments. 2. Concentration-response curves for noradrenaline (10(-9)-3 x 10(-4) M), phenylephrine (alpha 1-adrenoceptor agonist, 10(-9)-3 x 10(-4) M) and B-HT 920 (alpha 2-adrenoceptor agonist, 10(-7)-10(-3) M) were recorded isometrically in arteries with and without endothelium at 37 degrees C and at 24 degrees C (cooling). To analyze further the endothelial mechanisms in the responses to adrenoceptor stimulation during cooling, the effects of the adrenoceptor agonists on ear arteries in the presence of NG-nitro-L-arginine methyl esther (L-NAME) (10(-5) M) were also determined. 3. In every condition tested, the three adrenoceptor agonists produced a concentration-dependent arterial contraction and the order of potency in ear and femoral arteries was noradrenaline greater than or equal to phenylephrine greater than B-HT 920. The response of ear and femoral arteries to phenylephrine or B-HT 920 was blocked by prazosin (10(-6) M). Yohimbine (10(-6) M) decreased slightly the response of ear arteries and increased that of femoral arteries to B-HT 920. 4. The sensitivity of both ear and femoral arteries to the three adrenoceptor agonists was significantly lower at 24 degrees C than at 37 degrees C. 5. In ear arteries, endothelium removal or treatment with L-NAME did not influence the response at 37 degrees C, but did increase it during cooling to adrenoceptor stimulation.In femoral arteries, endothelium removal increased the sensitivity to noradrenaline and, especially, to B-HT 920 at 37 degrees C, but did not affect the response at 24 degrees C.6. The results suggest that: (a) rabbit ear and femoral arteries are equipped mainly with alpha 1-adrenoceptors;(b) at 37 degrees C, the contraction of the ear artery to adrenoceptor agonists is mostly endothelium-independent, and in the femoral artery the contraction to alpha 2-adrenoceptor activation is endothelium-dependent; (c) cooling inhibits the contraction to adrenoceptor agonists in both ear and femoral arteries: in the ear artery probably by increasing the availability of endothelial nitric oxide, but in the femoral artery by depressing the sensitivity of alpha-adrenoceptors in the smooth musculature.7. The results suggest that the endothelium may modulate the adrenoceptor response of cutaneous arteries during changes in temperature.

Adrenergic alpha-Agonists↗
PubMed1994

Modulation by the endothelium of sympathetic vasoconstriction in an in vitro preparation of the rat tail artery.

1. The influence of the endothelium on transmural electrical stimulation was investigated in isolated and perfused segments of the rat tail artery. Noradrenaline release (NA, quantified by h.p.l.c.-electrochemical detection) and changes in perfusion pressure (PP, measured at constant flow rate) were simultaneously recorded in unstimulated and stimulated arterial segments, in the absence and in the presence of drugs. The ratio PP/NA release (mmHg pg-1) was taken as an index of the noradrenergic effectiveness. 2. Removal of the endothelium produced an increase in NA release and PP, in unstimulated and stimulated arteries. This can be taken as evidence of an endothelium-derived inhibitory factor (EDIF) acting at the prejunctional level, inhibiting NA release. Furthermore, in unstimulated arteries, the ratio PP/NA release decreased suggesting the existence of an endothelium-derived contracting factor (EDCF). 3. Perfusion of arteries with N omega-nitro-L-arginine methyl ester (L-NAME, 10 microM) or methylene blue (MeB, 0.5 microM) had no effect on PP or NA release in unstimulated arteries. In stimulated arteries, both drugs potentiated the increase in PP without changing NA release and therefore, led to an increase in noradrenergic effectiveness. After removal of the endothelium, neither L-NAME nor MeB affected the increases in PP and NA release following electrical stimulation. 4. Carbachol (1 microM) attenuated both NA release and the increase in PP during electrical stimulation, and increased the ratio PP/NA release. L-NAME and MeB did not modify the inhibitory effect of carbachol on NA release, or the facilitatory effect of carbachol on the noradrenergic effectiveness. 5. Angiotensin II (All, 0.1 MicroM) potentiated the increase in PP, without modifying NA release following electrical stimulation, and facilitated the vasoconstriction induced by perfusion of NA. In the absence of endothelium, All potentiated both the increase in PP and NA release in arteries stimulated electrically but had no effect on the vasoconstriction induced by perfusion of NA. This suggests an endothelium dependent activity of All in this preparation.6. These findings suggest that, in the rat tail artery, sympathetic vasoconstriction is modulated by three endothelial factors: (1) nitric oxide (NO), the release ot which seems NA-dependent; (2) EDCF,predominant in the unstimulated state, the release of which; can be stimulated by All; and (3) EDIF,unmasked by removal of the endothelial layer, the release of which can be stimulated by All.

Angiotensin II↗
PubMed1996

Ligustrazine-induced endothelium-dependent relaxation in pulmonary arteries via an NO-mediated and exogenous L-arginine-dependent mechanism.

1. Ligustrazine (tetramethylpyrazine, TMP) is a vasodilator that has been reported to have pulmonary selective properties in vivo, but not in vitro. Although TMP is generally described as being endothelium-independent, we provide evidence here that TMP may have an endothelium-dependent and nitric oxide (NO)-mediated mechanism in pulmonary arteries that could predominate at concentrations used therapeutically in China. 2. The study was performed on isolated pulmonary (1-2 mm i.d.), intrapulmonary (200-850 microns) and mesenteric (200-400 microns) arteries of the rat using a Mulvaney-Halpen small vessel myograph, following preconstriction with phenylephrine (PE, 10 microM), prostaglandin F2 alpha (PGF2 alpha, 100 microM), or 75 mM K+ (KPSS, equimolar substitution for Na+). Values are shown as mean +/- s.e.mean, or for EC50S as mean [+/-95% confidence limits]. 3. TMP caused a concentration-dependent relaxation against all three agonists in both large (1.56 +/- 0.04 mm) and small (399 +/- 20 microM) pulmonary arteries; it was more potent in small compared to large arteries constricted with PE or PGF2 alpha (P < 0.05), but not those constricted with KPSS. The NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA, 100 microM) caused a significant shift to the right of these relationships, such that the EC50 for TMP in large pulmonary arteries constricted with PE increased from 522 [+130, -104] microM (n = 12) to 1828 [+395, -325] microM (n = 6, P < 0.01). Both removal of the endothelium and methylene blue (10 microM) had similar effects. 4. L-Arginine substantially reduced the EC50 for TMP in pulmonary arteries; in the presence of 400 microM L-arginine the EC50 for TMP in large arteries constricted with PE was 14.7 [+21.0, -8.6] microM, (n = 6, P < 0.001), and with 10 microM L-arginine 96.7 [+45.1, -30.7] microM, (n = 6, P < 0.001). Similar effects were seen in small arteries. L-Arginine had no effect in the absence of an endothelium. D-Arginine was ineffective, and inhibition of L-arginine uptake with L-lysine blocked the action of L-arginine. L-Arginine (400 microM) had no significant effect on TMP-induced relaxation in mesenteric arteries (n = 5). 5. L-Arginine itself caused a concentration-dependent relaxation in intrapulmonary arteries (639 +/- 34 microM) constricted with PE, reaching a maximum relaxation around 100-400 microM (42.4 +/- 3.0%, n = 16), but this was independent of the endothelium. TMP (10 and 100 microM) significantly enhanced the relaxation to L-arginine, with a maximum relaxation in the presence of 100 microM TMP of 81.7 +/- 6.2% (n = 5, P < 0.01), but the effect of TMP was entirely dependent on the endothelium. A similar effect was observed in PGF2 alpha-constricted pulmonary arteries. 6. These results show that TMP stimulates NO production at low concentrations in pulmonary arteries, via an apparently novel endothelium-resident mechanism that is dependent on exogenous L-arginine. Normal plasma L-arginine levels of around 150 microM would allow this mechanism to be maximally activated. As mesenteric arteries do not seem to express the mechanism to any significant extent, at low concentrations TMP would be effectively selective to the pulmonary vasculature, and may thus have potential as a therapeutic agent in pulmonary vascular disease.

Animals↗
PubMed1994

Endothelium dependence of prostanoid-induced relaxation in human hand veins.

The endothelium dependence of prostanoid-induced relaxation was examined in human isolated hand veins precontracted by endothelin. Indomethacin (10(-6) mol l-1) and the thromboxane A2-receptor antagonist BM 13.505 (10(-6) mol l-1) were present throughout. The endothelium was removed by insufflating carbogen through the vessel lumen. Prostaglandin (PG) F2 alpha, PGE1, PGE2, and prostacyclin (PGI2) elicited concentration-dependent relaxant effects. Removal of the endothelium reduced the relaxation induced by PGF2 alpha and PGE2, but not that elicited by PGE1 and PGI2. The order of potency was PGE2 approximately PGE1 approximately PGI2 > PGF2 alpha regardless of the presence or absence of endothelium. The relaxation elicited by an acidified solution of NaNO2 (generating nitric oxide) was almost identical in intact and endothelium-denuded vein segments. The results are compatible with the existence of two prostanoid receptor populations mediating relaxation: (1) one located on the smooth muscle cells and; (2) another present on the endothelium or possibly on the smooth muscle and modulated by the endothelium. The latter receptor appears to be activated by PGF2 alpha and PGE2, but not by PGE1 and PGI2.

Adolescent↗
PubMed1997

Twenty-four-hour variations in the effect of nitrodilators in rat aorta: lack of influence of the endothelium.

Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat thoracic aorta, both endothelium-intact and endothelium-denuded. For most of the concentrations of sodium nitroprusside used the induced relaxations were significantly dependent on the time the tissues were obtained. However, significant temporal differences were obtained for glyceryl trinitrate-induced relaxations at lower concentrations only for both endothelium-intact and endothelium-denuded preparations. EC50 values of sodium nitroprusside and glyceryl trinitrate (i.e. the concentrations inducing half the maximum response) were also significantly different and they had quite similar rhythmic features both in endothelium-intact and in endothelium-denuded preparations. These results clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator agents varies over a 24-h period and thus depends on when the animals were killed; the presence of endothelium does not change the rhythm of nitrodilator activity. These variations might be a result of circadian rhythm in the guanylate cyclase-cGMP system which mediates responses to nitrodilator agents.

Animals↗
PubMed1997

Role of the endothelium in the relaxation induced by propofol and thiopental in isolated arteries from man.

Induction of anaesthesia with intravenous propofol and thiopental is often accompanied by hypotension. This study evaluates whether propofol and thiopental induce relaxation of isolated arteries from man and whether this effect is modulated by the endothelium. Mesenteric artery rings (with and without endothelium) from 12 patients were placed in organ baths and precontracted with phenylephrine before addition of propofol (10(-3) M) or thiopental (10(-3) M). Relaxation induced by propofol and thiopental was evaluated for rings with intact endothelium in the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) or the cyclooxygenase inhibitor indomethacin (10(-5) M). The vasodilator effect of propofol was similar for intact and denuded endothelium rings whereas the relaxation induced by thiopental was significantly attenuated in denuded-rings. In intact endothelium rings, L-NAME and indomethacin caused marked inhibition of the relaxation induced by thiopental, but not that induced by propofol. These results suggest that propofol induces endothelium-independent relaxation of isolated mesenteric arteries in man, whereas thiopental causes endothelium-dependent relaxation mediated by nitric oxide and prostaglandins.

Aged↗
PubMed1995

The role of the endothelium in hypoxic pulmonary vasoconstriction.

The precise mechanisms underlying hypoxic pulmonary vasoconstriction (HPV) are still elusive. The recent discovery of K+ channels that are depressed by hypoxia in pulmonary vascular smooth muscle has provided a potential signal transduction mechanism for linking a reduction in Po2 to Ca2+ entry, but there are many reports suggesting that sustained HPV depends on the presence of the endothelium. Many endothelium-derived vasoactive factors have been investigated as possible mediators of HPV, including endothelium-derived relaxing factor (EDRF-NO), leukotrienes, prostanoids and endothelin, yet none have been found to be indispensable for HPV. They do, however, act as powerful modulators of the response to hypoxia. HPV is probably multifactorial in origin, as exemplified by the biphasic response to hypoxia seen in isolated pulmonary arteries over 40 min. The first phase is of rapid onset but transient, endothelium independent and partly related to Ca2+ release from intracellular stores. The second phase is slowly developing but sustained, dependent on the endothelium and associated with a stable elevation of cytosolic Ca2+. Since tension continues to rise while intracellular [Ca2+] remains constant, this implies Ca2+ sensitization of the contractile apparatus. This is independent of protein kinase C or pH. It is proposed that HPV depends upon both smooth muscle and endothelium resident mechanisms. Inhibition of K+ channels causes an elevation of cytosolic Ca2+, which may not be sufficient to generate substantive contraction on its own. However, release from the endothelium of an as yet unidentified mediator increases Ca2+ sensitivity of the contractile apparatus, and sustained contraction ensues.

Animals↗