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PubMed2003

Identification and cloning of the Na/HCO(3-) cotransporter (NBC) in human corneal endothelium.

Fluid secretion by the corneal endothelium is associated with the net flux of HCO(3)(-) from basolateral (stromal) to apical (anterior chamber) sides of the tissue. In this study we asked if Na(+)/HCO(3)(-) cotransporter (NBC-1) protein expression and functional activity are present in freshly isolated human corneal endothelium. Immunoblot analysis using a polyclonal antibody to NBC-1 showed a single band at approximately 130 kDa. Indirect immunofluorescence indicated that NBC-1 is expressed on the basolateral, but not apical side of human corneal endothelium. RT-PCR was used to determine whether the kidney or pancreatic isoform of NBC-1 is expressed. Using the specific primers for pNBC and kNBC isoforms, RT-PCR showed that only pNBC could be detected in human corneal endothelium. The product was cloned and confirmed by sequencing. Full-length NBC-1 was also cloned from human corneal endothelium. This clone (hcNBC) is 100% identical to the longer, more common form of NBC [pNBC; 1079 amino acids (aa); 122 kDa in human heart, pancreas and prostate]. To test for functional activity of NBC-1, freshly isolated endothelium was loaded with the pH sensitive fluorescent dye BCECF and HCO(3)(-) fluxes were measured. HCO(3)(-) fluxes were Na(+)-dependent, electrogenic and H(2)-DIDS sensitive. We conclude that the long isoform of the sodium bicarbonate cotransporter (pNBC-1) is expressed on the basolateral side of fresh human corneal endothelium (hcNBC). The shorter form, kNBC, could not be detected. As in bovine corneal endothelium, hcNBC is instrumental in loading HCO(3)(-) into endothelial cells from the basolateral membrane.

Amino Acid Sequence↗
PubMed1992

Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone.

Relaxation of penile corpus cavernosum smooth muscle is controlled by nerve and endothelium derived substances. In this study, endothelium-dependent relaxation of corporal smooth muscle was characterized and the role of arachidonic acid products of cyclooxygenase in endothelium-dependent relaxation was examined. Endothelium removal from rabbit corpora was performed by infusion with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate and was confirmed by transmission electron microscopy. Strips of human and rabbit corporal tissues were studied in the organ chambers for isometric tension measurement. The accumulation of cyclic guanosine monophosphate (cGMP) and the release of eicosanoids from corporal tissue was measured by radioimmunoassay and correlated to smooth muscle relaxation. Our study showed that relaxation of corpus cavernosum tissue to acetylcholine, bradykinin and substance P was endothelium-dependent; potentiated by indomethacin; and inhibited by NG-monomethyl-L-arginine, methylene blue or LY83583. Relaxation to papaverine and sodium nitroprusside was endothelium-independent, and unaffected by NG-monomethyl-L-arginine. Relaxation to vasoactive intestinal polypeptide was partially endothelium-dependent; potentiated by indomethacin; attenuated by NG-monomethyl-L-arginine or methylene blue. The tissue level of cGMP was enhanced by acetylcholine and nitric oxide. Methylene blue inhibited both basal and drug-stimulated levels of cGMP. The release of eicosanoids was enhanced by acetylcholine and blocked by indomethacin. In conclusion, nitric oxide or a closely related substance accounts for the activity of endothelium-derived relaxing factor in the corporal tissue. Inhibition of the release of eicosanoids potentiates the relaxing effect of nitric oxide. Nitric oxide increases tissue cGMP which appears to modulate corporal smooth muscle relaxation.

Acetylcholine↗
PubMed1995

Comparison of endothelial function between in situ and reversed vein graft: differences in endothelium-dependent responses.

BACKGROUND: The endothelium releases endothelium-derived relaxing factors that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses differed between in situ and reversed vein grafts. The influence of valve disruption or of dissection of the adventitia was also examined. METHODS: Segments of canine jugular veins were grafted into the carotid arteries during procedures such as reversed grafting, in situ grafting with valve disruption, in situ grafting without valve disruption, and in situ grafting with dissection of adventitia. After 4 weeks the endothelium-dependent responses of the grafts were examined by isometric tension recording. RESULTS: In the reversed and in situ vein graft with valve disruption, acetylcholine caused endothelium-independent contractions, whereas in the in situ vein graft without valve disruption acetylcholine-induced endothelium-dependent relaxations were preserved. Adenosine diphosphate (ADP) caused comparable endothelium-dependent relaxations in the in situ vein graft irrespective of valve disruption. In the reversed vein graft ADP-induced relaxations were significantly impaired. In the in situ vein graft with dissection of the adventitia, relaxations in response to acetylcholine and ADP were significantly reduced. CONCLUSIONS: These results suggest that endothelial function, in terms of endothelium-derived relaxing factors in the in situ vein graft, can be preserved and that adventitial dissection in the in situ vein graft should be minimized to preserve endothelial function.

Acetylcholine↗
PubMed2001

Cocaine toxic effect on endothelium-dependent vasorelaxation: an in vitro study on rabbit aorta.

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

Acetylcholine↗
PubMed1997

An arginine analog inhibits responses of both the endothelium and smooth muscle of canine in situ vein grafts.

Increased shear, pressure, and oxygen tension in vein grafts may alter production of endothelium-derived vasoactive and anti-mitogenic factors such as nitric oxide which subsequently affect development of neointimal hyperplasia. This study was designed to determine whether or not nitric oxide mediates endothelium-dependent responses in femoral in situ vein grafts. Non-reversed, canine femoral vein grafts were placed bilaterally to bypass a ligated segment of the femoral artery in dogs. After 6 weeks, the grafts were removed, cut into rings, and suspended in organ chambers for measurement of isometric force. In some rings the endothelium was removed deliberately. In the presence of indomethacin, the synthetic analog of L-arginine, L-N(G)-monomethyl-arginine (10(-4) M; L-NMMA) did not cause a significant change in baseline tension of rings with endothelium. L-NMMA reduced only contractions of rings with endothelium to the alpha-adrenergic agonist UK 14,304. The analog also reduced maximal relaxations to the calcium-ionophore, A23187 in rings with endothelium. In addition, L-NMMA reduced relaxations of rings without endothelium to adenosine diphosphate by 35%. Positive immunostaining for nitric oxide synthase was present in both the myointima and media of histological sections of grafts. In conclusion, these results suggest that in situ vein grafts exhibit two unique properties which are unlike unoperated arteries or veins: (i) alpha2-adrenergic receptors may be coupled to the release of contractile endothelium-derived factors associated with production of nitric oxide: and (ii) nitric oxide may be released by the smooth muscle in response to purinergic stimulation. The presence of nitric oxide synthase throughout the wall of the graft may result in production of nitric oxide in response to adenosine diphosphate released by platelets and to circulating catecholamines.

Adrenergic alpha-Agonists↗
PubMed2001

Endothelium-dependent vasoactive modulation in the ophthalmic circulation.

The vascular endothelium is strategically located between the circulating blood and the vascular smooth muscle cells. Different agonists or stimuli transported by the circulating blood can trigger the endothelium to release potent relaxing (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor) or contracting factors (endothelin, cycloxygenase products). These endothelium-derived vasoactive factors can modulate blood flow locally. Heterogeneity exists from one vascular bed to the other, or even between vessels, in the agonists able to stimulate the release of endothelium-derived vasoactive factors. In the ophthalmic circulation, nitric oxide and endothelin are strong vasoactive modulators. In many vascular diseases that are of importance in ophthalmology (hypercholesterolemia, arteriosclerosis, hypertension, diabetes, vasospastic syndrome, ischemia and reperfusion, etc) the function of the endothelium can be impaired. There exist different drugs that can modulate the vasoactive function of the vascular endothelium. In other words, it appears that the vascular endothelium plays an important role in both the physiology and pathophysiology of the regulation of blood flow. The modulation of this regulatory system by different drugs might open new therapeutical approaches to treat vascular disorders in ophthalmology.

Animals↗
PubMed1997

Alterations in endothelium-dependent hyperpolarization and relaxation in mesenteric arteries from streptozotocin-induced diabetic rats.

1. The aim of this study was to determine whether endothelium-dependent hyperpolarization and relaxation are altered during experimental diabetes mellitus. Membrane potentials were recorded in mesenteric arteries from rats with streptozotocin-induced diabetes and age-matched controls. The resting membrane potentials were not significantly different between control and diabetic mesenteric arteries (-55.3 +/- 0.5 vs -55.6 +/- 0.4 mV). However, endothelium-dependent hyperpolarization produced by acetylcholine (ACh; 10(-8)-10(-5) M) was significantly diminished in amplitude in diabetic arteries compared with that in controls (maximum -10.4 +/- 1.1 vs -17.2 +/- 0.8mV). Furthermore, the hyperpolarizing responses of diabetic arteries were more transient. 2. ACh-induced hyperpolarization observed in control and diabetic arteries remained unaltered even after treatment with 3 x 10(-4) M N(G)-nitro-L-arginine (L-NOARG), 10(-5) M indomethacin or 60 u ml (-1) superoxide dismutase. 3. Endothelium-dependent hyperpolarization with 10(-6) M A23187, a calcium ionophore, was also decreased in diabetic arteries compared to controls (-8.3 +/- 1.4 vs -18.0 +/- 1.9 mV). However, endothelium-independent hyperpolarizing responses to 10(-6) M pinacidil, a potassium channel opener, were similar in control and diabetic arteries (-20.0 +/- 1.4 vs - 19.2 +/- 1.1 mV). 4. The altered endothelium-dependent hyperpolarizations in diabetic arteries were almost completely prevented by insulin therapy. Endothelium-dependent relaxations by ACh in the presence of l0(-4) M L-NOARG and 10(-5) M indomethacin in diabetic arteries were also reduced and more transient compared to controls. 5. These data indicate that endothelium-dependent hyperpolarization is reduced by diabetes, and this would, in part, account for the impaired endothelium-dependent relaxations in mesenteric arteries from diabetic rats.

Acetylcholine↗
PubMed1998

P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation.

1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel.

Acetylcholine↗
PubMed2000

Platelet-derived growth factor causes endothelium-independent relaxation of rabbit mesenteric artery via the release of a prostanoid.

Recent evidence has indicated that the mitogen platelet-derived growth factor (PDGF) can act acutely to regulate arterial tone. In this study we demonstrate that the BB isoform of PDGF (PDGF-BB) can cause endothelium-independent relaxation of rabbit isolated mesenteric arteries. In endothelium-denuded arteries, PDGF-BB (40 pM - 8.0 nM) caused concentration-dependent relaxation of noradrenaline-induced tone. The relaxation to PDGF-BB was abolished by a cyclo-oxygenase inhibitor, indomethacin (10 microM) and by the PDGF receptor-associated tyrosine kinase inhibitor, tyrphostin AG1295 (50 microM), but not by N:(G)-monomethyl-L-arginine (L-NMMA, 200 microM), an inhibitor of nitric oxide (NO) synthase. PDGF-BB (4.0 nM) significantly increased the release of prostacyclin (PGI(2)) in endothelium-denuded arteries. Exogenously applied iloprost (1 microM), a stable analogue of PGI(2), relaxed the endothelium-denuded artery. PDGF-BB (4.0 nM) significantly increased the cyclic AMP content. In the absence of Ca(2+), PDGF-BB (4.0 nM) failed to relax the artery, and the release of PGI(2) was almost completely suppressed. In addition, the release of PGI(2) by PDGF-BB (4.0 nM) was significantly reduced in the presence of endothelium. The effect of endothelium was eliminated by L-NMMA (200 microM) and PGI(2) release increased. These data indicate that in rabbit mesenteric arteries, PDGF-BB can evoke endothelium-independent relaxation by stimulating the synthesis of PGI(2). The PDGF-BB-induced prostaglandin synthesis is dependent on both Ca(2+) and tyrosine phosphorylation of the PDGF receptor, and is attenuated by endothelium-derived NO.

Animals↗
PubMed2003

Calcium dobesilate potentiates endothelium-derived hyperpolarizing factor-mediated relaxation of human penile resistance arteries.

1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K(+) (35 mM) or by blocking Ca(2)(+)-activated K(+) channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 micro M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K(+) or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg(-1) i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.

Animals↗
PubMed2004

17beta-Oestradiol enhances aortic endothelium function and smooth muscle contraction in male spontaneously hypertensive rats.

17beta-Oestradiol (E(2); oestrogen) is known to increase endothelium-dependent vasodilatation and NO (nitric oxide) production. It is also known to decrease the response of VSMCs (vascular smooth muscle cells) to vasoconstrictors in vitro. E(2) induces a decrease in age-related BP (blood pressure) development in MSHR (male spontaneously hypertensive rats). Whether this decrease is due to an effect on the endothelium or smooth muscle is unknown. To determine this effect, we examined the role of E(2) on vascular endothelium and smooth muscle separately. We treated MSHR with E(2) (2 mg x kg(-1) of body weight x week(-1)) for 5-7 weeks and then examined the vasoconstrictor response in the intact and denuded rings (with or without endothelium respectively). SBP (systolic BP) was measured weekly. Aortic cGMP and cAMP contents, aortic vasoconstrictor response, endothelium suppression of the vasoconstrictor response and basal NO release from aortic rings were all measured at the end of the study. We found that the age-related development of SBP in MSHR was decreased in E(2)-treated rats. The vascular response of denuded rings to a vasoconstrictor (phenylephrine and KCl) was increased in E(2)-treated rats; however, this phenomenon was masked in intact rings. The enhanced endothelial function appears to override the E(2)-increased smooth muscle vasoconstrictor response. Endothelium suppression, NO release and aortic cGMP content were all significantly higher in E(2)-treated rats than in controls. Thus our results suggest that E(2) improves endothelium function; furthermore, the accompanied NO/cGMP increase and the endothelium suppression may be associated with an E(2)-induced BP-lowering effect in MSHR.

Aging↗
PubMed2001

An ordinary mixed meal transiently impairs endothelium-dependent vasodilation in healthy subjects.

This study was designed to evaluate the effects of an ordinary mixed meal on endothelium-dependent vasodilation. Ten young healthy volunteers were given a mixed meal (minced meat sauce with rice, 900 kcal, 34% of the energy content was fat). In the fasting state, at 60 and 120 min after the start of the meal, endothelium-dependent vasodilation and endothelium-independent vasodilation were evaluated by local infusion of metacholine (4 microg min (-1)) and sodium nitroprusside (10 microg min (-1)) in the brachial artery. Blood flow in the forearm was measured using venous occlusion plethysmography. Endothelium-dependent vasodilation decreased from 15.4 +/- 3.3 (mean +/- SD) at fasting to 13.7 +/- 3.5 mL min (-1) (100 mL tissue)-1 (P < 0.01) 60 min after feeding, but had returned to the fasting level at 120 min. At 60 min, but not in the fasting state, the serum level of free fatty acids was inversely related to endothelium-dependent vasodilation (r=-0.74, P < 0.05), although no significant net changes in FFA levels were seen. Endothelium-independent vasodilation was not affected by the mixed meal. No similar attenuations in endothelium-dependent vasodilation were seen during control meals. In conclusion, an ordinary mixed meal transiently attenuated endothelium-dependent vasodilation. Free fatty acids may be involved in this effect on endothelial function.

Adult↗
PubMed1999

Modelling the changes due to the endothelium and hypertension in the alpha-adrenoreceptor-mediated responses of rat aorta.

The present study focuses on the role of endothelium on alpha1-adrenoceptor-mediated vasoconstriction in aorta from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). To define and quantify changes in the parameters governing agonism at alpha1-adrenoceptor by hypertension and/or endothelium, the operational model of analysis was used. In either endothelium intact or denuded aorta, the sensitivity (P < 0.001) and the maximum contraction (P < 0.05) to phenylephrine were smaller in SHR than in WKY. However, in each strain of rats, removal of endothelium increased the sensitivity (P < 0.001) to phenylephrine but reduced (P < 0.05) KCl-evoked vasoconstriction, suggesting a modulation of these responses by the endothelium. The observed differences in sensitivity and maximum contraction are interpreted in terms of the operational parameters: Em, the maximum possible effect; pK(A), the agonist affinity; alpha, the agonist efficacy and n, the slope for the function relating receptor occupancy to pharmacological effect. The estimated parameters reflected differences, between strains, in the signal transduction processes linked to alpha1-adrenoceptor stimulation ascribed to the presence of the endothelium. N(G)-nitro-L-arginine methyl ester (L-NAME), enhanced to a similar extend in both rat strains the sensitivity (P < 0.001) and the maximum contraction to phenylephrine. Indomethacin reduced the maximum contraction to phenylephrine by 56.85% in SHR and by 11.80% in WKY suggesting that contracting prostanoids play a more major role in this response in SHR than in WKY. Nevertheless, these inhibitors were without effect on denuded vessels from both strains suggesting that NO and cyclooxygenase products from the media or the adventitia do not play a role on the phenylephrine-mediated responses. The studied endothelial factors partially explain the observed differences in modulation of alpha1-adrenoceptor responses by the endothelium but suggest the participation of other compounds released by the endothelium.

Adrenergic alpha-Agonists↗
PubMed1993

Role of the endothelium on extraluminal and intraluminal vasoactive mechanisms in the perfused rabbit basilar artery.

In order to investigate the role of the endothelium in the regulation of cerebrovascular tone, we studied selective intraluminal and extraluminal vasoactive mechanisms of acetylcholine, potassium and serotonin. We also examined the effects of removal of the endothelium on these vasoactive responses. With 0.75 g of tension, isolated rabbit basilar arteries were fixed in a perfusion system with the ability to isolate the intraluminal and extraluminal surfaces, and perfused at 8 ml-1 min-1 under a pressure of 8 mmHg. To remove the endothelium, we applied several concentrations of saponin. The endothelium was completely removed by 0.05 mg-1 ml-1 saponin, confirmed histologically. Extraluminal and intraluminal acetylcholine induced endothelium-dependent relaxations. Intraluminal potassium induced greater contraction than extraluminal potassium in both saponin denuded (p < 0.01) and intact preparations (p < 0.05, n = 8). Intraluminal and extraluminal serotonin induced symmetric contractions, and for both sides the response was enhanced by removal of the endothelium (p < 0.05, n = 6). Our results suggest that inhibitory (relaxant) contribution of the endothelium to contractile responses varies depending on the vasoactive agent. The fact that the effects of some extraluminal agents were enhanced when the endothelium was denuded, may be of some importance in potentiating the mechanism of vasospasm following subarachnoid haemorrhage.

Acetylcholine↗
PubMed2000

C-peptide inhibits leukocyte-endothelium interaction in the microcirculation during acute endothelial dysfunction.

C-peptide is a cleavage product that comes from processing proinsulin to insulin that induces nitric oxide (NO) -mediated vasodilation. NO modulates leukocyte-endothelium interaction. We hypothesized that C-peptide might inhibit leukocyte-endothelium interaction via increased release of endothelial NO. Using intravital microscopy of the rat mesentery, we measured leukocyte-endothelium interactions after administration of C-peptide to the rat. Superfusion of the rat mesentery with either thrombin or L-NAME consistently and significantly increased the number of rolling, adhering, and transmigrated leukocytes. C-peptide significantly attenuated either thrombin- or L-NAME-induced leukocyte-endothelium interactions in rat mesenteric venules. A control scrambled sequence of C-peptide characterized by the same amino acid composition in a randomized sequence failed to inhibit leukocyte-endothelium interactions. These effects of C-peptide were associated with decreased surface expression of the cell adhesion molecules P-selectin and ICAM-1 on the microvascular endothelium. Endothelial nitric oxide synthase (eNOS) mRNA levels were increased in rats injected with C-peptide. This enhanced eNOS expression was associated with a marked increase in basal NO release from the aorta of C-peptide-treated rats. We conclude that C-peptide is a potent inhibitor of leukocyte-endothelium interaction and that this effect is specifically related to inhibition of endothelial cell adhesion molecules via maintenance of NO release from the vascular endothelium.

Animals↗
PubMed1989

Local anesthetics inhibit endothelium-dependent vasodilation.

The effect of local anesthetics on endothelium-dependent and endothelium-independent vasodilation was determined using isolated rat thoracic aorta. Endothelium-intact rat aortic rings were mounted for isometric tension recording. Cumulative concentration-dependent vascular relaxation responses to the endothelium-dependent vasodilators methacholine (1 x 10(-8) to 3 x 10(-5) M), the calcium ionophore A23187 (1 x 10(-8) to 3 x 10(-7) M) and the endothelium-independent vasodilator sodium nitroprusside (1 x 10(-9) to 1 x 10(-7) M) were determined in the presence or absence of bupivacaine, lidocaine, etidocaine, or 2-chloroprocaine (1 x 10(-4) M). All of the local anesthetics studied significantly (P less than 0.05) inhibited endothelium-dependent relaxations to the receptor-mediated methacholine and the nonreceptor-mediated A23187. Bupivacaine was more potent (P less than 0.01) than the other three anesthetics tested. Direct, endothelium-independent vasodilation by sodium nitroprusside was not affected. The local anesthetics appear to exert their inhibitory effect on endothelium-dependent vasodilation at a site distal to receptor activation at the endothelial cell and proximal to guanylate cyclase activation in the vascular smooth muscle.

Anesthetics, Local↗
PubMed1997

Isoflurane anesthesia attenuates endothelium-dependent pulmonary vasorelaxation by inhibiting the synergistic interaction between nitric oxide and prostacyclin.

BACKGROUND: Endothelium-derived nitric oxide causes vasodilation in part by increasing the dilator activity of other endothelium-derived mediators, including prostacyclin and a K+ATP channel-dependent hyperpolarizing factor. Although previous studies have proposed that isoflurane (ISO) depresses endothelium-dependent vasorelaxation by inhibiting endothelium-derived nitric oxide activity, the effects of ISO on the interactions among endothelium-derived dilators have not been characterized. The aim of this study was to determine the mechanisms underlying the inhibitory effect of ISO on endothelium-dependent relaxation in canine pulmonary arteries. Specifically, the goal was to assess the effects of ISO on the individual actions and on the synergistic interactions of these endothelium-derived mediators. METHODS: Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of 1 minimum alveolar concentration ISO (0.4 mM) on vasorelaxation responses to bradykinin, A23187, acetylcholine, cromakalim, and SIN-1 were assessed in phenylephrine-precontracted rings with and without pretreatment with a nitric oxide synthase inhibitor (N omega-nitro-L-arginine methyl ester; L-NAME), a cyclooxygenase inhibitor (indomethacin), or a K+ATP channel inhibitor (glybenclamide). RESULTS: Isofluane attenuated pulmonary vasorelaxation induced by bradykinin, A23187, and cromakalim but had no effect on relaxation induced by acetylcholine or SIN-1. Neither the nitric oxide-mediated nor the prostacyclin-mediated components of relaxation induced by bradykinin and A23187 were altered by ISO. However, ISO abolished the K+ATP-mediated component of relaxation and the K+ATP-dependent synergistic interaction between nitric oxide and prostacyclin. CONCLUSIONS: These results suggest that ISO selectively attenuates endothelium-dependent relaxation in canine pulmonary arteries. It exerts its inhibitory effect by interfering with a synergistic interaction between nitric oxide and prostacyclin, possibly via an effect on K+ATP channels.

Anesthetics, Inhalation↗
PubMed1997

Halothane attenuates endothelium-dependent pulmonary vasorelaxant response to lemakalim, an adenosine triphosphate (ATP)-sensitive potassium channel agonist.

BACKGROUND: Lemakalim, an adenosine triphosphate (ATP)-sensitive potassium (K+(ATP)) channel agonist, causes profound pulmonary vasodilation in conscious dogs, which is attenuated during halothane anesthesia. The goal of the present study was to investigate the mechanism responsible for this attenuating effect of halothane. METHODS: Isolated canine pulmonary arterial rings were suspended for isometric tension recording in 25 ml organ baths. Rings with and without endothelium were contracted to 50% of their maximal response to phenylephrine, followed by the cumulative administration of lemakalim with or without exposure to halothane (0.5-1.5 minimum alveolar concentration [MAC] in dogs). Lemakalim dose-response curves were also generated in rings pretreated with the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (L-NAME); the cyclooxygenase inhibitor, indomethacin; or the K+(ATP) channel antagonist, glybenclamide. RESULTS: Compared with intact rings, the pulmonary vasorelaxant response to lemakalim was attenuated (P < 0.05) in endothelium-denuded rings. Halothane at 0.5 MAC had no effect on the vasorelaxant response to lemakalim. Halothane at 1 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in intact rings, but not in endothelium-denuded rings. Halothane at 1.5 MAC attenuated (P < 0.05) the vasorelaxant response to lemakalim in both intact and endothelium-denuded rings. In endothelium-intact rings, indomethacin attenuated (P < 0.05) the vasorelaxant response to lemakalim, whereas L-NAME had no effect. Further, indomethacin, but not L-NAME, abolished the endothelium-dependent, halothane-induced attenuation of the lemakalim vasorelaxation response. Glybenclamide markedly attenuated (P < 0.05) lemakalim vasorelaxation at lemakalim doses less than 10(-6) M. CONCLUSIONS: Lemakalim-induced pulmonary vasorelaxation involves an endothelium-dependent and vascular smooth muscle component. Further, halothane attenuates the endothelium-dependent pulmonary vasorelaxant response to lemakalim via an inhibitory effect on vasodilator metabolites of the cyclooxygenase pathway.

Adenosine Triphosphate↗